Science of the Total Environment 502 (2015) 571–577
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Photocatalytic degradation of rosuvastatin: Analytical studies and toxicity evaluations Tiele Caprioli Machado a,⁎, Tânia Mara Pizzolato b, Alexandre Arenzon c, Jeferson Segalin d, Marla Azário Lansarin a a
Chemical Engineering Department, Federal University of Rio Grande do Sul, Rua Engenheiro Luiz Englert s/n, CEP: 90040-040 Porto Alegre, RS, Brazil Chemical Institute, Federal University of Rio Grande do Sul, Avenida Bento Gonçalves, 9500, CEP: 91501-970 Porto Alegre, RS, Brazil Ecology Center, Federal University of Rio Grande do Sul, Avenida Bento Gonçalves, 9500, CEP: 91501-970 Porto Alegre, RS, Brazil d Biotechnology Center, Federal University of Rio Grande do Sul, Avenida Bento Gonçalves, 9500, CEP: 91501-970 Porto Alegre, RS, Brazil b c
H I G H L I G H T S • • • • •
The photocatalytic degradation of rosuvastatin was studied under UV irradiation. Commercial catalyst ZnO was used. Initial rosuvastatin concentration, photocatalyst loading and pH were evaluated. The byproducts generated during the oxidative process were detected and identified. Acute toxicity tests using Daphnia magna were carried out.
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Article history: Received 27 July 2014 Received in revised form 22 September 2014 Accepted 22 September 2014 Available online xxxx Editor: D. Barcelo Keywords: Photocatalysis Rosuvastatin Byproducts Toxicity
a b s t r a c t Photocatalytic degradation of rosuvastatin, which is a drug that has been used to reduce blood cholesterol levels, was studied in this work employing ZnO as catalyst. The experiments were carried out in a temperaturecontrolled batch reactor that was irradiated with UV light. Preliminary the effects of the photocatalyst loading, the initial pH and the initial rosuvastatin concentration were evaluated. The experimental results showed that rosuvastatin degradation is primarily a photocatalytic process, with pseudo-first order kinetics. The byproducts that were generated during the oxidative process were identified using nano-ultra performance liquid chromatography tandem mass spectrometry (nano-UPLC–MS/MS) and acute toxicity tests using Daphnia magna were done to evaluate the toxicity of the untreated rosuvastatin solution and the reactor effluent. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Statins are drugs used to lower blood cholesterol levels. Currently, the most frequently employed statins are lovastatin (Mevacor), pravastatin (Pravachol), simvastatin (Zocor), fluvastatin (Lescol), atorvastatin (Lipitor) and rosuvastatin (Crestor) (Nirogi et al., 2007; Lee et al., 2009). Due to their recalcitrance in sewage treatment systems, these drugs have been detected in surface waters (Miao and Metcalfe, 2003; Hernando et al., 2007; Piecha et al., 2010) and can pose a risk to humans and other living organisms (Klavarioti et al., 2009). Therefore, it is necessary to remove them from aqueous municipal and industrial effluents before they enter into environment. ⁎ Corresponding author. Tel.: +55 51 3308 3952; fax: +55 51 3308 3277. E-mail address: [email protected] (T.C. Machado).
http://dx.doi.org/10.1016/j.scitotenv.2014.09.076 0048-9697/© 2014 Elsevier B.V. All rights reserved.
Advanced Oxidation Processes (AOPs) have been previously evaluated for the removal of pharmaceuticals in water (Andreozzi et al., 2003; Arslan-Alaton and Dogruel, 2004; Kaniou et al., 2005; Zhang et al., 2007; Rizzo et al., 2009; Elmolla and Chaudhuri, 2010; De la Cruz et al., 2013). One of the most promising techniques among these processes is heterogeneous photocatalysis. This involves the generation of hydroxyl radicals by the irradiation of a semiconductor in water, which in turn can be used to promote the decomposition of organic contaminants. Although the most widely employed semiconductor is TiO2 (Reyes et al., 2006; Yurdakal et al., 2007; Sakkas et al., 2007; Mendez-Arriaga et al., 2008; Yang et al., 2008; Piecha et al., 2010; Razavi et al., 2011; De la Cruz et al., 2013), ZnO has been received more attention due to its low cost and high activity in several photochemical processes. Also, ZnO has an energy band gap similar to that of TiO2 (3.2 eV). Some published studies have shown that ZnO is slightly
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more efficient than TiO2 in pharmaceuticals degradation (Kaniou et al., 2005; Chatzitakis et al., 2008). There are few studies of the photocatalytic degradation of statins and none of these have examined rosuvastatin. Piecha et al. (2010) observed the formation of non-toxic byproducts arising from the TiO2assisted photocatalysis of aqueous lovastatin, pravastatin and simvastatin. Razavi et al. (2011) also reported substantial efficiency of TiO2 in the degradation of fluvastatin, lovastatin, pravastatin and simvastatin. While degradation mechanisms were proposed, no toxicological studies were carried out in this previous study. As such, still little is known about the photocatalytic behavior of statins in water. This work studied the photocatalytic degradation of rosuvastatin in aqueous solutions containing commercial ZnO in suspension. Byproducts were detected and identified and their toxicity evaluated to determine the efficiency, safety and feasibility of the photocatalytic processes applied. The effect of photocatalyst and rosuvastatin concentration and the initial pH were also evaluated to determine the optimal operating conditions for the photocatalytic setup. 2. Material and methods 2.1. Chemicals Rosuvastatin calcium (≥ 99%) (Johnson Pharmacy) and the photocatalysts zinc oxide (ZnO, Merck) were used in the photocatalytic experiments. Ultrapure water used in the experiments was provided by a Millipore purification system (Direct Q 3 UV). Acetonitrile (HPLC grade) (Merck), formic acid (Sigma-Aldrich) and an Acquity UPLC BEH130 C18 column (18 μm × 100 mm, 1.7 μm particle size) from Waters were used in the analyses of byproducts by nano-UPLC–MS/MS. 2.2. Instruments and methods To evaluate photodegradation kinetics and mineralization potential of the photocatalytic processes, the Total Organic Carbon (TOC) of initial and irradiated mixtures were measured using a Shimadzu VCSH TOC analyzer packed with a platinum catalyst supported on alumina pellets. Byproducts arising from the degradation of rosuvastatin were identified by nano-ultra performance liquid chromatography tandem mass spectrometry (nano-UPLC–MS/MS) on a Waters nanoAcquity UPLC system (Waters Corp., Milford, MA) equipped with a binary solvent delivery system and an autosampler with the volume injection set to 2 μL. Chromatographic separation was carried out on an Acquity UPLC BEH130 C18 column with a mobile phase consisting of (A) 0.1% formic acid (v/v) in ultrapure water and (B) 0.1% formic acid (v/v) in acetonitrile and was programmed with a gradient starting at 70% A. After 2 min, the percentage of A decreased linearly to 10% within 5 min, and after more than 5 min, the percentage of A was increased linearly to 95%. These conditions were held for 15 min; next, the mobile phase composition was restored to the initial composition in 1 min and was maintained for column regeneration for another 4 min. The flow rate was 0.6 μL min−1 and the total chromatographic run time, including the reconditioning time of the column, was 30 min. Accurate mass MS and MS/MS analyses were performed on a Q-TOF Micro™ (Micromass, Manchester, UK). MS analysis detection was carried out with an electrospray (ESI) interface operating in the positive ionization mode with a capillary voltage of + 3300 V. The source temperature was 100 °C. Nitrogen was used as the cone and desolvation gases. The cone gas flow was set to 5 L h−1, and the desolvation gas flow was set to 30 L h−1. MS spectra were acquired from m/z (mass to charge) 100 to 1200. Product ion MS/MS spectra were acquired at low and/or high collision energies using argon as the collision gas at a pressure of ~ 15 psi. External mass calibration for the positive ESI mode was conducted prior to analysis within the m/z range 100 to 2000 by infusing a solution of acetonitrile: water (50:50) and phosphoric acid 0.1% at a flow rate of 0.6 μL min−1. A phosphoric acid solution
was used as the internal lock mass. All MS data handling, including the calculations of the accurate masses and the elemental compositions of the precursor and product ions, was performed with the software package MassLynx V4.1. MS spectra were processed using a noise filter followed by smoothing and measuring the peak top with a centroid top of 80%. Toxicological evaluation of the byproducts arising from the ZnOassisted photocatalysis of rosuvastatin was carried out with Daphnia magna according to ABNT NBR 12713 (2009). An untreated rosuvastatin solution and the reactor effluent were used for these tests, which consist of a control (prepared only with dilution water) and sample dilutions, with one of four replicates using a total volume of 15 mL. Each bottle was covered with plastic and stored in an incubator with a photoperiod of 16 h of light and a controlled temperature of 20 ± 2 °C. After 48 h, the number of mobile individuals in each sample was determined. 2.3. Photodegradation experiments The experiments were carried out in a batch photochemical reactor (Fig. 1) irradiated with a modified mercury vapor lamp (Philips HPL-N 125 W) emitting only UV-A (365 nm) with an incident irradiance of 5.4 mW cm−2 as determined at the start of each experiment by a radiometer (Cole-Parmer Instrument, Radiometer Series 9811). Aeration was achieved by a 15 W compressor, the agitation of the reaction mixture was maintained using a magnetic stirrer and the temperature was monitored using a K-type thermocouple. The rosuvastatin solution was prepared using ultrapure water and maintained under vigorous magnetic stirring for approximately 2 h. For photocatalysis experiments, various loadings (0.3 to 1.5 g L−1) of ZnO were added to 330 mL aqueous rosuvastatin solution. Before an irradiation, the adsorption–desorption equilibrium for the drug on the photocatalyst surface was determined and carried out in the dark for 1 h. Photocatalysis experiments were then commenced and the reaction progress monitored by collecting samples (10 mL) at fixed intervals 0, 5, 15, 30 and 60 min. The collected samples were then centrifuged and stored in amber glass bottles. Subsequently, the rosuvastatin content was analyzed quantitatively by measuring the absorbance at 241 nm using Cary 100 (Varian) Spectrophotometer. A calibration curve was used to relate the rosuvastatin concentration in the collected samples during the tests to its absorbance at a wavelength of maximum absorption (241 nm), according to the Lambert–Beer Law. The pseudo-first order degradation rate constant and the percentage degradation of rosuvastatin were used as parameters to compare results obtained. All experiments were carried out in duplicate or triplicate, as necessary, and the average values used as the results.
Fig. 1. Photochemical reactor used in the photocatalysis of rosuvastatin in water.
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30
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35
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k 10-3 (min-1)
k 10-3 (min-1)
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15
20
25
30
Rosuvastatin concentration (mg
35
L-1)
Fig. 2. Effect of photocatalyst loadings on rosuvastatin degradation (CRosu = 27 mg L−1, T = 30 °C, pH = 7.0 and 5.4 mW cm−2).
Fig. 4. Effect of the initial concentration on rosuvastatin degradation (Ccat commercial ZnO = 0.55 g L−1, pH = 7.0, T = 30 °C and 5.4 mW cm−2).
3. Results and discussion
3.3. Effect of photocatalyst loadings
3.1. Preliminary tests
The rate of rosuvastatin degradation increased with increasing photocatalyst loading up to a limiting photocatalyst load. This observation was attributed to either aggregation of ZnO particles at high loadings, causing a decrease in the number of surface active sites, and an increase in the opacity of the reaction mixture, leading to a decrease in incident radiation penetration (Chen and Ray, 1998). The ideal photocatalyst loading depends on the geometry, the working conditions and the type of UV radiation (Konstantinou and Albanis, 2004). Therefore, experiments were carried out to determine the optimal photocatalyst loading for rosuvastatin degradation (Fig. 2). It can be observed that the pseudo-first order degradation constants were highest when the ZnO loading was between 0.55 g L− 1 and 0.9 g L− 1. The reaction rate declined upon addition of 0.90 g L−1 or more in the irradiation vessel.
To determine the contribution of ZnO to the rosuvastatin degradation process, rosuvastatin was irradiated in the absence and presence of ZnO. Substantial rosuvastatin decomposition (75.0%) was achieved over a 1 h irradiation period in the presence of ZnO while only 30.6% decomposition was observed with direct photolysis alone. Experiments that did not use irradiation were carried out in order to determine the time required to established adsorption equilibrium of rosuvastatin on the catalyst surface. Equilibrium on the ZnO surface was reached in 60 min, and approximately 1.85% of the drug was adsorbed. 3.2. Kinetics of degradation reaction The data were fitted as pseudo-first order kinetics and we determined the reaction rate constant as the negative slope of the linear regression: ln
c ¼ −kt: c0
3.4. Effect of pH The pH alters the electrostatic interactions between the semiconductor surface, the solvent molecules, the substrate and the charged
30
Carbon concentration (mg L-1)
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k 10-3 (min-1)
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24
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18
Rosuvastatin TOC
12 10 8 6 4 2 0 0
15 4
5
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7
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9
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Time (min)
initial pH Fig. 3. Effect of the initial pH on rosuvastatin degradation (CRosu = 27 mg L−1, Ccat commercial ZnO = 0.55 g L−1, T = 30 °C and 5.4 mW cm−2).
Fig. 5. Total organic carbon in the rosuvastatin photodegradation reaction mixture (CRosu = 27 mg L−1, T = 30 °C, Ccat commercial ZnO = 0.55 g L−1, pH = 7.0 and 5.4 mW cm−2).
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T.C. Machado et al. / Science of the Total Environment 502 (2015) 571–577 F
F
2: TOF MSMS 482.13ES+ 2.59e3
CH2
N
OH
CH3 N
H2N
CH3
100
OH
N
482.1595
H3C
CH3 N
N
S
O
258.1544
%
O
OH
CH3
O
CH3
300.1856
404.2288
217.1359
0 100
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Rosuvastatin Standard
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0 2,00
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Fig. 6. Chromatogram and MS spectrum (nano-UPLC–MS/MS) for the standard rosuvastatin solution (CRosu = 27 mg L−1).
radicals formed during photocatalysis (Qamar and Muneer, 2009). Thus, the effect of the pH (4 to 9) was studied. The pH was adjusted before the addition of the catalyst in the solution and was not monitored during the reaction. The other parameters, such as operating temperature,
radiation intensity, initial statin concentration and commercial photocatalyst loading, were the same for all experiments. In view of the results presented in Fig. 3, we concluded that the experiments must be carried out using pH 7 as initial value.
F
F
1: TOF MS ES+ 734
5 minutos min irradiation 5 de irradiação
Retention time – 21.38 minmin Tempo de retenção - 21.387 352.1366
100
OH
N
OH
H3C
CH3 NH
N
H3C
%
N
CH3
O
274.1656 217.1359
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N S
N CH3 O
CH3
482.2232
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m/z 5 min irradiation 1: TOF MS ES+ TIC 6,35e4
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%
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0
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14,00
16,00
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28,00
Fig. 7. Chromatogram and MS spectrum of the rosuvastatin solution after 5 min of irradiation (pH = 7.0, Ccat commercial ZnO = 0.55 g L−1, CRosu = 27 mg L−1, T = 30 °C and 5.4 mW cm−2).
T.C. Machado et al. / Science of the Total Environment 502 (2015) 571–577
575
F
O
Retention time – 16.00 minmin Tempode retenção - 15.973
H3C
390.2148
100
OH
N
M1 =
1: TOF MS ES+ 404
60 min irradiation 60 minutos de irradiação
[(M1 + Na)+] O
CH3 N
N
CH3
S
O
%
CH3 149.0532 330.1982
207.0998
0 100
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m/z 60 min irradiation 1: TOF MS ES+ TIC 2,28e4
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Time
28,00
Fig. 8. Chromatogram and MS spectrum of the rosuvastatin solution after 60 min of irradiation (Ccat commercial ZnO = 0.55 g L−1, CRosu = 27 mg L−1, T = 30 °C, pH = 7.0 and 5.4 mW cm−2).
Similar results were observed by Evgenidou et al. (2005). They concluded that ZnO presents an amphoteric behavior: at acidic pH, ZnO can react with acids to produce the corresponding salt and at alkalic pH it can react with a base to form complexes like [Zn(OH)4]2−.
3.5. Effect of the initial rosuvastatin concentration The effect of the initial rosuvastatin concentration on the photocatalytic degradation reaction rate was determined with initial rosuvastatin concentrations of 10, 20, 27, and 34 mg L−1 (Fig. 4).
5 min irradiation
60 min irradiation F
F
O OH
N
F
Rosuvastatin
H 3C
O
OH
CH 3
O
S
N
S
O
O
CH 3 N
N CH 3 O
Carboxylic acid
CH 3
O
CH 3 OH
N
CH 3 NH
S CH 3
F
hv
H 3C
OH
N H 3C
CH 3
CH 3
ZnO
O
N
N
OH
N H 3C N
OH
CH 3
N CH 3
Primary alcohol Fig. 9. Rosuvastatin degradation pathway.
T.C. Machado et al. / Science of the Total Environment 502 (2015) 571–577
As observed in Fig. 4, a decrease in the initial rosuvastatin concentration resulted in an increase in the reaction rate. Similar results have been presented for the degradation of other organic contaminants (Dijkstra et al., 2001; Gautam et al., 2005; Taffarel et al., 2011; De Franco et al., 2014). This behavior is derived from the fixed number of active sites on the photocatalyst surface. At low contaminant concentrations, a greater number of water molecules are adsorbed onto the ZnO particles. This process produces more hydroxyl radicals which increases the indirect degradation of adsorbed rosuvastatin molecules. 3.6. Detection of reaction intermediates and toxicity evaluation To determine if rosuvastatin was adequately mineralized by photocatalysis over an irradiation period of 4 h, the TOC was measured along with the rosuvastatin content in each sample (Fig. 5). As shown in Fig. 5, there was a difference between the TOC and the rosuvastatin carbon content. This suggests that the byproducts arising from the indirect transformation of rosuvastatin by ZnO were not mineralized to CO2 and H2O. Such oxidation intermediates can be potentially more toxic than the original contaminant (Rizzo et al., 2009). Therefore, it was necessary to identify major degradation mechanisms and to evaluate the toxicity of these byproducts. Nano-UPLC–MS/MS analyses were carried out to detect and identify the byproducts generated by the ZnO-assisted photocatalysis of rosuvastatin. Positive-mode MS obtained a rosuvastatin molecular ion [M + H]+ of 482 (Rosu-Ca is 1001.14 g mol− 1, that in water is dissociate) (Fig. 6) eluting on the total ion chromatogram (TIC) at 20.10 min and the fragmentation pattern obtained is in agreement with previous literature (Hull et al., 2002). After 5 min of irradiation, other peaks on the TIC at retention times of 16.00 and 21.38 min respectively appeared. The signal intensity of both peaks increased upon increasing irradiation timeframes (Fig. 7). The peak with retention time 21.38 min resulted from the oxidation of the double bond on the aliphatic side chain of rosuvastatin and subsequent formation of the respective primary alcohol. The peak at 16.00 min was identified as the carboxylic acid derivative obtained from further oxidation of the alcohol byproduct. The intensity of the corresponding MS signal increased until the end of the 1 h irradiation period applied (Fig. 8). The carboxylic acid derivative, from the rosuvastatin, was identified through the appearance of its sodium adduct [M + Na]+. The byproducts identified, until now, allow us to propose a preliminary degradation pathway (Fig. 9) arising from the ZnO-assisted photocatalysis of rosuvastatin. It can be observed that the byproducts generated by the ZnO-assisted photocatalysis of rosuvastatin resulted from the subsequent oxidation of the parent compound. Similar results have been observed for the degradation of other statins (Piecha et al., 2010; Razavi et al., 2011). Acute toxicity tests using D. magna were done to evaluate the toxicity of the untreated rosuvastatin solution and the reactor effluent. IC50 (half maximal inhibitory concentration) values observed for each sample were compared with the total degradation percentage (Fig. 10). It should be remembered that the IC50 values are inversely proportional to the toxicity. As observed in Fig. 10, the IC50 decreased with an increase in irradiation timeframes. This suggested that the byproducts formed upon irradiation of rosuvastatin were more toxic than rosuvastatin itself. Furthermore, the increase of the toxicity also may be attributed to the dissolution of ZnO (Evgenidou et al., 2005). 4. Conclusions Rosuvastatin was transformed by ZnO-assisted UV-induced photocatalysis by pseudo-first order kinetics with a maximum degradation rate constant of 0.025 min−1 observed when the concentration of
100 Toxicity (IC50) Degradation
Toxicity/Degradation (%)
576
80
60
40
20
0 Untreated
1h irradiation
5h irradiation
Fig. 10. Toxicity versus degradation.
rosuvastatin was 27 mg L−1, the loading of ZnO 0.55 g L−1 and pH 7. While the degradation rate constant increased proportionally with ZnO photocatalyst loading up to 0.55 g L−1, the rate constant decreased at ZnO loadings greater than 0.90 g L−1. A decrease in degradation efficiency was also observed with increased initial rosuvastatin concentrations. Products generated by the ZnO-assisted photocatalytic oxidation of rosuvastatin are more toxic than parent rosuvastatin. Based on the results presented, we conclude that rosuvastatin undergoes photocatalytic degradation but the safety, efficiency and feasibility of the treatment process may be compromised by the production of toxic byproducts and by presence of dissolved ZnO.
Acknowledgments The authors would like to thank CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) for financial support and the Dra. Célia Carlini (Unit of Protein Chemistry and Mass Spectrometry — Uniprote-MS, Biotechnology Center, Federal University of Rio Grande do Sul) for providing the essential equipment for this work.
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Photocatalytic degradation of rosuvastatin: Analytical studies and toxicity evaluations Tiele Caprioli Machado a,⁎, Tânia Mara Pizzolato b, Alexandre Arenzon c, Jeferson Segalin d, Marla Azário Lansarin a a
Chemical Engineering Department, Federal University of Rio Grande do Sul, Rua Engenheiro Luiz Englert s/n, CEP: 90040-040 Porto Alegre, RS, Brazil Chemical Institute, Federal University of Rio Grande do Sul, Avenida Bento Gonçalves, 9500, CEP: 91501-970 Porto Alegre, RS, Brazil Ecology Center, Federal University of Rio Grande do Sul, Avenida Bento Gonçalves, 9500, CEP: 91501-970 Porto Alegre, RS, Brazil d Biotechnology Center, Federal University of Rio Grande do Sul, Avenida Bento Gonçalves, 9500, CEP: 91501-970 Porto Alegre, RS, Brazil b c
H I G H L I G H T S • • • • •
The photocatalytic degradation of rosuvastatin was studied under UV irradiation. Commercial catalyst ZnO was used. Initial rosuvastatin concentration, photocatalyst loading and pH were evaluated. The byproducts generated during the oxidative process were detected and identified. Acute toxicity tests using Daphnia magna were carried out.
a r t i c l e
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Article history: Received 27 July 2014 Received in revised form 22 September 2014 Accepted 22 September 2014 Available online xxxx Editor: D. Barcelo Keywords: Photocatalysis Rosuvastatin Byproducts Toxicity
a b s t r a c t Photocatalytic degradation of rosuvastatin, which is a drug that has been used to reduce blood cholesterol levels, was studied in this work employing ZnO as catalyst. The experiments were carried out in a temperaturecontrolled batch reactor that was irradiated with UV light. Preliminary the effects of the photocatalyst loading, the initial pH and the initial rosuvastatin concentration were evaluated. The experimental results showed that rosuvastatin degradation is primarily a photocatalytic process, with pseudo-first order kinetics. The byproducts that were generated during the oxidative process were identified using nano-ultra performance liquid chromatography tandem mass spectrometry (nano-UPLC–MS/MS) and acute toxicity tests using Daphnia magna were done to evaluate the toxicity of the untreated rosuvastatin solution and the reactor effluent. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Statins are drugs used to lower blood cholesterol levels. Currently, the most frequently employed statins are lovastatin (Mevacor), pravastatin (Pravachol), simvastatin (Zocor), fluvastatin (Lescol), atorvastatin (Lipitor) and rosuvastatin (Crestor) (Nirogi et al., 2007; Lee et al., 2009). Due to their recalcitrance in sewage treatment systems, these drugs have been detected in surface waters (Miao and Metcalfe, 2003; Hernando et al., 2007; Piecha et al., 2010) and can pose a risk to humans and other living organisms (Klavarioti et al., 2009). Therefore, it is necessary to remove them from aqueous municipal and industrial effluents before they enter into environment. ⁎ Corresponding author. Tel.: +55 51 3308 3952; fax: +55 51 3308 3277. E-mail address: [email protected] (T.C. Machado).
http://dx.doi.org/10.1016/j.scitotenv.2014.09.076 0048-9697/© 2014 Elsevier B.V. All rights reserved.
Advanced Oxidation Processes (AOPs) have been previously evaluated for the removal of pharmaceuticals in water (Andreozzi et al., 2003; Arslan-Alaton and Dogruel, 2004; Kaniou et al., 2005; Zhang et al., 2007; Rizzo et al., 2009; Elmolla and Chaudhuri, 2010; De la Cruz et al., 2013). One of the most promising techniques among these processes is heterogeneous photocatalysis. This involves the generation of hydroxyl radicals by the irradiation of a semiconductor in water, which in turn can be used to promote the decomposition of organic contaminants. Although the most widely employed semiconductor is TiO2 (Reyes et al., 2006; Yurdakal et al., 2007; Sakkas et al., 2007; Mendez-Arriaga et al., 2008; Yang et al., 2008; Piecha et al., 2010; Razavi et al., 2011; De la Cruz et al., 2013), ZnO has been received more attention due to its low cost and high activity in several photochemical processes. Also, ZnO has an energy band gap similar to that of TiO2 (3.2 eV). Some published studies have shown that ZnO is slightly
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more efficient than TiO2 in pharmaceuticals degradation (Kaniou et al., 2005; Chatzitakis et al., 2008). There are few studies of the photocatalytic degradation of statins and none of these have examined rosuvastatin. Piecha et al. (2010) observed the formation of non-toxic byproducts arising from the TiO2assisted photocatalysis of aqueous lovastatin, pravastatin and simvastatin. Razavi et al. (2011) also reported substantial efficiency of TiO2 in the degradation of fluvastatin, lovastatin, pravastatin and simvastatin. While degradation mechanisms were proposed, no toxicological studies were carried out in this previous study. As such, still little is known about the photocatalytic behavior of statins in water. This work studied the photocatalytic degradation of rosuvastatin in aqueous solutions containing commercial ZnO in suspension. Byproducts were detected and identified and their toxicity evaluated to determine the efficiency, safety and feasibility of the photocatalytic processes applied. The effect of photocatalyst and rosuvastatin concentration and the initial pH were also evaluated to determine the optimal operating conditions for the photocatalytic setup. 2. Material and methods 2.1. Chemicals Rosuvastatin calcium (≥ 99%) (Johnson Pharmacy) and the photocatalysts zinc oxide (ZnO, Merck) were used in the photocatalytic experiments. Ultrapure water used in the experiments was provided by a Millipore purification system (Direct Q 3 UV). Acetonitrile (HPLC grade) (Merck), formic acid (Sigma-Aldrich) and an Acquity UPLC BEH130 C18 column (18 μm × 100 mm, 1.7 μm particle size) from Waters were used in the analyses of byproducts by nano-UPLC–MS/MS. 2.2. Instruments and methods To evaluate photodegradation kinetics and mineralization potential of the photocatalytic processes, the Total Organic Carbon (TOC) of initial and irradiated mixtures were measured using a Shimadzu VCSH TOC analyzer packed with a platinum catalyst supported on alumina pellets. Byproducts arising from the degradation of rosuvastatin were identified by nano-ultra performance liquid chromatography tandem mass spectrometry (nano-UPLC–MS/MS) on a Waters nanoAcquity UPLC system (Waters Corp., Milford, MA) equipped with a binary solvent delivery system and an autosampler with the volume injection set to 2 μL. Chromatographic separation was carried out on an Acquity UPLC BEH130 C18 column with a mobile phase consisting of (A) 0.1% formic acid (v/v) in ultrapure water and (B) 0.1% formic acid (v/v) in acetonitrile and was programmed with a gradient starting at 70% A. After 2 min, the percentage of A decreased linearly to 10% within 5 min, and after more than 5 min, the percentage of A was increased linearly to 95%. These conditions were held for 15 min; next, the mobile phase composition was restored to the initial composition in 1 min and was maintained for column regeneration for another 4 min. The flow rate was 0.6 μL min−1 and the total chromatographic run time, including the reconditioning time of the column, was 30 min. Accurate mass MS and MS/MS analyses were performed on a Q-TOF Micro™ (Micromass, Manchester, UK). MS analysis detection was carried out with an electrospray (ESI) interface operating in the positive ionization mode with a capillary voltage of + 3300 V. The source temperature was 100 °C. Nitrogen was used as the cone and desolvation gases. The cone gas flow was set to 5 L h−1, and the desolvation gas flow was set to 30 L h−1. MS spectra were acquired from m/z (mass to charge) 100 to 1200. Product ion MS/MS spectra were acquired at low and/or high collision energies using argon as the collision gas at a pressure of ~ 15 psi. External mass calibration for the positive ESI mode was conducted prior to analysis within the m/z range 100 to 2000 by infusing a solution of acetonitrile: water (50:50) and phosphoric acid 0.1% at a flow rate of 0.6 μL min−1. A phosphoric acid solution
was used as the internal lock mass. All MS data handling, including the calculations of the accurate masses and the elemental compositions of the precursor and product ions, was performed with the software package MassLynx V4.1. MS spectra were processed using a noise filter followed by smoothing and measuring the peak top with a centroid top of 80%. Toxicological evaluation of the byproducts arising from the ZnOassisted photocatalysis of rosuvastatin was carried out with Daphnia magna according to ABNT NBR 12713 (2009). An untreated rosuvastatin solution and the reactor effluent were used for these tests, which consist of a control (prepared only with dilution water) and sample dilutions, with one of four replicates using a total volume of 15 mL. Each bottle was covered with plastic and stored in an incubator with a photoperiod of 16 h of light and a controlled temperature of 20 ± 2 °C. After 48 h, the number of mobile individuals in each sample was determined. 2.3. Photodegradation experiments The experiments were carried out in a batch photochemical reactor (Fig. 1) irradiated with a modified mercury vapor lamp (Philips HPL-N 125 W) emitting only UV-A (365 nm) with an incident irradiance of 5.4 mW cm−2 as determined at the start of each experiment by a radiometer (Cole-Parmer Instrument, Radiometer Series 9811). Aeration was achieved by a 15 W compressor, the agitation of the reaction mixture was maintained using a magnetic stirrer and the temperature was monitored using a K-type thermocouple. The rosuvastatin solution was prepared using ultrapure water and maintained under vigorous magnetic stirring for approximately 2 h. For photocatalysis experiments, various loadings (0.3 to 1.5 g L−1) of ZnO were added to 330 mL aqueous rosuvastatin solution. Before an irradiation, the adsorption–desorption equilibrium for the drug on the photocatalyst surface was determined and carried out in the dark for 1 h. Photocatalysis experiments were then commenced and the reaction progress monitored by collecting samples (10 mL) at fixed intervals 0, 5, 15, 30 and 60 min. The collected samples were then centrifuged and stored in amber glass bottles. Subsequently, the rosuvastatin content was analyzed quantitatively by measuring the absorbance at 241 nm using Cary 100 (Varian) Spectrophotometer. A calibration curve was used to relate the rosuvastatin concentration in the collected samples during the tests to its absorbance at a wavelength of maximum absorption (241 nm), according to the Lambert–Beer Law. The pseudo-first order degradation rate constant and the percentage degradation of rosuvastatin were used as parameters to compare results obtained. All experiments were carried out in duplicate or triplicate, as necessary, and the average values used as the results.
Fig. 1. Photochemical reactor used in the photocatalysis of rosuvastatin in water.
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30
573
35
30
k 10-3 (min-1)
k 10-3 (min-1)
25
20
25
20
15 15
10 0,2
0,4
0,6
0,8
1,0
1,2
1,4
10
1,6
10
ZnO concentration (g L-1)
15
20
25
30
Rosuvastatin concentration (mg
35
L-1)
Fig. 2. Effect of photocatalyst loadings on rosuvastatin degradation (CRosu = 27 mg L−1, T = 30 °C, pH = 7.0 and 5.4 mW cm−2).
Fig. 4. Effect of the initial concentration on rosuvastatin degradation (Ccat commercial ZnO = 0.55 g L−1, pH = 7.0, T = 30 °C and 5.4 mW cm−2).
3. Results and discussion
3.3. Effect of photocatalyst loadings
3.1. Preliminary tests
The rate of rosuvastatin degradation increased with increasing photocatalyst loading up to a limiting photocatalyst load. This observation was attributed to either aggregation of ZnO particles at high loadings, causing a decrease in the number of surface active sites, and an increase in the opacity of the reaction mixture, leading to a decrease in incident radiation penetration (Chen and Ray, 1998). The ideal photocatalyst loading depends on the geometry, the working conditions and the type of UV radiation (Konstantinou and Albanis, 2004). Therefore, experiments were carried out to determine the optimal photocatalyst loading for rosuvastatin degradation (Fig. 2). It can be observed that the pseudo-first order degradation constants were highest when the ZnO loading was between 0.55 g L− 1 and 0.9 g L− 1. The reaction rate declined upon addition of 0.90 g L−1 or more in the irradiation vessel.
To determine the contribution of ZnO to the rosuvastatin degradation process, rosuvastatin was irradiated in the absence and presence of ZnO. Substantial rosuvastatin decomposition (75.0%) was achieved over a 1 h irradiation period in the presence of ZnO while only 30.6% decomposition was observed with direct photolysis alone. Experiments that did not use irradiation were carried out in order to determine the time required to established adsorption equilibrium of rosuvastatin on the catalyst surface. Equilibrium on the ZnO surface was reached in 60 min, and approximately 1.85% of the drug was adsorbed. 3.2. Kinetics of degradation reaction The data were fitted as pseudo-first order kinetics and we determined the reaction rate constant as the negative slope of the linear regression: ln
c ¼ −kt: c0
3.4. Effect of pH The pH alters the electrostatic interactions between the semiconductor surface, the solvent molecules, the substrate and the charged
30
Carbon concentration (mg L-1)
14
k 10-3 (min-1)
27
24
21
18
Rosuvastatin TOC
12 10 8 6 4 2 0 0
15 4
5
6
7
8
9
50
100
150
200
250
Time (min)
initial pH Fig. 3. Effect of the initial pH on rosuvastatin degradation (CRosu = 27 mg L−1, Ccat commercial ZnO = 0.55 g L−1, T = 30 °C and 5.4 mW cm−2).
Fig. 5. Total organic carbon in the rosuvastatin photodegradation reaction mixture (CRosu = 27 mg L−1, T = 30 °C, Ccat commercial ZnO = 0.55 g L−1, pH = 7.0 and 5.4 mW cm−2).
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T.C. Machado et al. / Science of the Total Environment 502 (2015) 571–577 F
F
2: TOF MSMS 482.13ES+ 2.59e3
CH2
N
OH
CH3 N
H2N
CH3
100
OH
N
482.1595
H3C
CH3 N
N
S
O
258.1544
%
O
OH
CH3
O
CH3
300.1856
404.2288
217.1359
0 100
150
200
250
300
350
400
450
500
550
m/z
Rosuvastatin Standard
1: TOF MS ES+ TIC 7,35e4
20,10
%
100
Time
0 2,00
4,00
6,00
8,00
10,00
12,00
14,00
16,00
18,00
20,00
22,00
24,00
26,00
28,00
Fig. 6. Chromatogram and MS spectrum (nano-UPLC–MS/MS) for the standard rosuvastatin solution (CRosu = 27 mg L−1).
radicals formed during photocatalysis (Qamar and Muneer, 2009). Thus, the effect of the pH (4 to 9) was studied. The pH was adjusted before the addition of the catalyst in the solution and was not monitored during the reaction. The other parameters, such as operating temperature,
radiation intensity, initial statin concentration and commercial photocatalyst loading, were the same for all experiments. In view of the results presented in Fig. 3, we concluded that the experiments must be carried out using pH 7 as initial value.
F
F
1: TOF MS ES+ 734
5 minutos min irradiation 5 de irradiação
Retention time – 21.38 minmin Tempo de retenção - 21.387 352.1366
100
OH
N
OH
H3C
CH3 NH
N
H3C
%
N
CH3
O
274.1656 217.1359
0 100
150
200
250
350
400
450
500
N S
N CH3 O
CH3
482.2232
300
CH3
550
600
m/z 5 min irradiation 1: TOF MS ES+ TIC 6,35e4
20,10
%
100
16,00 21,38
0
Time 2,00
4,00
6,00
8,00
10,00
12,00
14,00
16,00
18,00
20,00
22,00
24,00
26,00
28,00
Fig. 7. Chromatogram and MS spectrum of the rosuvastatin solution after 5 min of irradiation (pH = 7.0, Ccat commercial ZnO = 0.55 g L−1, CRosu = 27 mg L−1, T = 30 °C and 5.4 mW cm−2).
T.C. Machado et al. / Science of the Total Environment 502 (2015) 571–577
575
F
O
Retention time – 16.00 minmin Tempode retenção - 15.973
H3C
390.2148
100
OH
N
M1 =
1: TOF MS ES+ 404
60 min irradiation 60 minutos de irradiação
[(M1 + Na)+] O
CH3 N
N
CH3
S
O
%
CH3 149.0532 330.1982
207.0998
0 100
150
200
250
300
350
400
450
500
550
600
m/z 60 min irradiation 1: TOF MS ES+ TIC 2,28e4
20,10
100
%
16,00
21,38
0
2,00
4,00
6,00
8,00
10,00
12,00
14,00
16,00
18,00
20,00
22,00
24,00
26,00
Time
28,00
Fig. 8. Chromatogram and MS spectrum of the rosuvastatin solution after 60 min of irradiation (Ccat commercial ZnO = 0.55 g L−1, CRosu = 27 mg L−1, T = 30 °C, pH = 7.0 and 5.4 mW cm−2).
Similar results were observed by Evgenidou et al. (2005). They concluded that ZnO presents an amphoteric behavior: at acidic pH, ZnO can react with acids to produce the corresponding salt and at alkalic pH it can react with a base to form complexes like [Zn(OH)4]2−.
3.5. Effect of the initial rosuvastatin concentration The effect of the initial rosuvastatin concentration on the photocatalytic degradation reaction rate was determined with initial rosuvastatin concentrations of 10, 20, 27, and 34 mg L−1 (Fig. 4).
5 min irradiation
60 min irradiation F
F
O OH
N
F
Rosuvastatin
H 3C
O
OH
CH 3
O
S
N
S
O
O
CH 3 N
N CH 3 O
Carboxylic acid
CH 3
O
CH 3 OH
N
CH 3 NH
S CH 3
F
hv
H 3C
OH
N H 3C
CH 3
CH 3
ZnO
O
N
N
OH
N H 3C N
OH
CH 3
N CH 3
Primary alcohol Fig. 9. Rosuvastatin degradation pathway.
T.C. Machado et al. / Science of the Total Environment 502 (2015) 571–577
As observed in Fig. 4, a decrease in the initial rosuvastatin concentration resulted in an increase in the reaction rate. Similar results have been presented for the degradation of other organic contaminants (Dijkstra et al., 2001; Gautam et al., 2005; Taffarel et al., 2011; De Franco et al., 2014). This behavior is derived from the fixed number of active sites on the photocatalyst surface. At low contaminant concentrations, a greater number of water molecules are adsorbed onto the ZnO particles. This process produces more hydroxyl radicals which increases the indirect degradation of adsorbed rosuvastatin molecules. 3.6. Detection of reaction intermediates and toxicity evaluation To determine if rosuvastatin was adequately mineralized by photocatalysis over an irradiation period of 4 h, the TOC was measured along with the rosuvastatin content in each sample (Fig. 5). As shown in Fig. 5, there was a difference between the TOC and the rosuvastatin carbon content. This suggests that the byproducts arising from the indirect transformation of rosuvastatin by ZnO were not mineralized to CO2 and H2O. Such oxidation intermediates can be potentially more toxic than the original contaminant (Rizzo et al., 2009). Therefore, it was necessary to identify major degradation mechanisms and to evaluate the toxicity of these byproducts. Nano-UPLC–MS/MS analyses were carried out to detect and identify the byproducts generated by the ZnO-assisted photocatalysis of rosuvastatin. Positive-mode MS obtained a rosuvastatin molecular ion [M + H]+ of 482 (Rosu-Ca is 1001.14 g mol− 1, that in water is dissociate) (Fig. 6) eluting on the total ion chromatogram (TIC) at 20.10 min and the fragmentation pattern obtained is in agreement with previous literature (Hull et al., 2002). After 5 min of irradiation, other peaks on the TIC at retention times of 16.00 and 21.38 min respectively appeared. The signal intensity of both peaks increased upon increasing irradiation timeframes (Fig. 7). The peak with retention time 21.38 min resulted from the oxidation of the double bond on the aliphatic side chain of rosuvastatin and subsequent formation of the respective primary alcohol. The peak at 16.00 min was identified as the carboxylic acid derivative obtained from further oxidation of the alcohol byproduct. The intensity of the corresponding MS signal increased until the end of the 1 h irradiation period applied (Fig. 8). The carboxylic acid derivative, from the rosuvastatin, was identified through the appearance of its sodium adduct [M + Na]+. The byproducts identified, until now, allow us to propose a preliminary degradation pathway (Fig. 9) arising from the ZnO-assisted photocatalysis of rosuvastatin. It can be observed that the byproducts generated by the ZnO-assisted photocatalysis of rosuvastatin resulted from the subsequent oxidation of the parent compound. Similar results have been observed for the degradation of other statins (Piecha et al., 2010; Razavi et al., 2011). Acute toxicity tests using D. magna were done to evaluate the toxicity of the untreated rosuvastatin solution and the reactor effluent. IC50 (half maximal inhibitory concentration) values observed for each sample were compared with the total degradation percentage (Fig. 10). It should be remembered that the IC50 values are inversely proportional to the toxicity. As observed in Fig. 10, the IC50 decreased with an increase in irradiation timeframes. This suggested that the byproducts formed upon irradiation of rosuvastatin were more toxic than rosuvastatin itself. Furthermore, the increase of the toxicity also may be attributed to the dissolution of ZnO (Evgenidou et al., 2005). 4. Conclusions Rosuvastatin was transformed by ZnO-assisted UV-induced photocatalysis by pseudo-first order kinetics with a maximum degradation rate constant of 0.025 min−1 observed when the concentration of
100 Toxicity (IC50) Degradation
Toxicity/Degradation (%)
576
80
60
40
20
0 Untreated
1h irradiation
5h irradiation
Fig. 10. Toxicity versus degradation.
rosuvastatin was 27 mg L−1, the loading of ZnO 0.55 g L−1 and pH 7. While the degradation rate constant increased proportionally with ZnO photocatalyst loading up to 0.55 g L−1, the rate constant decreased at ZnO loadings greater than 0.90 g L−1. A decrease in degradation efficiency was also observed with increased initial rosuvastatin concentrations. Products generated by the ZnO-assisted photocatalytic oxidation of rosuvastatin are more toxic than parent rosuvastatin. Based on the results presented, we conclude that rosuvastatin undergoes photocatalytic degradation but the safety, efficiency and feasibility of the treatment process may be compromised by the production of toxic byproducts and by presence of dissolved ZnO.
Acknowledgments The authors would like to thank CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) for financial support and the Dra. Célia Carlini (Unit of Protein Chemistry and Mass Spectrometry — Uniprote-MS, Biotechnology Center, Federal University of Rio Grande do Sul) for providing the essential equipment for this work.
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