Oturan, N L Feng

Esposito E D Van Hullebusch

G Oturan

comparison of electro-Fenton and anodic oxidation processes 74

Keywords: Advanced Oxidation Processes, Electro-Fenton, Anodic Oxidation, Ozonation, Biofiltration, Ketoprofen, Naproxen, Piroxicam Pharmaceuticals, Emerging Pollutants, NSAIDs, EAOPs, Hydroxyl Radicals, Anodic Oxidation, Electro-Fenton, Degradation, Mineralization. Chapter 3: Degradation of anti-inflammatory drug ketoprofen by electro-oxidation: comparison of electro-Fenton and anodic oxidation processes 73 Chapter 3. Research Ketoprofen, Electro-Fenton, Anodic Oxidation, Hydroxyl Radicals, Mineralization, Toxicity. Chapter 4: Electro-Fenton removal of naproxen from aqueous medium: effect of anode material and operating conditions 99 Chapter 4. Research Keywordsμ Naproxen, Electro-Fenton, DD Anode, Degradation Pathways, yproducts, Toxicity Naproxen, Anodic Oxidation, Electro-Fenton, Boron-Doped Diamond Anode, Toxicity Assessment

The thesis mainly focused on the implementation of advanced oxidation processes for the elimination of three non-steroidal anti-inflammatory drugs-ketoprofen, naproxen and piroxicam in waters. The three compounds are among the most used medicines, whose presence in waters poses a potential ecotoxicological risk. Due to the low pharmaceuticals removal efficiency of traditional wastwater treatement plants, worldwide concerns and calls are raised for efficient and eco-friendly technologies.

Advanced oxidation processes, such as ozonation-biofiltration, electro-Fenton and anodic oxidation processes, which attracted a growing interest over the last two decades, could achieve almost complete destruction of the pollutants studied.

Firstly, removal of selected pharmaceuticals from tap water was investigated by electrochemical advanced oxidation processes -electro-Fenton‖ and -anodic oxidation‖ with Pt or boron-doped diamond anode and carbon felt cathode at lab-scale. Removal rates and minieralization current efficencies under different operatioanl conditions were analysed. Meanwhile, intermediates produced during the mineralization were also identified, which helps to propose plausible oxidation pathway of each compound in presence of  OH. Finally, the evolution of the global toxicity of treated solutions was monitored using Microtox method, based on the fluorescence inhibition of Vibrio fischeri bacteria.

In the second part, the three nonsteroidal anti-inflammatory molecules added in organics-free or surface water were treated under varying ozone treatment regimes with the quite well established technology ozone/biofiltration. A bench-scale biological film was employed to determine the biodegradability of chemical intermediates formed in ozonized surface water. Identification of intermediates formed during the processes and bacterial toxicity monitoring were conducted to assess the pharmaceuticals degradation pathway and potential biological effects, respectively.

iii Résumé La thèse a porté principalement sur la mise en oeuvre de procédés d'oxydation avancée permettant l'élimination de trois anti-inflammatoires non stéroïdiens, le kétoprofène, le naproxène et le piroxicam dans l'eau. Ces trois composés sont parmi les médicaments les plus utilisés, dont la présence dans les eaux naturelles présente potentiellement un risque toxicologique. En raison de la faible efficacité d'élimination des produits pharmaceutiques par les stations traditionnels de traitement des eaux usées, les scientifiques se sont mis à la recherche de technologies de traitements efficaces et respectueuses de l'environnement. Les procédés d'oxydation avancée, comme l'ozonation-biofiltration, l'électro-Fenton et l'oxydation anodique peuvent permettre d'atteindre la destruction presque complète des polluants étudiés et de ce fait ils ont suscité un intérêt grandissant au cours des deux dernières décennies.

Tout d'abord, ce travail s'intéresse à l'élimination de certains produits pharmaceutiques dans des solutions synthétiques préparées dans l'eau de robinet à l'aide des procédés électro-Fenton et oxydation anodique dans une cellule électrochimique équipée d'une anode de platine ou de diamant dopé au bore et d'une cathode de feutre de carbone. Cette étude a été menée à l'échelle du laboratoire. Les vitesses d'élimination des molécules pharmaceutiques ainsi que le degré de minéralisation des solutions étudiées ont été déterminées sous différentes conditions opératoires. Pendant ce temps, les sous-produits de l'oxidation générés au cours de la minéralisation ont également été identifiés, ce qui nous a permis de proposer les voies d'oxydation possible pour chaque composé pharmaceutique en présence du radical hydroxyl  OH. Enfin, l'évolution de la toxicité au cours des traitements a été suivie en utilisant la méthode Microtox, basée sur l'inhibition de la fluorescence des bactéries Vibrio fischeri.

Dans la deuxième partie de ce travail de thèse, les trois anti-inflammatoires non stéroïdiens ont été ajoutés dans une eau déminéralisée ou dans une eau de surface. Ces eaux ont été traitées à l'aide de différentes doses d'ozone; puis le traitement à l'ozone à été combiné à un traitement biologique par biofiltration. Un biofilm biologique déposé à la surface d'un filtre de charbon actif a été utilisé pour déterminer la biodégradabilité des sous-produits d'oxydation formés dans les eaux de surface ozonée. L'identification des intermédiaires formés lors des processus de traitment et des contrôles de toxicité bactérienne ont été menées pour évaluer la voie de dégradation des produits pharmaceutiques et des effets biologiques potentiels, respectivement. iv Mots Clés: Procédés d'Oxydation Avancée; Electro-Fenton; Oxydation Anodique; Ozonation; Biofiltration; Ketoprofen; Naproxène; Piroxicam v Abstract Dit proefschrift was voornamelijk gericht op de implementatie van geavanceerde oxidatie processen voor de verwijdering van drie niet-steroïdale anti-inflammatoire geneesmiddelen uit water: ketoprofen, naproxen en piroxicam. Deze drie stoffen behoren tot de meest gebruikte geneesmiddelen, en hun aanwezigheid in water vormt een potentieel ecotoxicologisch risico. Door het lage verwijderingsrendement van de traditionele afvalwaterzuivering voor deze farmaceutische stoffen is er wereldwijd zorg vanwege hun potentiële toxiciteit en vraag naar efficiënte en milieuvriendelijke verwijderingstechnologieën. Geavanceerde oxidatie processen, zoals ozonisatiebiofiltratie, electro-Fenton en anodische oxidatie processen kregen in de afgelopen twee decennia een groeiende belangstelling en zouden een bijna volledige verwijdering van de bestudeerde verontreinigende stoffen kunnen bereiken.

Ten eerste werd de verwijdering van de geselecteerde geneesmiddelen uit leidingwater onderzocht door de elektrochemische geavanceerde oxidatieprocessen "electro-Fenton" en "anode oxydatie" met Pt of boor gedoteerde diamant anode en koolstof kathode op laboratoriumschaal. Verwijderingssnelheden en mineralizatie efficiënties werden geanalyseerd onder verschillende operationele omstandigheden.

Tussenproducten geproduceerd tijdens de mineralisatie werden ook geïdentificeerd, wat hielp om de oxidatie pathway van elke verbinding in de aanwezigheid van • OH te reconstrueren. Tenslotte werd de evolutie van de globale toxiciteit van behandelde oplossingen gemonitord met behulp de Microtox methode, gebaseerd op de fluorescentie remming van Vibrio fischeri bacteriën.

In het tweede deel werden de drie niet-steroïde anti-inflammatoire stoffen toegevoegd aan organische-vrij water of oppervlaktewater dat werd behandeld onder wisselende ozon regimes met de gevestigde -ozon/biofiltratie‖ technologie. Een benchscale biofilm werd gebruikt om de biologische afbreekbaarheid van chemische tussenproducten gevormd in geozoniseerde oppervlaktewater te bepalen.

Tussenproducten gevormd tijdens het proces werden geïndentificeerd om de afbraakroute van de farmaceutische producten te bepalen en bacteriële toxiciteit werd gemonitord om mogelijke biologische effecten te evalueren.

Trefwoorden: Geavanceerde Oxidatie Processen; Electro-Fenton; Anode Oxydatie, Ozonisatie, Biofiltratie; Ketopofen, Naproxen, Piroxicam.

vi Astratto

Il presente lavoro di tesi è centrato sull'implementazione di processi di ossidazione avanzata per la rimozione dalle acque di tre farmaci non steroidei antinfiammatori: ketoprofene, naproxene e piroxicam. I tre composti sono tra i medicinali più usati e la loro presenza in acqua pone un rischio potenziale di tipo ecotossicologico. A causa delle ridotte efficienze di rimozione degli impianti tradizionali di trattamento delle acque reflue nei confronti di tali composti farmaceutici, si è resa necessaria la ricerca di nuove tecnologie più efficienti e eco-sostenibili. I processi di ossidazione avanzata, come ozonizzazione-biofiltrazione, elettro-.Fenton e ossidazione anodica, che hanno riscontrato un crescente interesse negli ultimi due decenni, sono in grado di degradare in maniera quasi completa i suddetti inquinanti.

Pertanto nella tesi è stato studiato, in primo luogo, l'impiego dei processi di ossidazione elettrochimica avanzata electro-Fenton e ossidazione anodica per la rimozione dei prodotti farmaceutici dall'acqua di rubinetto, usando Pt o boron-doped diamond come anodo e carbon felt come catodo, in scala di laboratorio. In particolare sono state esaminate le velocità di rimozione e le efficienze di mineralizzazione ottenute in condizioni operative diverse. Allo stesso tempo sono stati identificati i composti intermedi prodotti nel corso della mineralizzazione per individuare dei percorsi di ossidazione plausibili per ogni composto in presenza di  OH. Inoltre l'evoluzione della tossicità globale delle soluzioni trattate è stata monitorata utilizzando il metodo Microtox, basato sull'inibizione della fluorescenza dei batteri Vibrio fischeri.

Nella seconda parte della tesi i tre composti antinfiammatori non steroidei aggiunti ad acque prive di sostanza organica o acque superficiali sono stati trattati con la tecnologia già affermata dell'ozonizzazione/biofiltrazione. Una pellicola biologica in scala banco è stata impiegata per determinare la biodegradabilità degli intermedi chimici prodotti nell'acqua superficiale ozonizzata. L'identificazione degli intermedi formati durante i processi ossidativi e il monitoraggio della tossicità batterica sono stati condotti, rispettivamente, per valutare i percorsi di degradazione dei composti farmaceutici e i potenziali effetti biologici. ), hydroperoxyl radical (HO 2  ), and organic peroxide radical (ROO  ).

These oxidants can highly react with a wide range of organic compounds in a nonselective oxidation way. The target compounds could be quickly and efficiently converted into small inorganic molecules such as CO 2 and H 2 O. However, with the great power of the AOPs, the utilization of such processes in water treatments has not been applied in a large number because of the high costs of chemical reagents inputs or extra demanding of pre or after treatment. However, due to the request of clean and safe water sources, the interests of applying AOPs for wastewater treatment is rising in different countries.

The advanced treatment applied in wastewater treatment plants is called the tertiary treatment step. Wet oxidation, ozonation, Fenton process, sonolysis, homogeneous ultraviolet irradiation, and heterogeneous photo catalysis using semiconductors, radiolysis and a number of electric and electrochemical methods are Fenton process and related systems, electrochemistry, heterogeneous photocatalysis using TiO 2 /UV process and H 2 O 2 /UV light process seem to be most popular technologies for pharmaceuticals removal from wastewater effluents.

Problem Statement

Most of the traditional wastewater treatment plants (WWTPs) are especially not designed with tertiary treatment step to eliminate pharmaceuticals and their metabolites [4]. WWTPs therefore act as main pharmaceuticals released sources into environment.

The released pharmaceuticals into the aquatic environment are evidenced by the occurrence of pharmaceuticals up to g L -1 level in the effluent from medical care units and sewage treatment plants, as well as surface water, groundwater, and drinking water [5][6][7][8][9]. It is urgent to supply the adapted technologies to treat the pharmaceuticals in WWTPs before releasing them into natural water system.

Nevertheless, increased attention is currently being paid to pharmaceuticals as a class of emerging environmental contaminants [10]. Because of the presence of the pharmaceuticals in the aquatic environment and their low volatility, good solubility and main transformation products dispersed in the food chain, it is very important to investigate their greatest potential risk on the living organisms [11][12][13]. Since the pharmaceuticals are present as a mixture with other pollutants in the waste and surface waters, effect as synergistic or antagonistic can occur as well [14,15]. Therefore, their long-term effects have also being taken into consideration [16].

In the last years, European Union [17] and USA [18] have taken action to establish regulations to limit the pharmaceuticals' concentrations in effluents to avoid environmental risks. The focuses are on the assessments of effective dose of pharmaceuticals for toxicity in industrial effluents or surface water. In 2011, the World Health Organization (WHO) published a report on pharmaceuticals in drinking-water which reviewed the risks to human health associated with exposure to trace concentration of pharmaceuticals in drinking-water [19].

The trace level concentration of pharmaceuticals in aquatic environments results from ineffective removal of traditional water treatments processes. Therefore, to overcome the shortcomings, developments of more powerful and ecofriendly techniques are of great interests. Electrochemical advanced oxidation processes (EAOPs), as a combination of chemical and electrochemical methods, are mainly developed to oxidize the pollutants at the anodes or by the improvement of classic Fenton process [20]. This latter process favors the production of  OH, which are capable of oxidizing almost all the organic and inorganic compounds in a non-selective way [21,22].

The former one, as anodic oxidation (AO), oxidizes the pollutants directly by the adsorbed  OH formed at the surface of anode from water oxidation (Eq. (1.1)), with no need of extra chemical reagents in contrast to Fenton related processes [3]. The nature of anodes material greatly influences the performance of AO. With the techniques' development, a boron-doped diamond (BDD) thin film anode, characterized by its higher oxygen overvoltage, larger amount production and lower adsorption of  OH, shows a good organic pollutants removal yield [23]. AO process with BDD has been conducted with tremendous removal efficiency on pharmaceuticals.

M + H 2 O → M(  OH) ads + H + + e - (1.1)

Indirect oxidation as the electro-Fenton (EF) generates the H 2 O 2 by the reduction of oxygen in an acidic medium at cathode surface (Eq. (1.2)) [24]. Then, the oxidizing power is enhanced by the production of  OH in bulk solution through Fenton reaction (Eq. (1.3)). This reaction is catalyzed from electrochemical re-generation of ferrous iron ions (Eq. (1.4)) [25].

O 2 + 2 H + + 2 e - → H 2 O 2 (1.2) Fe 2+ + H 2 O 2 → Fe 3+ +  OH + OH - (1.3)
Fe 3+ + e - → Fe 2+ (1.4)

In an undivided cell system, the two oxidation mechanisms can coexist during the process. However, parasitic or competitive reactions also occur during the procedure [26,27].

Otherwise, ozonation is one of the most popular AOPs, using the oxidative power of ozone (O 3 ) and producing extra  OH as oxidant, that has been widely applied for drinking water production [28,29]. It has been proved that natural organic matter biodegradability and an efficient inactivation of a wide range of microorganisms could be achieved by ozonation via ozone or  OH [30]. At present, ozonation is the only AOPs that have been applied at full-scale for the degradation of pharmaceuticals still remaining in the wastewater effluents before discharge in the environment. This technology was shown to reduce of effluent toxicity after ozone treatment [31][32][33].

Biodegradable organic compounds generated by AOPs can be an energy and carbon sources for the heterotrophic bacteria and may cause serious problem of bacterial regrowth in the drinking water distribution system. This makes the combination of AOPs and microbiological treatments as an attractive and economical way for the purification of water treatments.

Biofiltration systems are operated robustly and constructed simply with low energy requirements [34]. This technology has been used for many years for water treatments, proved to be able to significantly remove natural organic matter, ozonation by-products, disinfection by-products precursors as well as pharmaceuticals [34,[35][36][37][38][39][40].

Among the media for the biofiltration, the one with a larger attachment surface for the microbial biofilm and the one with the higher adsorption capacity for organic compounds such as granular activated carbon (GAC) is mostly utilized [35,36].

Goal of the Research

As world concerned pollutants, three molecules of anti-inflammatory and analgesic pharmaceuticals -ketoprofen, naproxen and piroxicam were selected for this study. The selection was under the consideration of their detection frequency, ecotoxicity, removal rate in wastewater treatment plants and other oxidation techniques (see chapter 2) [3]. The efficient technologies promoted for the removal of these compounds are powerful EAOPs (EF and AO) and popular ozonation/biofiltration system.

The general research objective for this study is to find out the removal efficiency of the EAOPs and ozonation/biofiltration system. The emphases is on optimizing the parameters with the consideration of both degradation and mineralization rate of pharmaceuticals. Likewise, the kinetic study for three compounds oxidized by  OH/O 3 was also conducted by competition method in order to determine the absolute kinetic constant. Finally, oxidation intermediates and end-products (aromatic compounds, carboxylic acids and inorganic ions) were determined during the mineralization for the selected pollutants degradation pathways by EAOPs and ozonation processes.

Specific research objective of this study is on the toxicity of treated solution to assess the ecotoxicity of the treatment processes. The intent of application of ozonation Chapter 1 General Introduction 6 followed by biofiltration is to find the economical and ecofriendly energy input for drinking water treatment plants. With the investigation of the mineralization pathway and study of toxicity evolution during the processes operation, a deep understanding of pharmaceuticals removal from aquatic environment is expected to be achieved.

All the work above is intended to cope with water problems with removal of pharmaceuticals and to select the right method or most often the right combination of methods for an ecofriendly application in water treatments.

Research Questions

Considering the potential ecotoxicological risk of pharmaceuticals in aquatic environment and the need to develop efficient technologies for the removal of these pollutants, AOPs (i.e. EF, AO and ozonation) were studied. The present thesis aims at the determination of the kinetics, mechanisms, and evolution of the toxicity of pharmaceuticals in the treated solutions.

The following matters are the main questions to be answered in this thesis:

1.

What are the optimal operational parameters allowing to reach the best removal rate to achieve energy saving? Which process has better performance, and what is the reason for that?

2.

How the oxidants react with the pharmaceuticals? What kinds of intermediates will be produced during the mineralization process? Whether the mechanisms of pharmaceuticals oxidized by EAOPs can be proposed?

3.

How the toxicity values change during the EAOPs processes? What is the explanation for the results?

4.

Whether the combination of biofiltration with ozone treatment can improve the removal of these organic micropollutants and decrease the toxicity in treated water? In what kind of situation it works?

5.

With all the questions being answered, can this study help to reach a successful elimination of the pollutants and a low cost demand for per m 3 water treated for the application? If not, what kind of other solutions or perspective can be addressed to accelerate the implementation of AOPs/EAOPs at full-scale?

Outline of the Thesis

The whole thesis is divided into the following main sections.

In the chapter 2, a literature review summarizes the relevant removal of pharmaceuticals by AO and EF processes. The frequent detection and negative impact of pharmaceuticals on the environment and ecology are clarified. Therefore, efficient technologies as EAOPs (i.e AO and EF) for the removal of anti-inflammatory and analgesic pharmaceuticals from aqueous systems are well overviewed as prospective technologies in water treatments.

The chapter 3 is the research of comparison of EF and AO processes on ketoprofen removal. Ketoprofen is not efficiently removed in wastewater treatment plants. Its frequent detection in environment and various treatment efficiencies make it chosen as one of the pollutants investigated in this work. The results show promising removal rates and decreasing toxic level after treatment. Naproxen has been widely consumed as one of the popular pharmaceuticals. More researches have revealed its high level of detected concentration in environment and toxic risk on living species. In the chapter 4, the removal of naproxen from aqueous medium is conducted by EF process to clarify the effect of anode material and operating conditions on removal. It can be concluded that high oxidizing power anode can achieve better removal rate.

Then, different processes as EF and AO with same electrodes are compared in electrochemical oxidation of naproxen in tap water in the hcapter 5. It is showed, under the same condition, the removal rate is better by EF than that of AO. In the chapter 6, as one popular medicine used for almost 30 years, the degradation of piroxicam by EF and AO processes is performed. The research is divided into 4 parts: 1. The optimization of the procedure in function of catalyst concentration, pH, air input and current intensity applied on both degradation (HPLC) and mineralization (TOC) rate; 2. The kinetic constant of reaction studied between pollutant and  OH (competition kinetics method); 3. Intermediates formed during the mineralization (HPLC, standard material) and pathway proposed by the intermediates produced and related paper published; 4. The evolution of the toxicity (Microtox method) of the solution treated. General discussion is presented in chapter 8. Firstly, the overall results of the research are discussed. Except the work of this thesis, perspective of the future work of AOPs on removal of persistent or trace pollutants is proposed. Lastly, the conclusion of the all work of this thesis is given.

Chapter 2: Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes. A review 8

Introduction

In 1899, the first anti-inflammatory drug, aspirin (acetylsalicylic acid, C 9 H 8 O 4 ), was registered and produced extensively by German Bayer Company. During the following years, many other nonsteroidal anti-inflammatory drugs (NSAIDs) were developed and marketed. Nowadays, this group of medicines includes more than one hundred compounds and they are known to be largely used throughout the world as inflammatory reducer and pain killer. From the chemical structure point of view, they consist of an acidic moiety attached to a planar, aromatic functionality (Fig. 2.1).

Mechanistically, they inhibit the cyclooxygenase (COX) enzymes, which convert arachidonic acid to prostaglandins, thromboxane A2 (TXA2) and prostacyclin, reducing consequently ongoing inflammation, pain and fever. Since such a large amount of pharmaceutical compounds are consumed every year, significant unused overtime drugs, including human (household, industry, hospitals and services) and veterinary (aquaculture, livestock, and pets) medical compounds, are released into environment continuously. A small part of unused or expired drugs is gathered to be incinerated. However a large part, in the form of original drugs or metabolites, is discarded to waste disposal site or flushed down via toilet (human body only metabolizes a small percentage of drug) into municipal sewer in excrement. As an example, in Germany, it is estimated that amounts of up to 16 000 tons of pharmaceuticals are disposed from human medical care and 60-80% of those disposed drugs are either washed off via the toilets or disposed of with normal household waste each year [4,5]. Much of these medicines escape from being eliminated in wastewater treatment plants (WWTPs), because they are soluble or slightly soluble, and they are resistant to degradation through biological or conventional chemical processes. In addition, medicines entering into soil system, which may come from sewage sludge and manure, are not significantly adsorbed in the soil particles due to their polar structure.

Therefore, they have the greatest potential to reach significant levels in the environment.

Ground water for drinking water production may be recharged downstream from WWTPs by bank filtration or artificial ground water [6][7][8][9], making NSAIDs entering into the drinking water cycle that could be used for the production of drinking water.

Consequently, it is reported NSAIDs are detected on the order of ng L -1 to µg L -1 in the effluent of sewage treatment plants and river water [9][10][11][12]. All discharge pathways above mentioned act as entries of pharmaceuticals into aquatic bodies, waters and potable water supplies [13] (Fig. 2.2). (adapted from [14] with Copyright from 2011 American Chemical Society).

The pharmaceuticals are specially designed against biological degradation. This means that they can retain their chemical structure long enough to exist in human body, and mostly released into environment in original form. It is known that pharmaceuticals may not only target on specific metabolic pathways of humans and domestic animals but also have effect on non-target organisms, even at very low concentrations [15][16][17][18][19].

In 2011, the World Health Organization (WHO) published a report on pharmaceuticals in drinking-water which reviewed the risks to human health associated with exposure to trace concentrations of pharmaceuticals in drinking-water, raising the fear that the continuous input of pharmaceuticals may pose a potential risk for the organisms living in terrestrial and aquatic environment [20]. Inflammatory drugs, such as ibuprofen, naproxen, diclofenac and ketoprofen, which exist in effluents of WWTPs and surface water, being discharged without the use of appropriate removal technologies, may cause adverse effects on the aquatic ecosystem [21,22], and it has been considered as an emerging environmental problem. Recent studies had confirmed that the decline of the population of vultures in the India subcontinent was related to their exposure to diclofenac residues [23,24]. Furthermore, it is accepted that the co-existence of pharmaceuticals or other chemicals (so-called drug -cocktail‖) brings more complex toxicity to living organisms [25] that is uneasily to be forecasted and resolved. For example, the investigation of the combined occurrence of diclofenac, ibuprofen, Chapter 2: Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes. A review 13 naproxen and acetylsalicylic acid in water demonstrates synergistic effect on toxicity [39]. This fact has resulted in raising concerns about the recent elimination efficiency of pharmaceuticals in environment, and the need for the assessment of safety of drinking water, reclaimed, reused wastewater, and aquatic ecosystems.

Considering that conventional wastewater treatment processes display sometime poor removal efficiency for pharmaceuticals, this paper gives a quick overview of removal efficiency of some NSAID's that were investigated in the literature. Then, in the frame of this review, among the different Advanced Oxidation Processes (AOPs) available, the interest of using electrochemical advanced oxidation processes (in particular anodic oxidation and electro-Fenton) for the removal of NSAID's is discussed.

These technologies are still at a very early stage compared with other AOPs (i.e. ozonation, Fenton or UV/H 2 O 2 ) [26][27][28][29][30] with most studies found in the literature carried out at the lab-scale. However, as it will be discussed in this paper, they show a very promising potential and very soon scale up and effect of actual matrixes of water will become hot topics.

Anti-inflammatory and analgesic drugs discussed in this review

The NSAIDs constitute a heterogeneous group of drugs with analgesic, antipyretic and anti-inflammatory properties that rank intermediately between corticoids with antiinflammatory properties on one hand, and major opioid analgesics, on the other.

Considering the contamination level of anti-inflammatory and analgesic drugs in aqueous environment, aspirin, ibuprofen, ketoprofen, naproxen, diclofenac, paracetamol and mefenamic acid can be considered as the most significant ones. Their main physicochemical characteristics are given in Table 2.2. Such molecules have also been shown to be poorly removed or degraded by conventional water treatment processes in contrast to results obtained by application of AOPs.

Chapter 2: Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes. A review 14 [21,41,42]. This medicine and its metabolites are the most frequently detected NSAIDs in water, because they could resist biodegradation in the WWTPs effluents. It was investigated that prolonged exposure at the lowest observed effect concentration (LOEC) of 5 g L -1 , leads to impairment of the general health of fishes, inducing renal lesions and alterations of the gills [43].

Ibuprofen, (RS)-2-(4-(2-methylpropyl)phenyl)propanoic acid, hugely global consumed, has a high acute toxicity, which was suspected of endocrine disrupting activity in human and wildlife [44,45]. Quite similar toxicological consequences in aquatic environment have been shown by the intermediates formed by biological treatment [46].

Ketoprofen, (RS)-2-(3-benzoylphenyl)propanoic acid, is metabolized mainly in conjugation with glucuronic acid (a cyclic carboxylic acid having structure similar to that of glucose) and excreted mainly in the urine (85%) [47]. Surveys of livestock carcasses in India indicated that toxic levels of residual ketoprofen were already present in vulture food supplies [48].

Naproxen, (+)-(S)-2-(6-methoxynaphthalen-2-yl)propanoic acid, is widely used in human treating veterinary medicine [49], with a chronic toxicity higher than its acute toxicity shown by bioassay tests. It was also shown that the by-products generated by photo-degradation of naproxen were more toxic than itself [50].

Mefenamic acid, 2-(2,3-dimethylphenyl)aminobenzoic acid, has potential contamination of surface water, it is of significant environmental relevance due to its diphenylamine derivative [47].

Paracetamol, N-(4-hydroxyphenyl)acetamide, is one of the most frequently detected pharmaceutical products in natural water [51]. As an example, it was detected in a concentration as high as 65 g L -1 in the Tyne river (UK) [52]. In addition, by chlorination in WWTPs, two of its identified degradation compounds were transformed into unequivocally toxicants [53].

Conventional wastewater treatment on anti-inflammatory and analgesic drugs

Chapter 2: Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes. A review 16

Conventional wastewater treatment consists of a combination of physical, chemical, and biological processes. There are four removal stages: preliminary treatment, primary treatment, secondary treatment, tertiary treatment and/or advanced wastewater treatment. Preliminary treatment is used for removal of coarse solids and other large materials often found in raw wastewater, intended to reduce oils, grease, fats, sand, and grit, done entirely mechanically by means of filtration and bar screens.

Primary treatment is performed to remove organic suspended solids and a part of the colloids, which is necessary to enhance the operation and maintenance of subsequent treatment units. Secondary treatment is designed to substantially degrade the organic content of the sewage, usually using microorganisms in the purification step; in tertiary treatment step, the stronger and more advanced treatment is applied. This tertiary treatment and/or advanced wastewater treatment is employed when specific wastewater constituents which cannot be removed by secondary treatment must be removed such as phosphorus or pharmaceuticals. Therefore, biological and physicochemical processes could be applied. For instance, for the removal of pharmaceuticals residues, ozonation is currently used at full-scale [54] and the final effluent can be discharged into natural surface water bodies (stream, river or lake).

Wastewater treatment plants are not specifically designed to deal with highly polar micro pollutants, like anti-inflammatory and analgesic drugs (Table 2.3). It is assumed that pharmaceuticals are likely to be removed by adsorption onto suspended solids or through association with fats and oils during aerobic and anaerobic degradation, and chemical (abiotic) degradation by processes such as hydrolysis [55,56]. A recent study on the elimination of a mixture of pharmaceuticals in WWTPs including the betablockers, the lipid regulators, the antibiotics and the anti-inflammatory drugs exhibited removal efficiencies below 20% in the WWTPs [57].

Table 2.3 gives also information on environmental toxicity of the listed NAISDs.

Chronic toxicity investigations could lead to more meaningful ecological risk assessment, but only a few chronic toxic tests for pharmaceuticals have been operated.

In this context, Ferrari et al. [58] tested the ecotoxicological impact of some pharmaceuticals found in treated wastewaters. Higher chronic than acute toxicity was found for carbamazepine, clofibric acid, and diclofenac by calculating acute EC 50 /chronic NOEC (A/C) ratios for Ceriodaphnia dubia, for diclofenac, clofibric acid, and carbamazepine, while the chronic toxicity was conducted as 0. Regarding NSAIDs, ibuprofen, ketoprofen, diclofenac, and naproxen are highly hydrophilic compounds due to their pKa ranging between 4.1 and 4.9; consequently their elimination on sorption process is so inefficient and it mainly depends on chemical or biological processes [2]. Consequently, removal results are very dissimilar. Thus, in previous studies shown in the literature about treatability with conventional technologies, it was found that after being treated in a pilot-scale sewage plant [59],

approximately 95% of diclofenac was not eliminated, while ibuprofen concentration decreased down to 40% of its original concentration. Better results were obtained in other study, in which about 90% of ibuprofen was successfully transformed to hydroxyl and carboxyl derivatives [2]. However, results have to be carefully interpreted because in literature [60], it was also pointed that some of these metabolites maybe hydrolyzed and converted to the parent compound again. Another work pointed that an efficient elimination of ibuprofen and naproxen depends on the applied hydraulic retention times in WWTPs, with a considerable improvement by applying hydraulic retention times longer than 12 hours in all the processes [36]. Regarding other NSAIDs, the efficiency of ketoprofen removal in WWTPs varied from 15-98% [61] and the data on the elimination of mefenamic acid by standard WWTP operations are controversial. Aspirin can be completely biodegradable in laboratory test systems, but with a removal of 80-98% in full-scale WWTPs owing to complex condition of practical implication [62][63][64][START_REF] Kimura | Influence of residual organic macromolecules produced in biological wastewater treatment processes on removal of pharmaceuticals by NF/RO membranes[END_REF].

Consequently, the removal rate varies in different treatment plants and seasons, from -very poor‖ to -complete‖, depending strongly on the factors, like the nature of the specific process being applied, the character of drugs or external influences [START_REF] Zwiener | Oxidative treatment of pharmaceuticals in water[END_REF]. It had been reported that diclofenac, ibuprofen, ketoprofen and naproxen were found in the effluents of sewage treatment plants in Italy, France, Greece and Sweden [2], which indicated the compounds passed through conventional treatment systems without efficient removal, and were discharged into surface waters from the WWTP effluent (Fig. 2.2), entering into surface waters, where they could interrupt natural biochemistry of many aquatic organisms [START_REF] Sanderson | Probabilistic hazard assessment of environmentally occurring pharmaceuticals toxicity to fish, daphnids and algae by ECOSAR screening[END_REF].

Hence, from the observation mentioned above, common WWTPs operations are found insufficient for complete or appreciable elimination of these pharmaceuticals from sewage water which make anti-inflammatory and analgesic drugs remain in the aqueous phase [5,[START_REF] Holm | Occurrence and Distribution of Pharmaceutical Organic Compounds in the Groundwater Downgradient of a Landfill (Grindsted, Denmark)[END_REF] at concentration of g L -1 to ng L -1 in aquatic bodies. It was Chapter 2: Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes. A review 18 reported that the drug could be stable and remains nearly at the same concentration in the plant influent, effluent and downstream [START_REF] Hilton | Determination of selected human pharmaceutical compounds in effluent and surface water samples by high-performance liquid chromatography-electrospray tandem mass spectrometry[END_REF].

Considering the uncertainty of treatment in the WWTPs and potential adverse effect of original pharmaceuticals and or their metabolites on living organisms at very low concentrations [40,[START_REF] Bundschuh | Ecotoxicologial evaluation of wastewater ozonation based on detritus-detritivore interactions[END_REF], more powerful and efficient technologies are required to apply in treatment of pharmaceuticals

Ketoprofen >0.32/93 0.14-

Electrochemical Advanced Oxidation Processes

Among the AOPs, EAOPs were extensively studied during the last decade at labscale and several interesting works were published with perspective for up scaling as pilot-plant in the near future [START_REF] Brillas | Electro-Fenton process and related electrochemical technologies based on Fenton's reaction chemistry[END_REF][START_REF] Hammami | Degradation of Acid Orange 7 by electrochemically generated (*)OH radicals in acidic aqueous medium using a boron-doped diamond or platinum anode: a mechanistic study[END_REF][START_REF] Dirany | Electrochemical abatement of the antibiotic sulfamethoxazole from water[END_REF][START_REF] Panizza | Direct And Mediated Anodic Oxidation of Organic Pollutants[END_REF][START_REF] Panizza | Application of boron-doped diamond electrodes for wastewater treatment[END_REF]. In EAOPs, hydroxyl radicals can be generated Regarding the literature discussing the applications of EAOPs, most studies only pay attention to the mineralization of a specific organic molecule, and very few are paying attention to the removal of a specific organic molecule from wastewater matrices.

Therefore, it is worth to distinguish between studies intended to determine if a technology is suitable to degrade a specific pollutant and studies performed with complex aqueous matrices (e.g. wastewater).

In the first case, the main information that can be obtained is the reaction kinetics mechanisms of the oxidation process (in particular the occurrence of intermediates that could be even more hazardous than the parent molecule) and the possibility of formation of refractory or more toxic by-products. Inappropriate intermediates or final products may inform against the application of the technology just with the data obtained in this first stage of studies.

In the second case (assessment of the technology efficiency in a real with a real aqueous matrix), although the presence of natural organic matter or some inorganic species such as chloride ion, can affect the reaction rate and process efficacy (since part of  OH is consumed by theses organics), a complete characterization of the wastewater is generally difficult, since a complex matrix can contain hundreds of species. In this case, the main results are related to the operating cost and to the influence of the matrix composition on process effectiveness.

Nowadays, most EAOPs are within the first stage of development and far away for the pre-industrial applicability. Thus, as it is shown in this manuscript, most studies focused on the evaluation of intermediates and final products; and only few of them can Chapter 2: Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes. A review 22 be considered as second-stage studies, trying to determine the effect of the aqueous matrices.

Anodic oxidation Processes

Anodic oxidation can be defined as an electrochemical technology that is able to attain the oxidation of pollutants from water or wastewater, either by direct or by mediated oxidative processes originated on the anode surface of an electrochemical cell.

This means that these oxidative-processes should not necessarily be carried out on the anode but just initiated on its surface. As a consequence, this treatment combines two main type of processes [START_REF] Panizza | Direct And Mediated Anodic Oxidation of Organic Pollutants[END_REF].

-Heterogeneous oxidation of the pollutants on the anode surface. This is a complex process which consists of a series of simpler processes: transport of the pollutants from the bulk to the surface of the electrode, adsorption of the pollutant onto the surface, direct electrochemical reaction by electron transfer to the pollutant, desorption of products and transport of oxidation products to the bulk;

-Homogeneous oxidation of pollutants in the bulk by oxidants produced on the anode surface from components of the electrolyte. These oxidants can be produced by the heterogeneous anodic oxidation of water or ions contained in the water (or dosed to promote their production) and their action is done in the bulk of the electrochemical cell.

One of these oxidants is the hydroxyl radical. Production of this radical allowed to consider anodic oxidation as an AOP [START_REF] Marselli | Electrogeneration of Hydroxyl Radicals on Boron-Doped Diamond Electrodes[END_REF].

The significant role of hydroxyl radicals on the results of AO process has been the object of numerous studies during the recent years [106]. The short average lifetime of hydroxyl radicals causes that their direct contribution to anodic oxidation process is limited to the nearness of the electrode surface and hence, in a certain way, it could be considered as a heterogeneous-like mediated oxidation process. Thus, it is very difficult to discern the contribution between direct oxidation and mediated oxidation in the However, the extremely high oxidation capacity of hydroxyl radicals makes them promote the formation of many other oxidants from different species contained in the wastewater and this effect converts the surface-controlled quasi-direct electrochemical process into a significantly much more efficient volumetric-oxidation process. Thus, it has been demonstrated the production of persulfates, peroxophosphates, ferrates and many other oxidants using anodic oxidation processes [START_REF] Cañizares | Synthesis of novel oxidants by electrochemical technology[END_REF] and it has also been demonstrated their significant effects on the improvement of the remediation efficiency [START_REF] Rodrigo | Use of conductivediamond electrochemical oxidation for wastewater treatment[END_REF]. Synergistic effects of all these mechanisms can explain the good efficiencies obtained in this technology in the removal of pollutants and the huge mineralization attained as compared with many other AOPs [START_REF] Canizares | Electrochemical oxidation of wastewaters polluted with aromatics and heterocyclic compounds[END_REF][START_REF] Cañizares | Electrochemical oxidation of alcohols and carboxylic acids with diamond anodes: A comparison with other advanced oxidation processes[END_REF]. [START_REF] Sánchez-Carretero | Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes[END_REF] with Copyright from 2009 Wiley).

Two points are of particular importance in understanding of AO process: electrode material and cell design. The first one is important, because it may have a significant influence on the direct oxidation of a given organic pollutant (i.e. catalytic properties related to adsorption or the direct electron transfer processes) and on the production of oxidants, which can extend the oxidation of pollutants to the bulk of the treatment. The second one is also very important, particularly in the treatment of pollutant at low concentrations, such as the typically assessed in this study, because the kinetics of these processes is mass-transfer controlled. A good mechanical design, which promotes turbulence and modifies the key factors that limit the rate of oxidation, can increase the efficiency of processes. However, as it is going to be discussed during this section, removal of pharmaceutical compounds from water and wastewater is still in an earlier lab scale stage and optimization of the cell design is usually done in later scale up studies. Single flow or complete-mixed single-compartment electrochemical cells are proper cells to assess the influence of the electrode material at the lab scale, but in order to apply the technology in a commercial stage, much more work has to be done in order to improve the mechanical design of the reactor [113]. For sure, it will become into a hot topic once the applicability at the lab scale has been completely demonstrated.

Regarding the anode, material is the key point in the understanding of this technology, and two very different behaviors are described in the literature for the oxidation of organic pollutants [START_REF] Foti | Oxidation of organics by intermediates of water discharge on IrO2 and synthetic diamond anodes[END_REF]. Some types of electrode materials lead to a very powerful oxidation of organics with the formation of few intermediates and carbon dioxide as the main final product while others seems to do a very soft oxidation.

Although not yet completely clear, because a certain controversy still arises about mechanisms and even about the proposed names for the two types of behaviors (they have been called active vs. non active, high-oxygen vs. low-oxygen overvoltage electrodes, etc.), interaction of hydroxyl radicals formed during the electrochemical process with the electrode surface could mark the great differences between both behaviors and just during the treatments with high oxidation-efficiency materials, hydroxyl radicals can be fully active to enhance the oxidation of pollutants. In that case, hydroxyl radicals do not interact strongly with the surface, but they promote the Chapter 2: Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes. A review 25 hydroxyl radical mediated oxidation of organics and also the production of many other more-stable oxidants (which help to produce a volumetric control of the kinetics).

Graphite and other sp 2 carbon based electrodes, and also many metal (i.e. Pt, Ti/Pt), some metal oxide electrodes (i.e. IrO 2 , RuO 2 ) and mixed metal oxide electrodes (containing different Ir, Ru, Mo oxides) behave as low-efficiency electrodes for the oxidation of organics. These anodes promote a soft oxidation of organics, with a great amount of intermediates (most aromatics treated by these anodes are slowly degraded due to the generation of hardly oxidizable carboxylic acids [START_REF] Waterston | Electrochemical waste water treatment: Electrooxidation of acetaminophen[END_REF]), with small mineralization rates and in some cases (particularly, under high concentration of pollutants) with production of polymers. This produces a very low current efficiency and consequently small perspectives of application [START_REF] Foti | Oxidation of organics by intermediates of water discharge on IrO2 and synthetic diamond anodes[END_REF]. Low efficiencies are even more significant with the use of carbon-based materials because during the electrochemical process they can also be electrochemically incinerated (transformed into carbon dioxide) when high voltages are required to oxidize organic pollutants. and/or SnO 2 ) and conductive-diamond electrodes (particularly the boron doped diamond (BDD) electrodes) behave as high-efficiency electrodes for the oxidation of organics.

They promote the mineralization of the organics with an efficiency only limited by mass transport control, and usually very few intermediates are observed during the treatment.

As a consequence, AO, determined mainly on the power required for driving the electrochemical process, can be performed at affordable costs with such electrodes, without the common AOP drawbacks, being considered as a very useful technique [START_REF] Waterston | Electrochemical waste water treatment: Electrooxidation of acetaminophen[END_REF][START_REF] Andrade | On the performances of lead dioxide and boron-doped diamond electrodes in the anodic oxidation of simulated wastewater containing the Reactive Orange 16 dye[END_REF][START_REF] Song | Electrochemical degradation of azo dye C.I. Reactive Red 195 by anodic oxidation on Ti/SnO 2 -Sb/PbO 2 electrodes[END_REF]. Among these electrodes, metal oxides are not stable during polarity reversal, and they can even be continuously degraded during the process, which cause negative influence on the practical application of electrochemical wastewater treatment (such as the occurrence of lead species in the water). For this reason, just conductive-diamond electrodes are being proposed for this application. However, it is important to take into

Anodic oxidation for degradation of analgesic and anti-inflammatory pharmaceuticals

Research on the degradation of pharmaceutical products is still at a very early labscale stage and far from the commercial application. Many studies have focused on the degradation of analgesic and anti-inflammatory pharmaceuticals from synthetic water solutions, trying to increase the knowledge about the fundamentals of the process and in particular about the main intermediates, taking into account that those intermediates can be even more hazardous or persistent that the parent compound.

A pioneering contribution was the oxidation of aspirin with platinum and carbon fiber (modified manganese-oxides) electrodes, looking for a partial degradation of pharmaceutical molecules in order to increase the biodegradability of industrial wastewaters [START_REF] Weichgrebe | Electrochemical oxidation of drug residues in water by the example of tetracycline, gentamicine and aspirin[END_REF].

However, the development of BDD anodes and the huge advantages of this electrode as compared with others [START_REF] Panizza | Oxidation of organic pollutants on BDD anodes using modulated current electrolysis[END_REF] make that most of the works published in the literature have focused on this material (or in the comparison of performance between diamond and other electrodes). A first work reporting the use of anodic oxidation with DD electrodes was done by the rillas' group [START_REF] Brillas | Mineralization of paracetamol in aqueous medium by anodic oxidation with a boron-doped diamond electrode[END_REF] and the focus was on the oxidation of paracetamol (acetaminophen). It was found that anodic oxidation with BDD was a very effective method for the complete mineralization of paracetamol up to The formation of different oxidants was also suggested in rillas's work (Eqs.

(2.8)-(2.10)). As stated in other works, the effect of these oxidants is very important but contradictory: they are less powerful than hydroxyl radicals; however, their action is not limited to the nearness of the electrode surface but to the whole volume of reaction. This helps to understand that their effect on the whole process efficiency is very important and that it is indirectly related to the production of hydroxyl radicals on the surface of anode during anodic oxidation processes.

In all cases, chloride ion was released to the medium during the electrolysis of diclorofenac. This behavior seems to be characteristic of electrochemical treatment of chlorinated-organics and it is very important because hazardousness of the nonchlorinated intermediates is usually smaller than those of the parent compounds. Thus, dechlorination has been found in the literature to be characteristic of many anodic oxidation treatments of wastewaters [START_REF] Merica | Electrochemical reduction and oxidation of DDT[END_REF]124], although it is normally explained in terms of a cathodic reduction of the organic rather than by anodic processes.

The anodic oxidation of diclorofenac with BDD was also studied by Zhao et al. [START_REF] Zhao | Electro-oxidation of diclofenac at boron doped diamond: Kinetics and mechanism[END_REF]. Results showed that with 30 mg L -1 initial concentration of diclofenac, anodic oxidation was effective in inducing the degradation of diclofenac and degradation increased with increasing applied potential. Mineralization degree of 72% of diclofenac was achieved after 4 h treatment with the applied potential of 4.0 V. The addition of NaCl produced some chlorination intermediates as dichlorodiclofenac and led to a less efficient decrease in the mineralization. Regarding mechanisms, it was proposed that oxidative degradation of diclofenac was mainly performed by the active radicals produced in the anode with the application of high potential. At the low applied potential, direct electro-oxidation of diclofenac did not occur although there was observed an anode oxidation peak in the cyclic voltammetry curve. The main intermediates including 2,6-dichlorobenzenamine (1), 2,5-dihydroxybenzyl alcohol (2), benzoic acid (3) and 1-(2,6-Dichlorocyclohexa-2 4-dienyl) indolin-2-one (4) were identified. These aromatic intermediates were oxidized gradually with the extension of reaction time, forming small molecular acids. The proposal degradation pathway of diclofenac (Fig. 2.4) was provided. Another interesting comparative work was done by Murugananthan et al. [START_REF] Murugananthan | Anodic oxidation of ketoprofen-An anti-inflammatory drug using boron doped diamond and platinum electrodes[END_REF].

The studies of anodic oxidation with BDD or Pt electrodes on ketoprofen revealed that ketoprofen was oxidized at 2.0 V by direct electron transfer and the rate of oxidation was increased by increasing the current density, although the mineralization current efficiency dropped, which was better at lower current density at 4.4 mA cm -2 . This behavior was the same observed by Brillas with diclorofenac and paracetamol [START_REF] Brillas | Mineralization of paracetamol in aqueous medium by anodic oxidation with a boron-doped diamond electrode[END_REF][START_REF] Brillas | Electrochemical incineration of diclofenac in neutral aqueous medium by anodic oxidation using Pt and boron-doped diamond anodes[END_REF], and it could be explained in terms of a mass transfer control of the process. Thus, the degradation of ketoprofen was found to be current controlled at initial phase and became diffusion controlled process beyond 80% of TOC removal. The importance of the electrolyte was also assessed in this study. It was found that TOC removal was much higher with electrolytes containing sulfates, suggesting an important role of mediated oxidation. Figure 2 (Adapted from ref [START_REF] Murugananthan | Anodic oxidation of ketoprofen-An anti-inflammatory drug using boron doped diamond and platinum electrodes[END_REF] with permission of copyright 2010 Elsevier).

Comparing the performance of both electrodes, as expected, BDD is always more efficient than Pt. However, it was found that the initial rate of mineralization was better on Pt anode compared to BDD in the presence of NaCl although a significant concentration of refractory compounds were found with the Pt anodic oxidation and at larger oxidation times mineralization obtained by BDD are clearly better.

The negative effect of chloride observed for the degradation of ketoprofen with BDD anode was also observed by Zhao et al. ([125]) for diclofenac degradation with Chapter 2: Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes. A review

31

BDD electrode in aqueous solution. This observation is important because chlorides are known to be electrochemically oxidized to hypochlorite, which may act as an oxidation mediator.

Cl -+ H 2 O  HClO + H + + 2e - (2.17)

However, the lower efficiency obtained in that media suggest that these oxidants are not very efficient. This can be easily explained taking into account that the final product in the oxidation of chlorides with BDD is not hypochlorite but perchlorate [START_REF] Sánchez-Carretero | Electrochemical production of perchlorates using conductive diamond electrolyses[END_REF].

The formation of these species can be explained in terms of the oxidation of chloride

ClO 3 -+  OH •  ClO 4 -+ H + + e - (2.21)
The oxidation of ketoprofen using anodic oxidation with BDD electrodes was also studied by Domínguez et al. [START_REF] Domínguez | Anodic oxidation of ketoprofen on boron-doped diamond (BDD) electrodes. Role of operative parameters[END_REF]. In that work, experiments were designed not to assess the mechanisms of the process but to optimize the process and study the interaction between the different operative parameters. Accordingly, from the significance statistical analysis of variables carried out, it was demonstrated that the most significant parameters were current intensity, supporting electrolyte concentration and flow rate. The influence of pH was very small. This marks the importance of mass transfer control in these processes, influenced by current density and flow rate, in particular taking into account the small concentrations assessed. It also shows the significance of mediated oxidation processes, which are largely affected by the supporting electrolyte concentration. More recently, Loaiza-Ambuludi et al. [START_REF] Ambuludi | Kinetic behavior of anti-inflammatory drug ibuprofen in aqueous medium during its degradation by electrochemical advanced oxidation[END_REF] reported the efficient degradation of ibuprofen reaching almost total mineralization degree of 96% using BBB anode. In addition to the determination of second order rate constant k 2 = 6.41 x 10 9 L mol -1 s -1 , by competitive kinetic method, four aromatic intermediates (i.e. p-benzoquinone, 4-isobutyhlphenol, 1-(1-hydroxyethyl)-4isobutylbenzene, and 4-isobuthylacetophenone) were detected by GC-MS analysis from treated solution.

Chapter 2: Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes. A review

32

A last comparative work on the anodic oxidation of analgesic and antiinflammatory pharmaceuticals in synthetic water solutions was done by Ciríaco et al. [START_REF] Ciríaco | Electrochemical degradation of Ibuprofen on Ti/Pt/PbO2 and Si/BDD electrodes[END_REF]. In this case, two electrodes with an expected high efficiency in the removal of organics (BDD and Ti/Pt/PbO 2 ) were compared for the treatment of ibuprofen at room temperature under galvanostatic conditions. As expected, results showed a very good efficiency, with removals of COD between 60% and 95% and mineralization (TOC removal) varying from 48 to 92%, in 6 h experiments. The efficiency was found to be slightly higher with BDD at lower current density and similar for both anodes at 30 mA cm -2 .

Enhancement of the degradation of analgesic and anti-inflammatory pharmaceuticals by photoelectrochemical processes

As stated before, most of the research works published in the recent years focused on the assessment of electrochemical technologies with synthetic solutions which contain much higher concentration of analgesic and anti-inflammatory pharmaceuticals than those in which they are found in the environment and that are only representative of industrial flow. Hence a typical concentrations found in those assessments are within the range 1-100 mg organic L -1 which are several folds above the typical value found in a wastewater or in a water reservoir. This means that although conclusions about mineralization of the analgesic and anti-inflammatory pharmaceuticals and intermediates are right, mass transfer limitations in anodic oxidation processes will be more significant in the treatment of an actual wastewater and, even more, in the treatment of actual ground or surface water. Consequently, current efficiencies will be significantly lower than those reported in literature due to the smaller organic load. This effect of the concentration of pollutant was clearly shown in the treatment of RO concentrates generated in WWTPs [START_REF] Pérez | Electro-oxidation of reverse osmosis concentrates generated in tertiary water treatment[END_REF], and it has been assessed in many papers about other pharmaceutical products [START_REF] Martín De Vidales | Metoprolol abatement from wastewaters by electrochemical oxidation with boron doped diamond anodes[END_REF][135][START_REF] Martín De Vidales | Removal of sulfamethoxazole from waters and wastewaters by conductive-diamond electrochemical oxidation[END_REF], in which it is shown the effect of the concentration during the anodic oxidation of solutions of organics covering a range of initial concentrations of 4 orders of magnitude. In these papers, it has been observed that the same trends are reproduced within the four ranges of concentration without significant changes, except for the lower charges required to attain the same change for the smaller concentrations. This observation confirms that some of conclusions obtained in the more concentrated range of concentrations can be extrapolated to other less concentrated ranges of concentrations in the removal of pharmaceutical products.

Chapter 2: Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes. A review 33

The expected effect of mass transfer limitations on the efficiency of this processes (and hence on the economy) made researchers look for improvements of the anodic oxidation processes. Thus, an additional improvement in the results attained by anodic oxidation is obtained when light irradiation or ultrasounds are coupled to the anodic oxidation. In the first case, it is due to the promotion of the formation of hydroxyl radicals; in the second one, it is because of the enhancement of additional mass transfer.

To the author's knowledge, no works have been found regarding the removal of antiinflammatory and analgesic drugs by sono-enhanced anodic oxidation, although this technique seems to obtain great advantages in the destruction of other emerging pollutants [START_REF] Martín De Vidales | Removal of sulfamethoxazole from waters and wastewaters by conductive-diamond electrochemical oxidation[END_REF].

Regarding photo-electrochemical processes, some pioneering works have been published. For improving the efficiency of anodic oxidation, Zhao et al. [START_REF] Zhao | Photoelectrochemical degradation of anti-inflammatory pharmaceuticals at Bi2MoO6-boron-doped diamond hybrid electrode under visible light irradiation[END_REF], deposited Bi 2 MoO 6 onto a BDD surface to assess the degradation of ibuprofen and naproxen.

Anodic oxidation was performed in a cylindrical quartz reactor, in which the solution was irradiated with a 150W Xe lamp (wavelength above 420 nm). Further examples of the anodic oxidation application for the removal of NSAIDs are depicted in table 2.4.

Application of anodic oxidation for the removal of pharmaceuticals from aqueous systems

From the results obtained in the works described above, it can be stated that anodic oxidation is a very promising technology for the removal of analgesic and antiinflammatory pharmaceuticals from water, in particular when using BDD electrodes.

There is a strong influence of the supporting electrolyte, which account for the significance of mediated oxidative processes. The significant reduction in the hazard of the intermediates caused by dechlorination (most likely caused by a cathodic reduction process) seems to be also a good feature of the technology. The weak point of this research is the high concentrations of organics tested, far away from the concentration levels measured in a typical wastewater or in a water reservoir, but it should be taken into account that research is not focused on real applications but on a preliminary assessment of the technology.

Although some studies of oxidative degradation were carried out on different pharmaceuticals by various AOPs [START_REF] Lee | Kinetics of the Oxidation of Phenols and Phenolic Endocrine Disruptors during Water Treatment with Ferrate (Fe(VI))[END_REF][START_REF] Chowdhury | Sonochemical degradation of chlorinated organic compounds, phenolic compounds and organic dyes -A review[END_REF], few studies have been done regarding the removal of analgesic and anti-inflammatory pharmaceuticals from water in actual matrixes. Initially, strong differences are expected because of the different range of concentration and the huge influence of the media composition [START_REF] Rodrigo | Electrochemical technologies for the regeneration of urban wastewaters[END_REF]. Regarding this fact, there is a very interesting work about the application of anodic oxidation with BDD anodes for the treatment of reverse osmosis (RO) concentrates generated in WWTPs [START_REF] Pérez | Electro-oxidation of reverse osmosis concentrates generated in tertiary water treatment[END_REF]. In this study, a group of 10 emerging pollutants (including two analgesic and Chapter 2: Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes. A review 35 min -1 . Emerging pollutants contained in the concentrates were almost completely removed, with removal percentages higher than 92% in all the cases after 2 h oxidation.

Other interesting work [START_REF] Domínguez | Electrochemical Degradation of a Real Pharmaceutical Effluent[END_REF] was not focused on the treatment of urban wastewaters but on the treatment of an actual industrial wastewater produced in a pharmaceutical company. This wastewater had a concentration as high as 12000 ppm COD and consisted of a mixture of different solvents and pharmaceutical species.

Results demonstrate that complete mineralization of the wastewater can be obtained using proper operation conditions, showing the good prospects of this technology in actual matrix when using BDD anodes. However nothing was stated about cost, which is a very important point for the future application of this technology. This has been clearly stated for other technologies such as photocatalytic reactor membranes, nonthermal plasma advanced oxidation process [START_REF] Benotti | Evaluation of a photocatalytic reactor membrane pilot system for the removal of pharmaceuticals and endocrine disrupting compounds from water[END_REF] and ozone, O 3 /H 2 O 2 [START_REF] Gerrity | An evaluation of a pilotscale nonthermal plasma advanced oxidation process for trace organic compound degradation[END_REF] and UV/H 2 O 2 [START_REF] Katsoyiannis | Efficiency and energy requirements for the transformation of organic micropollutants by ozone, O 3 /H 2 O 2 and UV/H 2 O 2[END_REF]. Regarding this point, it is worth to take into account another work [146] that assessed the operating and investment cost for three different AOP (Fenton, Ozonation and Anodic Oxidation) applied in the treatment of many types of wastewater.

This work was not focused on wastewater produced in pharmaceutical industries but it assesses others with a similar behavior. Results showed that from the mineralization capability, anodic oxidation clearly overcomes ozonation and Fenton because it was the only technology capable to abate the organic load of the wastewater studied down to almost any range of concentration while the other technologies lead to the formation of refractory COD. However, within the range of concentrations in which the three technologies can be compared, Fenton oxidation was the cheaper and ozonation was much more expensive than anodic oxidation. This means that anodic oxidation could compete with them in many actual applications and that scale-up studies is a very interesting hot topic now to clarify its potential applicability.

Another interesting work on applicability of anodic oxidation [START_REF] Rodrigo | Use of conductivediamond electrochemical oxidation for wastewater treatment[END_REF] make a critical analysis of the present state of the technology and it clearly states the range of concentrations in which this technology is technically and economically viable and give light on other possible drawbacks which can be found in scale-up assessments. It is also important to take into account that energy supply to electrochemical systems can be easily made with green energies and this has a clear influence on operating cost as it was recently demonstrated for anodic oxidation [START_REF] Valero | Electrochemical Wastewater Treatment Directly Powered by Photovoltaic Panels: Electrooxidation of a Dye-Containing Wastewater[END_REF].

Regarding other applications of anodic oxidation, and although it is not the aim of this review, it is important to mention analytical methods. Over the last years, electrode [148], piroxicam with glassy carbon anode [START_REF] Shahrokhian | Electrochemical determination of piroxicam on the surface of pyrolytic graphite electrode modified with a film of carbon nanoparticle-chitosan[END_REF], mefenamic acid, diclofenac, and indomethacin with alumina nanoparticle-modified glassy carbon electrodes [START_REF] Hajjizadeh | Electrocatalytic oxidation of some anti-inflammatory drugs on a nickel hydroxidemodified nickel electrode[END_REF],

aspirin with cobalt hydrotalcite-like compound modified Pt electrodes [START_REF] Gualandi | Electrocatalytic oxidation of salicylic acid by a cobalt hydrotalcite-like compound modified Pt electrode[END_REF], aspirin and acetaminophen with cobalt hydroxide nanoparticles modified glassy carbon electrodes [START_REF] Houshmand | Electrocatalytic oxidation of aspirin and acetaminophen on a cobalt hydroxide nanoparticles modified glassy carbon electrode[END_REF], mefenamic acid, diclofenac, and indomethacin with alumina nanoparticlemodified glassy carbon electrodes [START_REF] Mahla Tabeshnia | Electro-oxidation of some non-steroidal anti-inflammatory drugs on an alumina nanoparticle-modified glassy carbon electrode[END_REF], mefenamic acid and indomethacin with cobalt hydroxide modified glassy carbon electrodes [START_REF] Saghatforoush | Kinetic Study of the Electrooxidation of Mefenamic Acid and Indomethacin Catalysed on Cobalt Hydroxide Modified Glassy Carbon Electrode[END_REF].

Chapter 2: Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes. A review 37 but a very different one at 30 mA cm -2 ; BDD has a slightly higher combustion efficiency at lower current density and equal to 100%

for both anodes at 30 mA cm -2 .

[132] Chapter 2: Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes. A review 43

Electro-Fenton process

Electro-Fenton (EF) process, which can be defined as electrochemically assisted Fenton's process, is one of the most popular techniques among EAOPs. A suitable cathode applied to be fed with O 2 or air reduces dioxygen to superoxide ion (O 2 -), leading to the formation of H 2 O 2 continuously in an acidic medium (Eq. (2.22)).

Catalysts such as Fe 2+ , Fe 3+ , or iron oxides react with H 2 O 2 (Eq. (2.23)), following Fenton's reaction to yield  OH radicals. Fe 3+ ions produced by Fenton's reaction are electrochemically reduced to Fe 2+ ions (the Fe 3+ /Fe 2+ electrocatalytic system), which catalyze the production of  OH from Fenton's reaction [START_REF] Brillas | Electro-Fenton process and related electrochemical technologies based on Fenton's reaction chemistry[END_REF][START_REF] Oturan | An ecologically effective water treatment technique using electrochemically generated hydroxyl radicals for in situ destruction of organic Chapter 2: Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes. A review 68 pollutants: Application to herbicide 2,4-D[END_REF]. On the other hand, molecular oxygen can also be produced in the anodic compartment simply by the oxidation of water with Pt or other low O 2 overvoltage anodes (Eq. (2.25)). the maximum  OH production rate in the bulk [START_REF] Oturan | Oxidative degradation of herbicide diuron in aqueous medium by Fenton's reaction based advanced oxidation processes[END_REF][START_REF] Sirés | Catalytic behavior of the Fe3+/Fe2+ system in the electro-Fenton degradation of the antimicrobial chlorophene[END_REF] and consequently pollutant removal efficiency.

O 2 (g) + 2H + + 2e - → H 2 O 2 E 0 = 0.695 V/SHE (2.22) Fe 2+ + H 2 O 2 + H + → Fe 3+ + H 2 O +  OH (2.23) Fe 3+ + e - → Fe 2+ E 0 = 0.77 V/SHE (2.24) H 2 O → 1/2 O 2 + 2H + + 2e - E 0 = 1.23 V/SHE (2.
Three and two-electrode divided and undivided electrolytic cells are chosen to utilize in EF process. Cathode materials are mostly carbon-felt [START_REF] Pimentel | Phenol degradation by advanced electrochemical oxidation process electro-Fenton using a carbon felt cathode[END_REF] or gas diffusion Chapter 2: Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes. A review 44 electrodes (GDEs) [START_REF] Agladze | Comparative study of hydrogen peroxide electro-generation on gas-diffusion electrodes in undivided and membrane cells[END_REF], however other materials such as graphite [START_REF] Wang | Removal of color from real dyeing wastewater by Electro-Fenton technology using a three-dimensional graphite cathode[END_REF], reticulated vitreous carbon (RVC) [START_REF] Xie | Interactive oxidation of photoelectrocatalysis and electro-Fenton for azo dye degradation using TiO 2 -Ti mesh and reticulated vitreous carbon electrodes[END_REF], activated carbon fiber (ACF) [START_REF] Wang | Mineralization of an azo dye Acid Red 14 by electro-Fenton's reagent using an activated carbon fiber cathode[END_REF], and carbon nanotubes (NT) [START_REF] Ai | Electro-Fenton Degradation of Rhodamine B Based on a Composite Cathode of Cu2O Nanocubes and Carbon Nanotubes[END_REF] are also studied. The classical anode is Pt while metal oxides, such as PbO 2 [START_REF] Guivarch | Degradation of azo dyes in water by Electro-Fenton process[END_REF], SnO 2 [START_REF] Fockedey | Coupling of anodic and cathodic reactions for phenol electro-oxidation using three-dimensional electrodes[END_REF], DSA [START_REF] Brillas | Aniline degradation by Electro-Fenton® and peroxicoagulation processes using a flow reactor for wastewater treatment[END_REF] (mixed metal oxide anodes) were also employed in EF processes. Recently the BDD anode reveled to have better characteristics as anode material, therefore BDD is usually chosen as anode materials [START_REF] Panizza | Application of boron-doped diamond electrodes for wastewater treatment[END_REF].

The significant enhancement of electro-Fenton process has been achieved in the replacement of the classical anode Pt by the emergent anode BDD. Except the generation of supplementary heterogeneous hydroxyl radicals, BDD(  OH) could provide additional homogeneously  OH in bulk solution (Eq. ( 2.

3)). The extra advantages of application of BDD in the treatment are: i) higher oxidizing power of BDD(  OH) than others M(  OH) for its larger O 2 overvoltage (Eq. (2.4)); ii) high oxidation window (about 2.5 V) makes it oxidizing the organics directly.

The usual application of EF in experiment can be seen in Fig. 2.6a.

Electro-Fenton process was successfully applied to removal of organic pollutants from water with high oxidation and/or mineralization rates, mainly by Oturan's and Brillas' groups. The removal from water of several organic pollutants such as pesticide active ingredients [START_REF] Oturan | Degradation of chlorophenoxyacid herbicides in aqueous media, using a novel electrochemical method †[END_REF][167][START_REF] Özcan | Removal of Acid Orange 7 from water by electrochemically generated Fenton's reagent[END_REF][START_REF] Da Pozzo | Removal of the herbicide amitrole from water by anodic oxidation and electro-Fenton[END_REF][170], pesticide commercial formulations [START_REF] Abdessalem | Treatment of a mixture of three pesticides by photo-and electro-Fenton processes[END_REF], synthetic dyes [START_REF] Guivarch | Degradation of azo dyes in water by Electro-Fenton process[END_REF][START_REF] Losito | Electro-Fenton and photocatalytic oxidation of phenyl-urea herbicides: An insight by liquid chromatography-electrospray ionization tandem mass spectrometry[END_REF][START_REF] Garcia-Segura | Comparative decolorization of monoazo, diazo and triazo dyes by electro-Fenton process[END_REF][START_REF] Panizza | Degradation of Alizarin Red by electro-Fenton process using a graphite-felt cathode[END_REF], pharmaceuticals [START_REF] Sires | Remediation of water pollution caused by pharmaceutical residues based on electrochemical separation and degradation technologies: A review[END_REF][START_REF] Sirés | Catalytic behavior of the Fe3+/Fe2+ system in the electro-Fenton degradation of the antimicrobial chlorophene[END_REF]175,[START_REF] Dirany | Electrochemical Treatment of the Antibiotic Sulfachloropyridazine: Kinetics, Reaction Pathways, and Toxicity Evolution[END_REF], industrial pollutants [START_REF] Bellakhal | Olive Oil Mill Wastewater Treatment by the Electro-Fenton Process[END_REF],

landfill leachates [START_REF] Wang | Electro-Fenton treatment of concentrates generated in nanofiltration of biologically pretreated landfill leachate[END_REF]179], etc., was thoroughly studied with almost mineralization efficiency in each case, showing that the electro-Fenton process can be an alternative when conventional treatment processes remain inefficient. Reprinted with permission from ref [START_REF] Brillas | Aniline degradation by Electro-Fenton® and peroxicoagulation processes using a flow reactor for wastewater treatment[END_REF]. Copyright 2002 Elsevier.

1 Application to the removal of NSAIDs

Although the electro-Fenton process has been successfully applied to the treatment of a very large group of organic pollutants during the last decade, studies on NSAIDs are scarce, unlike the anodic oxidation process. Preliminary work dealing with the electro-Fenton process on pharmaceutical residues was started by Oturan et al. using a divided cell with a mercury pool as cathode under air bubbling [START_REF] Oturan | Reaction of inflammation inhibitors with chemically and electrochemically generated hydroxyl radicals[END_REF][START_REF] Oturan | Hydroxylation by Electrochemically Generated OH.bul. Radicals. Mono-and Polyhydroxylation of Benzoic Acid: Products and Isomer Distribution[END_REF] Reactivity of several NSAIDs, including, among others, salicylic acid (aspirin), ketoprofen, diclofenac, naproxen, sulindac, and proxicam with electrochemically generated  OH was investigated at pH 4 and 7 showing that all NSAID tested behave as  OH scavengers with high reactivity, rate relative constant of the reaction between NSAIDs and  OH ranging between 1.0 -1.9 times compared that of salicylic acid (k = 2.2 x 10 10

L mol -1 s -1 ) [START_REF] Benotti | Evaluation of a photocatalytic reactor membrane pilot system for the removal of pharmaceuticals and endocrine disrupting compounds from water[END_REF].

These studies investigated also the product distribution of salicylic acid, showing that the main reaction was the successive hydroxylation of parent molecule leading to the formation of 2,3-, 2,4-, 2,5-and 2,6-dihydroxybenzoic acids, 2,3,4-, 2,3,5-and 2,4,6-trihydroxybenzioic acids, the major hydroxylation products being the 2,3dihydroxybenzoic acid (35%) and 2,5-dihydroxybenzoic acid (10%). Determination of rate constants of formed hydroxylated derivatives of salicylic acid showed that they are more or as well as reactive than the parent molecule; for example the rate constant of hydroxylation of 2,4,6-trihydroxybenzoic acid was found three time higher than that of salicylic acid. These findings showed that hydroxylated products are able to react with  OH until oxidative breaking of aromatic ring leading to the formation of short-chain carboxylic acids which can be mineralized in their turn by further reactions with  OH.

As regards the ketoprofen, three hydroxylated derivatives (2-hydroxy, 3'-hydroxy and 4'-hydroxy ketoprofene) are found as main oxidation products.

Chapter 2: Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes. A review 46

More recently, Brillas' group carried out a number of reports on the electro-Fenton treatment of several pharmaceuticals and in particular some NSAIDs such as paracetamol [START_REF] Sirés | Paracetamol Mineralization by Advanced Electrochemical Oxidation Processes for Wastewater Treatment[END_REF][START_REF] Sires | Electrochemical degradation of paracetamol from water by catalytic action of Fe2+, Cu2+, and UVA light on electrogenerated hydrogen peroxide[END_REF], salicylic acid [START_REF] Guinea | Mineralization of salicylic acid in acidic aqueous medium by electrochemical advanced oxidation processes using platinum and boron-doped diamond as anode and cathodically generated hydrogen peroxide[END_REF] and ibuprofen [START_REF] Skoumal | Electro-Fenton, UVA photoelectro-Fenton and solar photoelectro-Fenton degradation of the drug ibuprofen in acid aqueous medium using platinum and borondoped diamond anodes[END_REF], using undivided cell equipped with a GDE as cathode, the anode being Pt or BDD. Results on oxidation kinetics and mineralization power of the process confirm the superiority of BDD compared to Pt as anode in all cases. Higher removal rates were obtained as the current density increased due to the enhancement of generation rate of homogeneous (  OH produced in the bulk) and heterogeneous (BDD(  OH) generated at the anode surface) hydroxyl radicals. Almost total mineralization was found for paracetamol, salicylic acid and ibuprofen with BDD anode while mineralization efficiency remained low with Pt anode confirming the interest of the BDD anode as a better alternative in electro-Fenton process. The mixture of Fe 3+ and Cu 2+ as catalyst was found to have positive synergetic effect on mineralization degree.

Electro-Fenton related processes

EF lays the foundation for a large variety of related processes, which aim at minimizing or eliminating the drawbacks of individual techniques or enhancing the efficiency of the EF process by coupling with other methods, including UV-irradiation combined technologies, like photoelectro-Fenton (PEF) [START_REF] Brillas | Aniline mineralization by AOP's: anodic oxidation, photocatalysis, electro-Fenton and photoelectro-Fenton processes[END_REF] and solar photoelectro-Fenton (SPEF) [START_REF] Almeida | Solar photoelectro-Fenton degradation of paracetamol using a flow plant with a Pt/air-diffusion cell coupled with a compound parabolic collector: Process optimization by response surface methodology[END_REF]; coagulation involved methods as peroxi-coagulation (PC) [START_REF] Brillas | Aniline degradation by Electro-Fenton® and peroxicoagulation processes using a flow reactor for wastewater treatment[END_REF] ;

UV-irradiation with coagulation (photoperoxi-coagulation (PPC)) [START_REF] Brillas | Peroxi-coagulation and photoperoxi-coagulation treatments of the herbicide 4-chlorophenoxyacetic acid in aqueous medium using an oxygen-diffusion cathode[END_REF]; and ultrasonic coupled with electro-Fenton (sonoelectro-Fenton (SEF)) [START_REF] Guivarch | Degradation of azo dyes in water by Electro-Fenton process[END_REF]. There are other combined Fenton processes as Fered-Fenton [START_REF] Zhang | Oxidation and coagulation removal of COD from landfill leachate by Fered-Fenton process[END_REF], electrochemical peroxidation (ECP)

[189], anodic Fenton treatment (AFT) [START_REF] Hong | Degradation of methyl tertiary-butyl ether (MTBE) by anodic Fenton treatment[END_REF], and plasma-assisted treatments [START_REF] Ghezzar | Enhancement of the bleaching and degradation of textile wastewaters by Gliding arc discharge plasma in the presence of TiO2 catalyst[END_REF].

Electrocoagulation and internal micro-electrolysis processes can be applied as pretreatments to deal with high organic loads, are the most straightforward and cheap ones, while Photoelectrocatalysis (PEC) and plasma technologies are complex and need expensive accessories [START_REF] Brillas | Electro-Fenton process and related electrochemical technologies based on Fenton's reaction chemistry[END_REF]. and solar irradiation by the rapid photodecomposition of complexes of Fe (III) with acidic intermediates. SPEF with BDD was the most potent method, giving 92% mineralization with a small proportion of highly persistent final by-products formed during the process preventing total mineralization. Higher mineralization with BDD than Pt means the use of a BDD anode instead of Pt yielded much more oxidation power in this procedure. The decay of ibuprofen followed a pseudo-first-order kinetics by using BDD (  OH), Pt (  OH) and/or  OH formed homogeneously in the bulk, and current density and UV intensity influenced significantly its destruction rate.

The author of this study identified aromatic intermediates (Fig. 2.7), such as 1-(1hydroxyethyl)-4-isobutylbenzene, 4-isobutylacetophenone, 4-isobutylphenol and 4ethylbenzaldehyde. The carboxylic acids such as pyruvic, acetic, formic and oxalic were identified as oxidation by-products. Oxalic acid was the ultimate by-product and the fast photo decarboxylation of its complexes with Fe(III) under UVA or solar irradiation contributes to high mineralization rate. The operational factor, as Fe 2+ content, pH and current density on PEF degradation also had been studied. For the SPEF degradations, the best operating conditions were achieved using Fe 2+ between 0.2 and 0.5 mM, pH 3.0 and low current density. Thus, during the SPEF-BDD treatment of ibuprofen, 86% mineralization in 3 h was achieved at solution close to saturation with 0.5 mM Fe 2+ and 0.05 M Na 2 SO 4 at pH 3.0 and 6.6 mA cm -2 with an energy cost as low as 4.3 kW hm -3 . With the results obtained, PEF methods have the higher oxidation power in comparison to EF process in the case of gas diffusion cathode.

CH 3 O O H CH 3 CH 3 CH 3 O O H CH 3 CH 3 O H O CH 3 CH 3 O H CH 3 CH 3 CH 3 O CH 3 CH 3 OH CH 3 CH 3 CH 3 CH 3 O OH C H 3 OH O H O H O H O H O H O H hv -CO 2 -CH 3 -CHOH-CH 3 -CH 3 -COOH hv -CO 2 2-[4-(1-hydroxyisobutyl)phenyl]propionic acid 4-ethylbenzaldehyde Iburofen 2-(4-isobutylphenyl)- 2-hydroxypropionic acid 1-(1-hydroxyethyl)- 4-isobutylbenzene 4-isobutylacetophenone 4-isobutylphenol
Fenton and electro-Fenton processes treatment on paracetamol was investigated by application of anodes as mesh-type titanium metal coated with IrO 2 /RuO 2 and cathodes as stainless steel. The effect of operating parameters on degradation were investigated and compared; Fe 2+ concentration had great influence on the degradation rate, followed by H 2 O 2 concentration and pH [START_REF] Zhang | Oxidative removal of acetaminophen using zero valent aluminum-acid system: Efficacy, influencing factors, and reaction mechanism[END_REF].

The opposite result was obtained that electro-Fenton treatment of paracetamol was more efficient than the photoelectro-Fenton method in wastewater, though the differences of removal efficiencies are negligible [START_REF] De Luna | Acetaminophen degradation by electro-Fenton and photoelectro-Fenton using a double cathode electrochemical cell[END_REF]. Considering the energy consumption (additional UVA irradiation for PEF), the electro-Fenton processes are more suitable and economical. The processes were designed by using a double cathode electrochemical cell, and the results showed that initial Fe 2+ concentration, H 2 O 2 concentration and applied current density all positively affected the degradation efficiency while Fe 2+ concentration has most significant influence on the efficiency. The removal efficiency of paracetamol was all above 97% and COD removal above 42% for both methods operated at optimum conditions.

Finally a degradation pathway was proposed. Hydroquinone and amide were produced by  OH attack in the para position. The amide is further degraded till finally turned into nitrates. On the other hand, the hydroquinone is converted into benzaldehyde which oxidized to benzoic acid, following further degradation into short chain carboxylic acids (Fig.

H 2 O + ))) →  OH + H + (2.26)
Chapter 2: Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes. A review 50 where ))) denotes the ultrasonic irradiation. Simultaneously  OH is produced in the medium by electro-Fenton process via electrochemically induced Fenton's reaction.

There are more interests in the development on this technique [START_REF] Bringas | Kinetics of ultrasound-enhanced electrochemical oxidation of diuron on boron-doped diamond electrodes[END_REF][START_REF] Sillanpää | Ultrasound Technology in Green Chemistry[END_REF].

Fered-Fenton process is another one of the Fenton family methods, in which both H 2 O 2 and Fe 2+ are simultaneously added to the solution. Unlike the electro-Fenton process, Fenton's reagent is externally added to the solution to be treated; nevertheless Fenton reaction is catalysed electrochemically by regeneration of Fe 2+ ion (catalyst).

The Fenton reaction takes place with the production of  OH and Fe 3+ ions (Eq. (2.23)).

Formed Fe 3+ is cathodically reduced to Fe 2+ (Eq. (2.24)) in order to catalyse Fenton's reaction [START_REF] Liu | Ferric Reduction and Oxalate Mineralization with Fered-Fenton Method[END_REF][START_REF] Huang | Comparison of a novel electro-Fenton method with Fenton's reagent in treating a highly contaminated wastewater[END_REF][START_REF] Zhang | Removal of COD from landfill leachate by electro-Fenton method[END_REF]. The oxidation can be also occurred at anode when the adequate is selected. ECP process combined with a more inexpensive biological treatment in practical application can reduce the toxicity of suspended solids and effluent, improving the quality of the treated water for potential reuse. A practical application of electrochemical process on wastewater treatment plants [START_REF] Oller | Combination of Advanced Oxidation Processes and biological treatments for wastewater decontamination-A review[END_REF] was performed as pre- From the results, electrolysis led to a decrease of the toxicity EC 50 value and an increase of biodegradability; during activated sludge culture, an almost total mineralization of the electrolyzed solution was recorded. It was noticed that the high cathodic potential used made another reduction occur; the reduction of water could lead to hydrogen production. The faradic yield was therefore very low (below 10%) and can be less cost effective. For this purpose, application of higher hydrogen overvoltage electrolytes, the optimization of flow rate in the percolation cell as well as the thickness of the graphite felt and reuse of the acclimated activated sludge for successive experiments could be helpfully considered to enhance the efficiency and reduce the process duration; all of these work will be helpful as a guide for the treatment of real polluted wastewater afterwards.

M + H 2 O → M (  OH) + H + +
To the best of our knowledge, there are no detailed studies on economic assessment of this technology taking into account operating and investment cost that permitting to compare with other AOPs. However, a recent work conducted by one of the author of this paper [200] focused on the mineralization of a synthetic solution of the pharmaceutical tetracycline by EF process, showed that the operating electrical energy consumption is significantly lower compared to that obtained in other assessments done in the recent literature for other EAOPs. Thus, the 1.1 kWh/g TOC removed obtained

Chapter 2: Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes. A review 52

for the removal of tetracycline during electro-Fenton treatment compares favorably with the 1.8 kW h/g TOC obtained in the degradation of a dye with anodic oxidation [START_REF] Socha | Electrochemical and photoelectrochemical degradation of direct dyes[END_REF] and with the 2.9 or 2.2 kW h/g TOC removed obtained in the removal of phenol by a single electrochemical and an photoelectrochemical process, respectively, in very similar conditions (range of concentration of pollutant) [START_REF] Zhang | Degradation of phenol by a combined independent photocatalytic and electrochemical process[END_REF].

Conclusions and suggestions for future research

A large part of the pharmaceuticals is excreted in original form or metabolite into environment due to the low removal efficiency of standard WWTPs on such compounds.

This combined with the special effects of pharmaceuticals on target even unintended organisms at low doses, makes it urgent to develop more efficient technologies for their elimination.

AOPs, designed to eliminate in source persistent or toxic organic xenobiotic present in small volumes, avoiding their release into the natural water streams and could be applied for treating pharmaceutical residues and pharmaceutical wastewaters. Indeed, the application of typical AOPs would become technically and economically difficult or even impossible once the environmentally dangerous persistent organic pollutants are diluted in large volumes. However, with the advanced feature and developed improvement, the AOPs and in particular the EAOPs, overcoming the usual reluctance to electrochemistry approach, could be applied as a plausible and reliable alternative promising method to treat pharmaceutical containing wastewaters. In the case of applicability of EAOPs for wastewater volumes EAOPs were successfully used as bench-scale post-treatment to reverse osmosis concentrates [START_REF] Zhou | Degradation of organics in reverse osmosis concentrate by electro-Fenton process[END_REF] or nano-/ultrafiltration concentrates [START_REF] Wang | Electro-Fenton treatment of concentrates generated in nanofiltration of biologically pretreated landfill leachate[END_REF].

In this review, the applicability of EAOPs for the removal of NSAIDs, which are operational as well as the influent parameters, such as: pH, inorganic salts (ions from the supporting electrolyte or already present in wastewater), presence of natural organic matter, catalyst concentration, and temperature on the treatment efficiency. These new tests to be carried out at pilot-scale will determine if lab-scale research can be transposed to pilot-scale to show feasibility of using EAOPs for industrial scale reactor.

In addition, several researchers have interest on the new materials applied to enhance the performance and efficiency of the NSAIDs elimination process. Significant progress has been evidenced from the development of novel electrodes and membranes and the amelioration of the reactor setup. For instance, the use of BDD anode gives high mineralization efficiency when applied under optimal conditions. Process pre-modelling and pollutant behaviour prediction are helpful for the economical and practical application of EAOPs in real wastewater treatment. They can be used to optimize the operational parameters of the process, as pH, current applied, catalyst concentration, UV length, supporting electrolyte, nature of electrode (either cathode or anode material). UVA and solar irradiation applied in electrochemical processes could make the decomposition processes more rapid.

Concerning the economic aspects, cheap source of electrical power by using sunlight-driven systems is considered as an economical application. Combination of other technologies is also practical in industrial treatment, which could provide a significant savings of electrical energy on the overall decontamination process. For example, it has been demonstrated [START_REF] Benotti | Evaluation of a photocatalytic reactor membrane pilot system for the removal of pharmaceuticals and endocrine disrupting compounds from water[END_REF] the feasibility and utility of using an electrooxidation device directly powered by photovoltaic panels to treating a dye-containing wastewater. Further reductions in electrode price and use of renewable energy sources to power the EAOPs will enhance the development of more sustainable water treatment processes.

Chapter 3: Degradation of anti-inflammatory drug ketoprofen by electro-oxidation: comparison of electro-Fenton and anodic oxidation processes 75

Introduction

The non-steroidal anti-inflammatory drugs (NSAIDs) are designed against biological degradation that they can keep their chemical structure long enough to last in environment. A large number of reports revealed their presence and that of their metabolites in the wastewater treatment effluents, surface and ground water, due to their widely use since several decades ago [1][2][3][4]. Some of them are in the high risk that may cause adverse effects on the aquatic ecosystem [5][6][7]. It was shown that prolonged exposure to the chemicals as NSAIDs is expected to affect the organism health [8]. Due to the low removal efficiency of the wastewater treatment plants (WWTPs) on pharmaceuticals compounds, and in particular, NSAIDs accumulated in natural waters [9][10][11].

Ketoprofen, 2-(3-benzoylphenyl) propanoic acid), is categorized as a pharmaceutically active compound. It has high hydrophilic ability due to its pKa (i.e.

4.45), making the elimination on sorption process in WWTPs inefficient; its elimination being mainly dependent to chemical or biological process used [12]. Therefore the removal efficiency of ketoprofen in WWTPs varied from 15 to 98% [11]. The unstable removal rate varies in different treatment plants and seasons, from -very poor‖ to -complete‖, depending strongly on the nature of the specific processes being applied.

Due to the inefficient removal from WWTPs, ketoprofen remains in water stream body at concentration from ng L -1 to g L -1 [13].

Various treatment methods were explored to remove NSAIDs from water, while advanced oxidation processes (AOPs) that involves in situ generation of hydroxyl radicals (  OH) and/or other strong oxidant species, have got more interest as promising powerful and environmentally friendly methods for treating pharmaceuticals and their residues in wastewater [14][15][16]. Among the AOPs, electrochemical advanced oxidation processes (EAOPs), with attractive advantages, being regarded as the most perspective treatments, especially in eliminating the low concentration pollutants [17][18][19][20]. The EAOPs are able to generate the strong oxidizing agent  OH either by direct oxidation of water (anodic oxidation, AO) [21,22], or in the homogeneous medium through electrochemically generated Fenton's reagent (electro-Fenton (EF) process) [17,23].

 OHs thus generated are able to oxidize organic pollutants until their ultimate oxidation state, c.a., mineralization to CO 2 , water and inorganic ions [17,24].

Fe 2+ + H 2 O 2 → Fe 3+ +  OH + OH - (3.3)
One of the main advantages of this process is the electrocatalytic and continues regeneration of ferrous iron ions from Fe 3+ produced by Fenton's reaction according to the following reaction [26]:

Fe 3+ + e -→ Fe 2+ (3.4)
In this work, the degradation of the anti-inflammatory drug ketoprofen was carried out, for the first time, by EAOPS anodic oxidation and electro-Fenton with Pt and BDD anodes. Different operating parameters influencing the oxidation power of the processes and its mineralization efficiency during treatment of ketoprofen aqueous solutions were investigated. Apparent and absolute rate constants of the oxidation of ketoprofen by  OH were determined. The aromatic/cyclic reaction intermediates were identified by HPLC analysis. The formation of short-chain carboxylic acids as endproducts before complete mineralization was monitored by ion exclusion chromatography. Combining by TOC measurements, these data allowed a plausible mineralization pathway for ketoprofen by  OH proposed.

Materials and methods

Chemicals

Chapter 3: Degradation of anti-inflammatory drug ketoprofen by electro-oxidation: comparison of electro-Fenton and anodic oxidation processes Milli-Q-Simplicity 185 system with resistivity > 18 MΩ cm at 25 °C. The pH of solutions was adjusted using analytical grade sulfuric acid or sodium hydroxide (Acros).

Electrochemical cell and apparatus

Experiments were carried out in a 250 mL open, undivided cylindrical glass cell of inner diameter of 7.5 cm at room temperature, equipped with two electrodes. The working electrode (cathode) was a 3D carbon-felt (18.0 cm × 6.0 cm × 0.6 cm, from Carbone-Lorraine) placed on the inner wall of the cell, covering the total internal perimeter. The anode was a 4.5 cm 2 Pt cylindrical mesh or a 24 cm 2 BDD thin-film deposited on both sides of a niobium substrate, centered in the electrolytic cell. 0.05 M Na 2 SO 4 was introduced to the cell as supporting electrolyte. Prior to electrolysis, compressed air at about 1 L min -1 was bubbled for 5 min through the solution to saturate the aqueous solution and reaction medium was agitated continuously by a magnetic stirrer (800 rpm) to make mass transfer to/from electrodes. For the electro-Fenton experiment, the pH of the medium set to 3.0 by using 1.

Analytical measurements

High performance liquid chromatography (HPLC)

The determination of decay kinetics of ketoprofen and identification of its aromatic intermediates, as well as the measure of the absolute rate constants for oxidation of ketoprofen were monitored by high performance liquid chromatography (HPLC) using a Merck Lachrom liquid chromatography equipped with a L-2310 pump, fitted with a reversed phase column Purospher RP-18, 5 m, 25 cm x 4.6 mm (i.d.) at 40°

C and coupled with a L-2400 UV detector selected at optimum wavelengths of 260 nm.

Mobile phase was consisted of a 49:49:2 (v/v/v) methanol/water/acetic acid mixtures at a flow rate of 0.7 mL min -1 . Carboxylic acid compounds produced during the processes were identified and quantified by ion-exclusion HPLC using a Supelcogel H column (φ = 4.6 mm × 25 cm), column at room temperature at = 210 nm. 1% acetic acid solution at a flow rate of 0.2 mL min -1 was performed as mobile phase solution.

In the analysis, all the injection volume was 20 L and measurements were controlled through EZChrom Elite 3.1 software. The identification and quantification of the intermediates were conducted by comparison of the retention time with that of authentic substances.

Total organic carbon (TOC)

The mineralization reaction of ketoprofen by hydroxyl radicals can be written as follows:

C 16 H 14 O 3 + 72  OH → 16 CO 2 + 43 H 2 O (3.5)
The mineralization degree of initial and electrolyzed samples was monitored by the abatement of their total organic carbon content, determined on a Shimadzu VCSH TOC analyzer. The carrier gas was oxygen with a flow rate of 150 mL min -1 . A nondispersive infrared detector, NDIR, was used in the TOC system. Calibration of the analyzer was attained with potassium hydrogen phthalate (99.5%, Merck) and sodium hydrogen carbonate (99.7%, Riedel-de-Haên) standards for total carbon (TC) and inorganic carbon (IC), respectively. Reproducible TOC values with ±1% accuracy were found using the non-purgeable organic carbon method. The mineralization current efficiency (MCE in %) at a given electrolysis time t (h) was calculated according to the following equation [27]:

MCE = n F Vs TOC exp 4.32 ×10 7 m I t ×100 (3.6)
where n is the number of electrons consumed per molecule mineralized [START_REF] Miege | Fate of pharmaceuticals and personal care products in wastewater treatment plants--conception of a database and first results[END_REF], F is the Faraday constant (96487 C mol -1 ), V s is the solution volume (L), (TOC) exp is the experimental TOC decay (mg L -1 ), 4.32×10 7 is a homogenization factor (3600 sh -1 × 12,000 mg mol -1 ), m is the number of carbon atoms of ketoprofen ( 16) and I is the applied total current (0.1-2A).

Toxicity tests

For testing the potential toxicity of ketoprofen and of its reaction intermediates, the measurements were carried out with the bioluminescent marine bacteria Vibrio fischeri (Lumistox LCK 487), provided by Hach Lange France SAS, by means of the Microtox ® method, according to the international standard process (OIN 11348-3). The two values of the inhibition of the luminescence (%) were measured after 5 and 15 min of exposition of bacteria to treated solutions at 15 °C. The bioluminescence measurements were realized on solutions electrolyzed at several constant current intensities (I= 100, 300 mA), and on a blank (C 0 = 0 mg L -1 ).

Results and discussion

Effect of experimental parameters on the electrochemical treatments efficiency

Among different operating parameters affecting the efficiency of the electro-Fenton process, the most important are applied current intensity, catalyst concentration, solution pH, temperature, and electrode materials [17,[28][29][30][31]. The solution pH value is now well known as 3.0 [32], and room temperature is convenient to the process since higher temperature lower the O 2 solubility and can provoke H 2 O evaporation. Regarding electrodes materials, carbonaceous cathode and BDD anode were shown to be better materials [17,33]. Thus, we will discuss the effect of other parameters in the following subsections. According these data, the catalyst concentration of 0.1 mM was chosen as the optimum value under our experimental conditions and was used in the rest of the study.

Effect of catalyst (Fe 2+ ) concentration on degradation kinetics of ketoprofen

Influence of the applied current intensity on degradation rate

The applied current intensity is one of main parameter of process efficiency in AO and EF process, since the generation of hydroxyl radicals is governed by this parameter through Eqs. 3.1 (obtained from Fig. 3.2) at the same current intensity, confirm that the oxidation ability follows the order:

EF-BDD > EF-Pt > AO-BDD (Table 3.1), indicating the BDD anode has a larger oxidizing power than Pt anode in EF process.

Effect of pH and introduced air on the AO process

The pH of the solution is well known to influence the rate of Fenton and electro-Fenton process [17,32]. In contrast, there are inconsistent values reported in the literature for AO process [38][39][40]. Therefore, the effect of pH on the treatment of ketoprofen still needed to be examined. For this, AO treatments of 250 mL 0.198 mM Experiments regarding the effect of introduced compressed air on the removal of ketoprofen in AO process at pH of 3 were then performed. Results obtained were expressed in TOC removal terms and show that continuous air input significantly influenced the mineralization degree of ketoprofen. The mineralization rate was much better at pH 3 with continuous air bubbling through the solution than that at pH 3 without air input, followed by the values obtained at pH 7 and 10 (Fig. 3b). TOC removal was fast at beginning 4 h, which reached 96.9% (pH 3.0 with air bubbling), [START_REF] Almeida | Solar photoelectro-Fenton degradation of paracetamol using a flow plant with a Pt/air-diffusion cell coupled with a compound parabolic collector: Process optimization by response surface methodology[END_REF].4% (pH 3.0 without air bubbling), 86.1% (pH 7.5) and 82.8% (pH 10.0), respectively, being then slower on longer treatment times, due to the formation of recalcitrant end products such as carboxylic acids [41,42]. This results show that O 2 play a significant role in the oxidation mechanism.

Kinetic study of ketoprofen degradation

The absolute (second order) rate constant (k KP ) of the reaction between ketoprofen and  OH was determined by the competition kinetics method selecting phydroxybenzonic acid (p-HBA) as standatd competitor [43], since its absolute rate constant is well established as k p-HBA : 2.19 × 10 9 M -1 s -1 [44]. The electro-Fenton treatment was performed with both compounds in equal molar concentration (0.2 mM) and under the same operating conditions (I = 100 mA, [Fe 2+ ] = 0.1 mM, Na 2 SO 4 = 100 mM, pH = 3.0, V = 250 mL). To avoid the influence of their intermediates produced during the process, the kinetic analysis was performed at the early time of the degradation.

During the treatment, hydroxyl radicals concentration is considered as practically constant due to its high destruction rate and very short life time, which can not accumulate itself in the reaction solution [20]. The absolute rate constant for the k KP was then calculated following the Eq. (3.10) [43,45].

k KP k p-H Z ln [ ] [KP] t / ln [ ] [ ] (3.10)
where the subscripts 0 and t are the reagent concentrations at time t = 0 (initial concentration) and at any time t of the reaction. A progressive mineralization of the drug solution with prolonging electrolysis time to 360 min was found in all cases, while the solution pH decayed up to 2.7 -2.8

Ln ([KP]

owing to the production of acidic by-products (see Fig. oxidation rate of ketoprofen is depended to the transfer rate to the anode. After 2 hours of treatment, the percentage of TOC removal rised from 79% to 96% for EF-Pt, from 94% to 99% for EF-BDD and from 71% to 93% for AO process at 300 and 2000 mA applied currents, respectively, due to higher amount of  OH produced with higher applied current. These results confirm again the order of mineralization power in the sequence AO-BDD < EF-Pt < EF-BDD. Similarly, the MCE of EF was better than AO, and that of EF-BDD were better than EF-Pt. There was an obvious difference on MCE between current density of 100 and 300 mA, while not too much from 300 to 2000 mA. In all the case, the MCE < 51% was obtained, and decreased gradually along the electrolysis time. The progressive decrease in MCE on longer treatment time can be explained by the low organic concentration, the formation product more difficult to oxidize (like carboxylic acids) and enhancement of parasitic reactions [17,34,47].

A B

Chapter 3: Degradation of anti-inflammatory drug ketoprofen by electro-oxidation: comparison of electro-Fenton and anodic oxidation processes 88

Formation and evolution of aromatic and aliphatic by-products

The identification of the reaction intermediates from oxidation of ketoprofen was performed at a lower current intensity of 60 mA, which allowed accumulation of formed intermediates and their easy identification. Figure 5 shows that the aromatic intermediates were formed at the early stage of the electrolysis in concomitance with the disappearance of the parent molecule.

Toxicity tests

The evolution of toxicity during EF treatment of ketoprofen of the solution at two different current intensities (100 and 300 mA) was investigated over 120 min electrolysis. A 15 min exposure of Vibrio fischeri luminescent bacteria to the ketoprofen solutions was monitored by Microtox ® method (Fig. 3.8). The global toxicity (% luminescence inhibition) was increased quickly at the early treatment time, indicating the formation of intermediates more toxic than ketoprofen. Figure 8 exhibits several peaks due to the degradation primary intermediates and formation to secondary/tertiary intermediates than can be more or less toxic and then previous intermediates. After about 50 min, the samples displayed a lower percentage of bacteria luminescence inhibition compared to the initial condition, which clearly shows the disappearance of toxic intermediate products.

Conclusion

The complete removal of the anti-inflammatory drug ketoprofen from water was studied by electrochemical advanced oxidation EF and AO. The effect of operating conditions on the process efficiency, such as catalyst (Fe 2+ ) concentration, applied current value, nature of anode material, solution pH were studied. While the by-products produced and micro-toxicity of the solution during the mineralization of ketoprofen, have been conducted. From the obtained results, we can conclude that: 2. The oxidation power and the removal ability of ketoprofen was found to be followed the sequence AO-BDD < EF-Pt < EF-BDD, indicating higher oxidation power of BDD anode compared to Pt anode. The similar trend was also observed in the mineralization treatments of ketoprofen aqueous solution.

3. Solution pH and air bubbling through the solution affect greatly the oxidation/ mineralization efficiency of the process.

4. The absolute (second order) rate constant of the oxidation reaction of ketoprofen was determined as (5.4  0.1) × 10 9 M -1 s -1 by using competition kinetic method.

5. High TOC removal (mineralization degree) values were obtained using high applied current values. A complete mineralization (nearly 100% TOC removal) was obtained at 2 h using EF-BDD at 2 A applied current.

6. The evolution of global toxicity of treated solutions highlighted the formation of more toxic intermediates at early treatment time, while it was removed progressively by the mineralization of aromatic intermediates.

Finally the obtained results show that the EAOPs, in particular electro-Fenton process with BDD anode and carbon felt cathode, are able to achieve a quick elimination of the ketoprofen from water.

Introduction

It is reported that more than 2000 pharmaceuticals are consumed in the international pharmaceutical market in Europe [1 . Among these pharmaceuticals, nonsteroidal anti-inflammatory drugs (NSAIDs) are used by more than 30 million people every day. It was confirmed that 400 tons of aspirin, 240 tons of ibuprofen, 37 tons of naproxen, 22 tons of ketoprofen, 10 tons of diclofenac were consumed in France in 2004 (AFSSAPS 2006). The frequent detection of these compounds in environment [2-4 is due to the continuous input and inefficiency of the wastewater treatment plants.

Their potential risks on living organisms in terrestrial and aquatic environments are well documented by literatures and public concern are rising accordingly [5-7 . As there is scare research (except the work done in Ref. [41 ) of the elimination on naproxen by EAOPs, this work aims at studying the effect of anode materials on EF removal efficiency of naproxen in tap water. For clearly understanding the efficiency of the electrochemical oxidation set-ups, the influence of experimental variables (such as current density and catalyst concentration) on elimination of naproxen was also investigated. The mineralization of treated solutions, the decay kinetics of naproxen, as well as the generated carboxylic acids were monitored. ased on these by-products, a reaction sequence for naproxen mineralization was proposed. Finally, the evolution of the toxicity of intermediates produced during processes was monitored.

Materials and methods

Materials

Naproxen powder was purchased from Sigma-Aldrich and used without further Naproxen solutions were prepared in tap water. The pH of solutions was adjusted using analytical grade sulfuric acid or sodium hydroxide.

Electrolytic systems

Experiments were performed at room temperature (23 ± 2℃) in an open, cylindrical and one-compartment cell of inner diameter of 7.5 cm, with a working volume of 250 mL. A 3D carbon-felt (18.0 cm × 6.0 cm × 0.6 cm, from Carbone-Lorraine, France) was placed beside the inner wall of the cell as working electrode,

Apparatus and analytical procedures

Naproxen and its aromatic intermediates were monitored by high performance liquid chromatography (HPLC). Mobile phase for analyses was a mixture of 6λμ2λμ2 (v/v/v) methanol/water/acetic acids at a flow rate of 0.2 mL min -1 . The measurement was carried out by a Purospher RP-18μ 5 m, 25 cm  3.0 mm (i.d.) column, coupled with an L-2400 UV detector under the optimum setting at 240 nm and 40°C. The identification and quantification of carboxylic acid compounds as end by-products produced during the electrochemical processes were monitored by ion-exclusion HPLC with a Supelcogel H column (4.6 mm  25 cm). For the detection, the mobile phase solution was 1% H 3 PO 4 solution, and UV length was fixed to 210 nm. The by-products were analyzed by comparison of retention time with that of pure standard substances under the same conditions. For the analysis, all the injection volume was 20 L and measurements were controlled through EZChrom Elite 3.1 software.

The mineralization degree of samples was determined on a Shimadzu VCSH TOC analyser, as the abatement of total organic content. Reproducible TOC values with ±2% accuracy were found using the non-purgeable organic carbon method.

The test of potential toxicity of naproxen and its intermediates was conducted following the international standard process (OIN 11348-3), by the inhibition of the

Results and discussion

Influence of iron concentration on naproxen electro-Fenton removal

Catalyst concentration is an important parameter in the EF processes which is strongly influencing organic pollutants removal efficiency [43 . The electro-Fenton experiments at a low current intensity (i.e. 100 mA) with Pt/carbon felt cell (EF-Pt)

were performed with 45.6 mg L -1 naproxen solution (0.1λ8 mM), in order to determine the optimal catalyst concentrations for naproxen degradation by EF process.

The degradation curves of naproxen by  OH within electrolysis time followed pseudo-first-order reaction kinetics, whose rate expression can be given by the

following [45 μ Ln (C 0 /C t ) = k app t (4.7)
which k app is apparent (pseudo-first-order) rate constant, and C 0 and C t are the concentrations of naproxen at the beginning and at the given time t, respectively. Table 4.2 shows the apparent rate constants (k app ) of naproxen at various Fe 2+ concentrations. The degradation curves (data not shown) were fitting well as showed by the R-squared values above 0.λ87. The apparent rate constants reported in Table 4.2

shows that ferrous ion concentration significantly influenced the removal rate of naproxen by electro-Fenton treatment. A ferrous ion concentration of 0.1 mM shows the highest k app value followed by that of 0.05 mM and 0.2 mM. However, higher ferrous ion concentrations (i.e. 0.5 mM and 1 mM) displayed lower k app value, which means that the naproxen removal rate decreased with increasing ferrous ion concentration from 0.2 to 1 mM. This is an indication that optimized iron concentration for electro-Fenton on naproxen removal was fluctuating from 0.05 mM to 0.2 mM, while 0.

Kinetics of naproxen degradation and mineralization efficiency

As another important parameter in the EF process (Eq. The removal rate of naproxen and its mineralization were found increased by increasing applied current value, which resulted from more amount of  OH generated in the medium by higher current that could accelerate the H 2 O 2 formation rate (Eq. ). The removal percentage is 84.6% and λ7.2% at 100 mA, while λ2.1% and λ6.5% at 2000 mA in 4 and 8 h electrolysis with EF-Pt and EF-DD processes, respectively.

All the degradation curves of naproxen decreased exponentially in all the current values and it fitted well the pseudo-first-order reaction kinetic (Fig. where n is the number of electrons consumed per molecule mineralized (i.e. 64), F is the Faraday constant (λ6487 C mol -1 ), V s is the solution volume (L), (TOC) exp is the experimental TOC decay (mg L -1 ), 4.32 × 10 7 is a homogenization factor (3600 sh -1 × 12,000 mg mol -1 ), m is the number of carbon atoms of naproxen ( 14) and I is the applied current intensity (0.1-2 A).

Kinetic study of naproxen oxidation

The absolute (second order) rate constant (k NAP ) of the reaction between naproxen and  OH was determined by the competition kinetics method selecting phydroxybenzonic acid (p-H A) as standard competitor [52 , since its absolute rate constant is well established as k p-H A μ 2.1λ × 10 λ M -1 s -1 [53 . The electro-Fenton treatment was performed with both compounds in equal molar concentration (0.2 mM) and under the same operating conditions (I = 100 mA, [Fe 2+ = 0.1 mM, Na 2 SO 4 = 50 mM, pH = 3.0, V = 250 mL). To avoid the influence of their intermediates produced during the process, the kinetic analysis was performed at the early time of the oxidation process. During the electrochemical treatment,  OH cannot accumulate itself in the reaction solution due to its high disappearance rate and very short life time. Therefore the steady state approximation can be applied to its concentration. Taking into account then the absolute rate constant of naproxen oxidation with  OH can be calculated from the slope of the integrated kinetic equation, which is well fitting (R 2 =0.λλ8). The value of kNAP was determined as 3.67 (± 0.03)  10 λ M -1 ·s -1 . This value is lower than the data reported for naproxen oxidation by Fenton's reagent as λ.6 (± 0.5)  10 λ M -1 ·s -1 [55 , and UV photolysis as 8.61 (± 0.002)  10 λ M -1 ·s -1 [56 , respectively.

Evolution of the degradation intermediates of naproxen

To investigate the detail of the reaction between naproxen and  OH by electro-Fenton process, the produced intermediates (i.e. aromatic intermediates and short-chain carboxylic acids) were identified and quantified. The experiments were performed at a lower current intensity of 50 mA with Pt as anode, which allows slow reactions to proceed and ease the monitoring the by-products produced during the degradation. However, these by-products were all formed in small quantities. All the detected intermediates except benzoic acid were completely removed before the total elimination of naproxen. Considering the fact that persistent intermediates were formed in Fenton-Chapter 4: Electro-Fenton removal of naproxen from aqueous medium: effect of anode material and operating conditions 111 based reactions, containing polar functional moieties, such as hydroxyl and carboxyl groups, they are expected to be highly mobile in environmental systems, even if they are of high molecular weight. The low amount of the oxidant, which does not allow complete mineralization, should stimulate oxidation operated under economically and ecologically feasible conditions, aiming at reducing high operating costs.

The concentration of carboxylic acid produced were higher than that of aromatics (Fig. 4.2 ), indicating that short-chain carboxylic acids were quickly transformed from the oxidative breaking of the aryl moiety of aromatic in the electro-Fenton process [45 .

Glycolic and malic acids were identified at the beginning electrolysis time and disappeared gradually. Formic acid got to its maximum peak concentration of 0.08 mM after 60 min electrolysis time and then decreased gradually. Glyoxylic acid constantly appeared in the electrolysis time below 0.004 mM. Acetic acid was formed as the largest amount with its highest amount of 0.076 mM formed after 120 min electrolysis time.

Oxalic acid gradually increased to its maximum peak concentration of 0.1λ7 mM at 120 min, meaning it can be produced from other carboxylic acids oxidized by  OH (Fig.

4.2.

). The glyoxylic acid may also come from the oxidation of aryl moieties and then converted to oxalic acid [50 . Oxalic and acetic acids were persistent as the ultimate intermediates during the whole processes. Further reaction with the cleavage of the aromatic ring in the electron-rich benzene formed hydroxylated benzenes as di/tri-hydroxybenzenes of corresponding as 3hydroxybenzoic acid, phenol, catechol, benzoic acid, phthalic, pyrogallol, phthalic anhydride and hydroquinone. Finally, these intermediates were mineralized to carbon dioxide by further reactions with  OH, such as acetic, oxalic, formic, glycolic, malic and succinic acids, which originate from the oxidative breaking of the benzenes' moiety of aromatic intermediates. In the end, the ultimate carboxylic acids were oxidized to carbon dioxide and water or oxalic acid and its hardly oxidizable iron complexes.

Chapter 4: Electro-Fenton removal of naproxen from aqueous medium: effect of anode material and operating conditions 114

C H 3 O O OH C H 3 C H 3 O C H 3 O C H 3 O CH 3 O H OH O OH C H 3 OH O O H O OH O 1-naphthalene acetic

Toxicity analysis

As mentioned earlier in the present paper, the intermediates produced from naproxen could have a higher toxicity than the parent molecule itself [18 . In parallel, it is of importance to understand naproxen's evolution of toxicity since EF processes have showed such high removal efficiency. For this test, the bioluminescence measurements were conducted under standard conditions after 15 min exposure of marine bacteria V. fischeri with solutions electrolyzed at two constant current intensities (I = 100, 300 mA) with DD and Pt anodes at different time over 120 min electrolysis (Fig. 4.4). The experiments conducted were in triplicate. It can be seen from the curves, that there were significant increase of luminescence inhibition peaks within 10 min of electrolysis time, Chapter 4: Electro-Fenton removal of naproxen from aqueous medium: effect of anode material and operating conditions 115 which clearly showed that highly toxic intermediates were produced. After about 20 min treatment, compared to the initial condition, all the samples displayed a lower percentage of bacteria luminescence inhibition, indicating that toxic intermediates were eliminated during the treatment. Afterwards, the curves continuously decreased and there was no much difference between the curves of different anodes application. It may due to the main products in the medium were short-chain carboxylic acids, as evolution curve of carboxylic acids showed (Fig. 4.2. ).

It was observed that luminescence inhibition was higher at lower current intensity value, comared with the one at higher current intensity value, the reason of which can be attributed to the lower rate of destruction of intermediates at low formation of the  OH.

Energy cost

For the consideration of economic aspect of EF treatment, the energy cost for the tests was calculated by the equation (4.12) at 100, 300 and 1000 mA current density As expected, the energy cost increases with increasing current density.

Application with DD in EF process has a slightly higher consumption than that with

Pt. The values were between 0.012 and 0.036, 0.012 and 0.047 kWh g -1 TOC at 100 mA for EF-Pt and EF-DD, respectively. However, at 1000 mA, the initial values were 0.0λ and 0.11 kWh g -1 TOC at 0.5 hour for EF-Pt and EF-DD, respectively. It is clear that in the first 2 hours, the energy cost did not increase too much at 300 mA, even with a decrease at 100 mA in both EF processes. The results confirm that the fast mineralization of naproxen and intermediates (Fig. 4.1 ) at the beginning time would enhance the efficiency with a lower energy cost but later, the slower mineralization rate due to the persistent by-products formed during the processes could higher up the energy cost, which decrease cost efficiency of the treatments.

The results obtained as mineralization, evolution of the toxicity and energy cost proved that the removal of naproxen solution could be considered operated under lower current density (100 to 300 mA).

Conclusions

The electro-Fenton removal of naproxen in aqueous solution was carried out at lab-scale. It has been found out that 0.1λ8 mM naproxen could be almost completely eliminated in 30 and 40 min at 300 mA by EF-Pt and EF-DD processes, respectively.

In addition, the TOC removal yield could reach 84.6% and λ7.2% at 100 mA after 8 h treatment with EF-Pt and EF-DD processes, respectively. The optimized ferrous ion concentration was determined as 0.1 mM. A high MCE value was obtained at low current density. The degradation curves of naproxen by hydroxyl radicals within electrolysis time followed pseudo-first-order reaction kinetics and the absolute rate constant of naproxen was determined as (3.67 ± 0.3) × 10 λ M -1 ·s -1 . Electro-Fenton with DD anode showed higher removal ability than electro-Fenton with Pt anode because of generation of additional  OH and high oxidation/mineralization power of the former anode. From the intermediates identified during the treatment, a plausible oxidation pathway of naproxen by  OH was proposed. The formation of short-chain carboxylic acids (that are less reactive toward  OH) produced from the cleavage of the aryl moiety explained the residual TOC remaining at the end of the treatment. From the evolution of toxicity of the treated solution, it can be noticed that some highly toxic products produced at the beginning of the electrolysis disappeared quickly with electrolysis time.

It can be concluded that electro-Fenton process could eliminate naproxen rapidly and could be applied as an environmentally friendly technology to efficient elimination of this pharmaceuticals from water.

Chapter 5: Electrochemical oxidation of naproxen in aqueous medium by the application of a boron-doped diamond anode and a carbon felt cathode 126

Introduction

The electrochemical advanced oxidation processes (EAOPs), such as electro-Fenton (EF) and anodic oxidation (AO), have been gained great interests as outstanding effective technologies to remove toxic and biorefractory micropollutants [1][2][3][4]. The oxidation processes mainly depend on the formation of electrogenerated species such as hydroxyl radicals (  OHs) to oxidize the organic pollutants till the final products as water and carbon dioxide in a non-selected way [5].

Among the EAOPs, the EF process has been applied for the degradation of pesticides, pharmaceuticals and other pollutants [6][7][8][9][10], which is operated successfully on cathodically electrogenerated H 2 O 2 by continuous supply of O 2 gas. The catalyst (i.e.

Fe 2+ ) reacts with the H 2 O 2 generated in acidic medium to produce  OH and Fe 3+ via Fenton's reaction [11,12]. More interesting, the reaction benefits by less input of catalyst as regeneration of Fe 2+ from electrochemical reduction at the cathode of Fe 3+

formed from Fenton's reaction [5]. Cathode materials, as graphite [13], carbon-PTFE O 2 diffusion [14,15] and three-dimensional carbon felt [16], are proposed as suitable materials for the electrochemical oxidation application. Especially, lower H 2 O 2 decomposition, fast O 2 reduction, large surface area, and lower cost make the 3D carbon felt as a favoring cathode in removal of pollutants with H 2 O 2 electrogeneration [5,16,17].

In the AO process,  OH is mainly generated at the anode surface from water oxidation, whose production rate is determined by the character of the anode material [18,19]. On the other hand, the high-efficiency electrodes of metal oxide (PbO 2 ) and conductive-diamond (boron-doped diamond (BDD)) anodes, with a promotion of higher mineralization rate of organics, have been widely applied to treat persistent pollutants [10,20,21]. BDD electrode, with a high O 2 over potential and lower adsorption ability, could generate others reactive oxygen species, as ozone and H 2 O 2 [22,23], is able to allow the total mineralization of organics as:

BDD(  OH) + R → DD + CO 2 + H 2 O + inorganic ion (5.1)
Naproxen, in the list of popular pharmaceutical consumed, known as non-steroidal anti-inflammatory analgesic drug, which has been used widely higher than several decades of tons per year for nearly 40 years. Due to its desired therapeutic effect, a stable polar structure and adsorption ability make it persistent against the biological Chapter 5: Electrochemical oxidation of naproxen in aqueous medium by the application of a boron-doped diamond anode and a carbon felt cathode 127 degradation, which may be responsible for the incomplete removal in the conventional wastewater treatment plants [24]. The frequent detection of naproxen up to µg L -1 level in effluent of wastewater confirmed once again the non-complete removal and therefore it is accepted that the pharmaceutical effluents play an important role as pollutant source.

The by-products of naproxen degradation in water has been proved as toxicant [25],

whereas, higher toxicity than that of naproxen was also confirmed by bioassay test [26].

There is a lack of information of the long-term ingestion of the mixtures of residual pharmaceuticals and other pollutants in aqueous system. As the lower efficiency of the traditional wastewater treatments is responsible for the presence of naproxen in aqueous system, high performance treatments such as EF and AO processes with BDD anode were applied in this study on the removal of naproxen in drinking water.

Therefore, in this work, the elimination of naproxen in drinking water was conducted by the highly efficient EAOPs. The experiments were designed to study the effect of pH, air bubbling condition, and current density on AO and EF processes, in which condition would benefit the higher production of  OH at carbon felt cathode and BDD anode surface. The aim was to find the optimum values for operating conditions.

Monitoring of the by-products formation and evolution of the toxicity during the mineralization for the optimal operating conditions was studied. A detailed study of the oxidation process on naproxen by EAOPs was provided to assess the environmental impact of the treatments.

Materials and methods

Materials

Naproxen was obtained from Sigma-Aldrich, dissolved at a higher concentration as 45.6 mg L -1 (0.198 mM) in 250 mL drinking water without any other purification (45.6 mg L -1 , 0.198 mM). Sodium sulfate (anhydrous, 99%, Acros) and iron (II) sulfate heptahydrate (97%, Aldrich) were supplied as background electrolyte and catalyst, respectively. Reagent grade p-hydroxybenzoic acid from Acros Organics was used as the competition substrate in kinetic experiments. All other materials were purchased with purity higher than 99%. The initial pH of solutions was adjusted using analytical grade sulfuric acid or sodium hydroxide (Acros).

Procedures and equipment

Chapter 5: Electrochemical oxidation of naproxen in aqueous medium by the application of a boron-doped diamond anode and a carbon felt cathode 128

The experiments were performed at room temperature in an undivided cylindrical glass cell of 250 mL capacity, equipped with two electrodes. A 3D carbon-felt (18.0 cm × 6.0 cm × 0.6 cm, from Carbone-Lorraine) covering the total internal perimeter, and a 24 cm 2 BDD thin-film deposited on both sides of a niobium substrate, centered in the electrolytic cell. All the trials were controlled under constant current density by using a DC power supply (HAMEG Instruments, HM 8040-3). 0.05 M Na 2 SO 4 was introduced to the cell as supporting electrolyte. Prior to electrolysis, compressed air at about 1 L min -1 was bubbled for 5 min through the solution to saturate the aqueous solution and reaction medium was agitated continuously by a magnetic stirrer (800 rpm) to homogenize the solution and transfer of reagents towards/from electrodes. For the electro-Fenton experiment, the pH of the medium set to 3.0 by using 1.0 M H 2 SO 4 , and

was measured with a CyberScan pH 1500 pH-meter from Eutech Instruments, and an adequate concentration of FeSO 4 7H 2 O was added to initial solutions as catalyst.

Total organic carbon (TOC)

The mineralization of naproxen solution was measured by the dissolved organic carbon decay, as total organic carbon (TOC). The analysis was determined on a Shimadzu VCSH TOC analyzer. The carrier gas was oxygen with a flow rate of 150 mL min -1 . A non-dispersive infrared detector, NDIR, was used in the TOC system.

Calibration of the analyzer was attained with potassium hydrogen phthalate (99.5%, Merck) and sodium hydrogen carbonate (99.7%, Riedel-de-Haën) standards for total carbon (TC) and inorganic carbon (IC), respectively. Reproducible TOC values with ±1% accuracy were found using the non-purgeable organic carbon method. From the mineralization data, the Mineralization Current Efficiency (MCE in %) for each test at a given electrolysis time t (h) was estimated by using the following equation [27]:

MCE = n F Vs TOC exp 4.32 ×10 7 m I t × (5.2)
where F is the Faraday constant (λ6487 C mol -1 ), V s is the solution volume (L), (TOC) exp is the experimental TOC decay (mg L -1 ), 4.32 × 10 7 is a homogenization units (3600 sh -1 × 12,000 mg mol -1 ), m is the number of carbon atoms of naproxen (14, following Eq. (5.3)) and I is the applied total current (0.

High performance liquid chromatography (HPLC)

The time course of the concentration decay of naproxen and p-HBA, as well as that of aromatic by-products, was monitored by reversed phase high performance liquid chromatography (HPLC) using a Merck Lachrom liquid chromatography equipped with a L-2310 pump, fitted with a reversed phase column Purospher RP-18, 5 m, 25 cm × In the analysis, all the injection volume was 20 L and measurements were controlled through EZChrom Elite 3.1 software.

Toxicity test

For testing the potential toxicity of naproxen and of its reaction intermediates, the measurements were carried out with the bioluminescent marine bacteria Vibrio fischeri (Lumistox LCK 487), provided by Hach Lange France SAS, by means of the Microtox ® method, according to the international standard process (OIN 11348-3). The two values of the inhibition of the luminescence (%) were measured after 5 and 15 min of exposition of bacteria to treated solutions at 15°C. The bioluminescence measurements were performed on solutions electrolyzed at constant current intensities of 100 and 300 mA, and on a blank (C 0 (Nap) = 0 mg L -1 ).

Results and discussion

Optimization of pH and air bubbling for anodic oxidation process by BDD

A series of experiments were performed by oxidizing naproxen (0. Low pH favors the degradation and mineralization of naproxen in anodic oxidation process. This can be ascribed to that more H 2 O 2 can be produced at cathode surface in acidic contaminated solution [5]:

O 2 (g) + 2H + + 2e -→ H 2 O 2 (5.4)
Moreover, in the alkaline solution, the O 2 gas is reduced to the weaker oxidant as

HO 2 -[5 μ O 2 (g) + H 2 O + 2e -→ HO 2 -+ OH - (5.5)
Under the same current density application, with the help of production of  OH by anode, the oxidants produced by cathodic process can be highly promoted by adjusting pH in anodic oxidation process.

Influence of current density on EAOPs of naproxen

The current density is an important parameter in EAOPs which could determine the oxidation efficiencies. The effect of current density on EF-BDD and AO-BDD was tested with naproxen (0.198 mM, 45.6 mg L -1 ) solutions in 50 mM Na 2 SO 4 . For EF process, the optimum pH was set as 3.0 and catalyst (Fe 2+ ) concentration at 0. The degradation of naproxen under the same condition as TOC decay was conducted ranging from 100 to 2000 mA current density. The concentration of naproxen removal curves were well fitted a pseudo-first-order kinetics (k app ). The analysis of k app showed in Table 5.1 illustrated an increasing k app values from 100 to 2000 mA current density were obtained from 1.25 × 10 -1 to 9.11 × 10 -1 min -1 for EF-BDD and from 1.8 × 10 -2 to 4.17 × 10 -1 min -1 for AO-BDD, respectively. The value of k app at 1000 mA current density of AO-BDD was similar with the one for EF-BDD at 300 mA current density. Meanwhile, the k app of EF-BDD could be about 10 times higher than that of AO-BDD at same current density (100 to 300 mA). The higher k app values were due to more  OH generated at higher current density at anode surface (Eq (5.6)), and in the bulk, high amount of Fe(II) is regenerated accelerating Fenton's reaction (Eqs. (5.4),

(5.9) and (5.10)) [30]: (R 2 = 0.997)

Fe 2+ + H 2 O 2 + H + → Fe 3+ + H 2 O +  OH (5.

Detection and evolution of by-products of naproxen by EAOPs

The aromatic intermediates of oxidation of naproxen by Oxalic and formic acids persisted longer, being ultimate carboxylic acids that are directly converted into CO 2 [31, 32 . Figure 5.3 highlights that in EF, oxalic acid was accumulated up to 0.1λ6 mM at 60 min, further being reduced to 0.03λ mM at 360 min, since their Fe(III) complexes are slowly destroyed by DD(  OH). The glycolic acid was the most accumulated acid formed in EF reaching the maximum concentration up to 0.208 mM at 30 min, then quickly degraded. Other acids all reached to less than 0.08 mM and gradually disappeared. For AO, Figure 5.3 evidences a slower accumulation of oxalic acid, reaching 0.072 mM at 120 min, and practically disappearing at 480 min as a result of the combined oxidation of Fe(III)-oxalate and Fe(III)-oxamate complexes by DD(  OH). Acetic acid was mostly produced in AO, up to 0.108 mM around 60 min, and while others only reached lower to 0.04 mM during the whole process.

A lower acids concentration obtained by AO-DD than EF-D, but a higher TOC remaining, as well as later the higher micro-toxicity (mainly due to aromatic intermediates) showed for AO-DD, indicates slower oxidation of naproxen solution by AO compared with EF process. There is smaller mass balance of the acids with TOC, value at the end of treatment that means there were undetected products formed, which are not removed by  OHs.

Toxicity test for naproxen under EAOPs treatment

In the last step of the experiments, the evolution of the toxicity of the solution electrolyzed at different constant current intensities (I = 100, 300 mA) with EF-BDD and AO-BDD, and on a blank (C 0 = 0 mg L -1 ) over 120 min electrolysis treatment was studied. The measurements were conducted under standard conditions after 15 min exposure to marine bacteria V. fischeri, by the inhibition of the bioluminescence. Figure 5.4 shows that a significant increase of luminescence inhibition percentage (around 20%) occurred within the first 20 min for all the processes, indicating highly toxic intermediates were produced during this electrolysis time. Then, the inhibition curves decreased vs. electrolysis time that means the toxic intermediates were eliminated Chapter 5: Electrochemical oxidation of naproxen in aqueous medium by the application of a boron-doped diamond anode and a carbon felt cathode 138 gradually during the treatments. The lower percentage of bacteria luminescence inhibition than the initial condition was achieved in all the samples. As evolution of toxicity for EF-BDD and AO-BDD showed, lower applied current intensity produced a higher luminescence inhibition, which was attributed to the slower destruction of the naproxen and its oxidation products by smaller  OH amount produced under lower current density. At the same current intensity, AO treatment exhibits higher inhibition degree, due to the lower oxidation power of AO with the slower degradation of the organic matters in solutions, as indicated by lower TOC abatement. At the later stage, the value of the inhibition was similar for all the process, which related to formed short-chain carboxylic acids which are biodegradable. Isidori et al. [26] obtained similar results showing higher toxic intermediates produced than the naproxen by phototransformation. High efficiency on removal of naproxen and decreased toxicity of the treated naproxen solution make EF processes as a practicable wastewater treatment.

Conclusion

It can be concluded that the electrochemical oxidation processes with BDD as anode and carbon-felt as cathode could be efficiently applied to remove naproxen in synthetic solution prepared with tap water. Electro-Fenton process showed a higher oxidation power than anodic oxidation process. In both EAOPs, the increasing current density accelerates the degradation and mineralization processes, but with a loss in mineralization current efficiency due to the side reaction and energy loss on the persistent byproducts produced. In both oxidation processes, the lower pH favors higher efficiency. The decay of naproxen followed a pseudo-first-order reaction. The aromatic intermediates were oxidized at the early stage by addition of  OH on the benzenic ring (hydroxylation) or by H atom abstraction from side chain, leading to increase of the inhibition of the luminescence of bacteria Vibrio fischeri. Then, the oxidative cleavage of polyhydroxylated aromatic derivatives conducts to the formation of short chain carboxylic acids (glycolic, malic, succinic, formic, oxalic, and acetic acids), causing the decrease of solution toxicity.

a pseudo-first-order reaction and its oxidation rate constant increased with increasing current intensity. A total organic carbon abatement could be achieved to 92% for piroxicam by BDD anode at 6 h treatment at 100 mA current intensity, while 76% of TOC abatement was achieved when using Pt anode. Lower mineralization current efficiency was obtained at higher current intensity in all processes. The absolute rate constant of the second order reaction kinetics between piroxicam and  OH was evaluated by competition kinetic method and its value was determined as (2.19 ± 0.01) × 10 9 M -1 ·s -1 . Ten short-chain carboxylic acids, identified and quantified by ionexclusion HPLC, were largely accumulated using Pt but rapidly eliminated under BDD anode, thus explaining the partial mineralization of piroxicam by electro-Fenton with the former anode. The release of inorganic ions such as NO 3 -, NH 4 + and SO 4 In the last decade, the presence of pharmaceutical ingredients in the aquatic environment has become a subject of growing concern worldwide [1][2][3][4][5]. This is mostly due to rather low removal efficiency of the traditional wastewater treatment plants, who plays an important role as releasing sources for pharmaceuticals [6][7][8]. One of the most consumed medications group corresponds to the pharmaceutical class -Non-Steroidal

Anti-Inflammatory Drugs‖ (NSAIDs) that is considered as a new class of emerging environmental pollutants [9,10], with a concentration from ng L -1 to g L -1 detected in effluents of wastewater treatment plants, surface water, groundwater and drinking water [11][12][13][14]. Great concern of their potential toxicological effect on humans and animals has been raised highlighted from the related researches revealed recently [15][16][17]. More effective technologies are needed in order to prevent significant release of such contaminants into natural environment [18][19][20][21].

Piroxicam belongs to the list of NSAIDs popular consumed medicines, and has been used in the management of chronic inflammatory diseases for almost 30 years [22].

It has a low solubility and high permeability in environment, with a reported of LD 50 for barnacle nauplii of 2.26 mg L -1 [23]. The piroxicam concentration detected concentration in wastewater effluent could be in the range of 0.5-22 ng L -1 [24].

Due to non-satisfaction in the removal of micro-pollutants by conventional biological wastewater treatment processes, advanced oxidation processes (AOPs) have been widely studied for removing biologically toxic or recalcitrant molecules such as aromatics, pesticides, dyes and volatile organic pollutants potentially present in wastewater [25][26][27][28][29][30]. In these processes, hydroxyl radical (  OH) as main oxidant (known as the second strongest oxidizing agent (E⁰ (OH/H2O) = 2.80 V/SHE)), is generated in situ and can effectively reacts with a wide range of organic compounds in a non-selective oxidation way. Thus, electrochemical advanced oxidation processes (EAOPs) are based on the production of this highly oxidizing species from water oxidation on the anode surface (direct oxidation) or via electrochemically monitored Fenton' s reaction in the bulk (indirect oxidation), which are regarded as powerful, environmental friendly technologies to remove pollutants at low concentration [31,32].

Indirect electro-oxidation is achieved by continuous generation of H 2 O 2 in the solution by the reduction of O 2 (Eq. (6.1)) at the cathodic compartment of the electrolytic cell. In such procedures, mostly used cathodes are carbon-felt (CF), graphite and O 2diffusion ones [31,33]. The most prevalent indirect oxidation process is electro-Fenton (EF), with  OH homogeneously produced by the reaction of ion catalyst (Fe 2+ added initially and regenerated in the system) with the H 2 O 2 in an acidic medium (Eq. (6.2)).

At the same time, Fe 3+ can be propagated by the cathodic reduction to Fe 2+ as Eq. ( 6.3)

showed [34][35][36] in order to catalyse Fenton's reaction (Eq. (6.2)):

Fe 2+ + H 2 O 2 → Fe 3+ +  OH + OH - (6.2)
Fe 3+ + e -→ Fe 2+ (

The oxidation rate of pollutant to be treated mainly depends on H 2 O 2 formation and iron electrogeneration rates, which could be highly accelerated by the usage of better performance cathode. As known, CF electrode has a large active surface and allows fast reaction of H 2 O 2 formation and reduction of Fe 3+ to Fe 2+ to guarantee a high proportion of Fe 2+ in the solution. In an undivided cell, high amount  OH can be formed due to high and quick regenerated Fe 2+ in the solution that could lead to a nearly total mineralization of the micropollutants [37,38].

Direct electrochemistry, well known as anodic oxidation (AO), involves the charge transfer at the anode (M) with the formation of adsorbed hydroxyl radical (M(  OH)), which from the oxidation of water [39,40]. Especially mentioned, BDD, which has high O 2 overvoltage, is able to produce high amount of  OH from reaction (6.4), and shows a high efficiency on degradation of pollutants [41] M + H 2 O → M(  OH) + H + + e - (

The oxidation of pollutants by EF process, not only happens via reaction of homogeneous  OH in the bulk solution but also the heterogeneous of M(  OH) at anode surface. While in an undivided electrochemical cell, other weaker oxidants like hydroperoxyl radical (HO 2  ) is formed at the anode [42] contributing to overall oxidation process:

H 2 O 2 → HO 2  + H + + e - (6.5)
To the best of our knowledge, there is no study related to the removal efficiency of piroxicam from contaminated wastewater. Therefore we report in this study its comparative removal efficiency from water by two EAOPs, namely electro-Fenton (EF)

Chapter 6: Removal of piroxicam from aqueous solution: comparison of anodic oxidation and electro-Fenton processes performances 147 and anodic oxidation (AO) processes in tap water for the first time. The optimization of the operating parameters as well as the impact of the electrode materials on piroxicam removal and mineralization efficiency was monitored. Meanwhile, the intermediates produced and their toxicological impacts were investigated during the mineralization procedure. Piroxicam solution with the concentration of 0.08 mM (max solubility, 26.48 mg L -1 ) was prepared in tap water, and all other stock solutions were prepared with ultrapure water obtained from a Millipore Milli-Q-Simplicity 185 system (resistivity > 18

Materials and methods

Chemicals

Piroxicam (4-hydroxy-2-methyl-2H-1,2-benzothiazine-1-(N-(2- pyridinyl)carboxamide)-1,1-dioxide) (C
MΩ at 25°C). The pH of solutions was adjusted using analytical grade sulfuric acid or sodium hydroxide (Acros).

Electrolytic systems for the degradation of piroxicam

For all the EAOPs, the electrolysis was performed in an open, undivided and cylindrical electrochemical cell of 250 mL capacity. Two electrodes were used as anode: a 4.5 cm high Pt cylindrical grade or a 24 cm 2 boron-doped diamond (BDD, thin-film deposited on a niobium substrate (CONDIAS, Germany)). A tri-dimensional, large surface area carbon-felt (18.0 cm × 6.0 cm × 0.6 cm, Carbone-Lorraine, France) electrode was used as cathode.

In all the experiments, the anode was cantered in the electrochemical cell and surrounded by the cathode (case of carbon-felt), which covered the inner wall of the cell. Especially, for the EF experiments, pH of 3.0 was considered optimum for the process, which was adjusted by H 2 SO 4 /HCl (for inorganic detection experiments) with a CyberScan pH 1500 pH-meter from Eutech Instruments, and FeSO 4 7H 2 O was added to initial solutions as catalyst.

Analytical methods

The mineralization of initial and electrolyzed samples of piroxicam solution was measured by Shimadzu VCSH TOC analyzer in terms of total organic carbon (TOC).

Reproducible TOC values with ±2% accuracy were found using the non-purgeable organic carbon method.

Piroxicam and p-HBA were determined by reversed-phase high performance liquid chromatography (HPLC, Merck Lachrom liquid chromatography) equipped with a Purospher RP-18: 5 m; 25 cm  3.0 mm (i.d.). The measurement was made under an optimum wavelength of 240 nm at 40 °C with a mobile phase of 40:60 (v/v) KH 2 PO 4 (0.1 M)/methanol mixtures at flow rate of 0.6 mL min -1 . Under this condition, the corresponding retention time for piroxicam was 5.6 min.

Carboxylic acid compounds generated were identified and quantified by ionexclusion HPLC with a Supelcogel H column (9 m, φ = 4.6 mm × 25 cm (i.d.)).

Mobile phase solution was chosen as 1% H 2 SO 4 solution. The condition of the analysis of the equipment was set at a flow rate of 0.2 mL min -1 , and under = 210 nm at room temperature.

Inorganic ions produced during the mineralization were determined by ion chromatography-Dionex ICS-1,000 Basic Ion Chromatography System. For the determination of anions/cations (NO 3 -, SO 4 2-and NH 4 + ), the system was fitted with an IonPac AS4A-SC (anion-exchange) or IonPac CS12A (cation-exchange) column of 25

Chapter 6: Removal of piroxicam from aqueous solution: comparison of anodic oxidation and electro-Fenton processes performances 149 cm × 4 mm (i.d.). For ion detection, measurements were conducted with a 1.8 mM Na 2 CO 3 + 1.7 mM NaHCO 3 aqueous solution as mobile phase. The mobile phase was circulated at 2.0 mL min -1 at 35 °C. For cation determination, a 9.0 mM H 2 SO 4 solution was applied as mobile phase, circulating at 1.0 mL min -1 at 30 °C. The sensitivity of this detector was improved by electrolyte suppression in using an ASRS-ULTRA II or CRS-ULTRA II self-regenerating suppressor for anions and cations, respectively.

In the analysis, all the injection volume was 20 L and measurements were controlled through EZChrom Elite 3.1/Chromeleon SE software. The identification and quantification of the intermediates were conducted by comparison of retention time with that of pure standard substances.

The monitoring of toxicity of the piroxicam solution and its electrolyzed intermediates were performed on the samples collected on regular time points during the electrolytic treatments. The measurements were performed under the international standard process (OIN 11348-3), based on the inhibition of luminescence of the bacteria V. fischeri (Lumistox LCK 487) after 15 min of exposition to these treated solutions at 15 °C. The measurements were conducted on samples electrolyzed at two constant current intensities (I = 100 and 300 mA) as well as on blank (C 0 = 0 mM) samples.

Results and discussion

Kinetic analysis of piroxicam degradation by the electrochemical treatments

The performance of EF process depends on catalyst concentration applied [43 . Therefore, the effect of iron concentration (0.05 to 1 mM) on the degradation kinetics was firstly monitored for electro-Fenton process with DD anode. The degradation of piroxicam by  OH exhibited an exponential behaviour indicating a pseudo-first-order kinetic equation. The apparent rate constants k app was calculated from the pseudo firstorder kinetic model (see from chapter 3.3) and inserted in figure 6.1 in table form.

Figure 6.1 shows the degradation rate increasing with Fe 2+ concentration from 0.05 to 0.2 mM then decreasing with increasing Fe 2+ concentration from 0.2 to 1 mM. The highest decay kinetic was obtained with 0.2 mM of Fe 2+ in the electro-Fenton process with k app = 0.24 min -1 (R 2 = 0.λλ4), while the lowest at 1 mM of Fe 2+ input with k app = 0.1 min -1 (R 2 = 0.λλ6). The little difference of k app for 0.05 (0.17 min -1 , R 2 = 0.λλ6) and 0.1 mM (0.1λ min -1 , R 2 = 0.λλ6) iron concentration was evidenced in this study. As shown, in the electro-Fenton process, there is an optimal iron concentration to reach the The influence of pH as another parameter influencing anodic oxidation process was examined. The effect of pH (pH 3.0, 5.5 (natural pH) and 9.0) on the decay kinetics of piroxicam (0.08 mM) was studied at an applied current intensity of 300 mA in 50 mM Na 2 SO 4 of 250 mL solution. Results show that pH significantly influenced the decay of piroxicam in AO process (Fig. 6.2). The decay kinetic at pH 3 was more than 5 times comparing of that of pH 9. This is an indication that AO treatment efficiency of pharmaceuticals selected in acidic condition was higher than that of alkaline condition (see chapter 3, 4 and 5). The reason may be more easily oxidizable products are formed during the oxidation in acidic solution, and at the same time, more BDD (  OH) will be produced at low pH [45], and lower adsorption ability of anode in acidic condition [46, For electrode reactions, electrogenerations of oxidants are affected by the current intensity supplied in the cell. Then oxidative degradation of piroxicam (0.08 mM) at different current intensities (ranging from 100 to 1000 mA) was investigated in 50 mM Na 2 SO 4 by EF-Pt, EF-BDD and AO-BDD processes. As Figure 6.3 shows, a decreasing concentration of piroxicam was obtained for all the treatments and the apparent rate constants increased with increasing applied current. The time needed to reach a complete piroxicam removal by EF-BDD process was 10 min electrolysis time at 1000 mA, while 20 min were needed for AO-BDD process. As data shows, the removal efficiency of EF process was better than that of AO process. The apparent kinetic constant of EF-BDD at 100 mA was 7 times higher than that of AO-BDD, confirming

Chapter 6: Removal of piroxicam from aqueous solution: comparison of anodic oxidation and electro-Fenton processes performances 152 that Fenton's reaction (Eq. (6.2) and (6.3)) highly improved the efficiency of the oxidation processes on piroxicam. The enhancement of oxidation ability with increasing current intensity is due to higher current intensity leading to the higher generation of  OH in the medium and at the anode surface. Increase of applied current intensity increases H 2 O 2 concentration generated (Eq. (6.1)), and accelerate iron regeneration rate (Eq. (6.3)), which also lead to an increasing generation of  OH (Eq. (6.2)). Comparison of the kinetic constant of EF-BDD and EF-Pt at 100 mA current intensity shows that EF-BDD displays a constant which is more than 2 times than that of the EF-Pt process.

The BDD(  OH) has a higher oxidative ability than that of Pt(  OH) that enhances the oxidation power of the process. As degradation curve shows, above 300 mA current applied in AO, the degradation rate remained constant, which mean there is an optimal current intensity for practical application to save the energy and also avoid adverse effect such as heat on equipment. The mineralization reaction of piroxicam by  OH can be written as follows: where n is the number of electrons consumed per molecule mineralized (i.e. 86), F is the Faraday constant (λ6487 C mol -1 ), V s is the solution volume (L), (TOC) exp is the experimental TOC decay (mg L -1 ), 4.32×10 7 is a homogenization factor (3600 sh -1 × 12,000 mg mol -1 ), m is the number of carbon atoms of piroxicam (15) and I is the applied total current (0.1-1A). The EF and AO treatments of 250 mL piroxicam solution (0.08 mM) were comparatively tested to clarify their relative oxidation power on mineralization. Figure 6.5 shows that, mineralization rate increased with increasing current intensity in all cases, due to high concentration of  OH produced accelerating the oxidation process (Eqs. (6.1), (6.2) and (6.4)). The evolution of MCE with electrolysis time decreased with current intensity increased, and with an obvious difference between current density of 100 and 300 mA, but not too much from 300 to 1000 mA. About λ7% mineralization percentage was achieved in DD anode applied system after 6 h electrolysis at 1000 mA in both EF and AO system. However, it was about 80% mineralization percentage for Pt anode in EF. Meanwhile, the maximum value of MCE in DD (  OH) system was about 30% but only 8% for Pt (  OH), indicating a lower oxidative ability of Pt(  OH) compared to DD(  OH) in mineralization of piroxicam. In DD(  OH) application system, EF leads to a faster mineralization than that of AO [4λ, 50 .

C
As showed in Fig. 6.5, mineralization process can be divided into two stages. In the early electrolysis time, piroxicam and its intermediates are mineralized into CO 2 , which was evidenced by a quick TOC decrease and a higher MCE achieved. In the later stage, the mineralization rate as well as MCE slow down and become similar in different processes. This could be ascribed to the formation of more hardly oxidizable by-products in the treated solution, such as carboxylic acids, ion-complexes and etc.

Less oxidizing ability oxidants are produced when overload  OH produced in solution, as reaction listed below, which wastes the oxidative ability energy, lowers the efficiency vs. electrolysis time [51, 52 ,

2  OH → H 2 O 2 (6.8)
 OH + H 2 O 2 → HO 2  + H 2 O (6.9)

Kinetic study of piroxicam oxidation with hydroxyl radicals

The determination of absolute rate constant (k pir ) of piroxicam oxidized by  OH was achieved by the method of competitive kinetics [53], which was performed in equal molar concentration (0.08 mM) of piroxicam and p-hydroxybenzoic acid (p-HBA) by

EAOPs. The analysis was performed at the early time of the degradation to avoid the influence of intermediates produced during the process. The reaction of most organic Chapter 6: Removal of piroxicam from aqueous solution: comparison of anodic oxidation and electro-Fenton processes performances 159 molecules with  OH is assumed as a pseudo -first -order kinetic, that the absolute rate constant is calculated by [54]:

Ln [] [] / Ln [pH A 0 [pH A t (6.10)
where kpHBA is well known as 2.19 × 10 9 M -1 s -1 [55], the subscripts 0 and t are the reagent concentrations at time t = 0 (initial concentration) and at any time t of the reaction.

Ln [pir] 0 /[pir] t / Ln [pHBA] 0 /[pHBA] t provides a good linear relationship (R 2 = 0.λλλ), with -b‖ as 1.002. The value of the rate constant kpir was calculated as 2.19 ( 0.01) × 10 9 M -1 s -1 , which is less than the data reported as 17 × 10 9 M -1 s -1 [56]

Evolution of the intermediates formed during the EAOPs

The final by-products of piroxicam generated by EAOPs are not only water, carbon dioxide, but also inorganic ions such as ammonium, nitrate, and sulfate ions, and some short chain carboxylic acids. Due to similarities of piroxicam mineralization rate and evolution of inorganic ions release for EF-BDD and AO-BDD processes, the identification and quantification of short chain carboxylic acids produced during piroxicam electrolysis were performed at the same current intensity for EF-Pt and EF-BDD processes. Figure 6.7 shows that, maleic, malonic, oxamic, glyoxylic acids appeared at early electrolysis time and reached their maximum concentration after about 50 min electrolysis time, while acetic and oxalic acids were persistent for both processes. It can be observed that the main Chapter 6: Removal of piroxicam from aqueous solution: comparison of anodic oxidation and electro-Fenton processes performances 161 carboxylic acids produced were largely accumulated using Pt but rapidly eliminated using BDD anode. All the organic acids formed during the process, except the persistent ones, were reduced to a non-detected level and finally the ultimate carboxylic acids were converted to carbon dioxide and water with an almost total mineralization. The highest amount of organic acids formed were glycolic (0.02 mM) and oxamic (0.015 mM) acids for EF-Pt, while maleic (0.019 mM) and oxalic acids (0.015 mM) for EF-BDD, respectively. At 6 h electrolysis time, oxalic acid contributed 0.078% and 0.03% to the TOC in EF-Pt and BDD processes, respectively. The persistence of oxalic acid in solution may be able to explain the remaining TOC observed for the treatments. The formation of stable complex of oxalic acid with Fe 2+ or some other hardly oxidizable compounds may explain the non-complete removal of organic compounds [39,57]. It is obvious that there was no clear difference between processes applied (EF-Pt, EFF-BDD or AO-BDD) on the evolution of toxicity of piroxicam treated samples.

However, at 1 A, the toxicity was lower than the initial value after 40 min electrolysis.

The presence of luminescence inhibition peaks is related to formation of toxic intermediates accumulated or degraded at different rate vs. electrolysis time. As the results show, later, the toxicity decreased enough low that indicated that EAOPs could be operated as effective and practicable treatments at wastewater treatment plants.

Conclusion

The electrochemical oxidation of piroxicam by electro-Fenton and anodic oxidation processes by using BDD or Pt anode at lab-scale have been studied to get insight on the applicability of this technology for the removal of piroxicam in tap water.

The fastest degradation and mineralization rates of piroxicam were achieved upon addition of 0.2 mM Fe 2+ in EF process. It was found that pH of solution influenced the degradation rate as well as air bubbling on mineralization efficiency of piroxicam in AO process. The higher current intensity applied, the higher removal rate was achieved, but with lower value of MCE obtained. The EF system provided higher degradation efficiency compared to AO process, while BDD (  OH) showed a higher mineralization rate compared to Pt(  OH). The absolute rate constant of piroxicam with  OH was obtained as (2.19  0.01) × 10 9 M -1 s -1 by competitive kinetics method. The evolution of short chain carboxylic acids and inorganic ions concentrations during piroxicam mineralization by EAOPs were monitored. The results were in good agreement with TOC abatement under the same operation condition. Finally, the toxicity of solution oxidized by EAOPs showed that current intensity influenced more on the toxicity removal than the kind of treatment applied. As showed by the results of degradation, mineralization, evolution of the intermediates and toxicity of piroxicam in tap water, EF-BDD could be an effective and environment friendly technology applied in wastewater treatment plants. NSAIDs have been detected in the order of ng L -1 or g L -1 in effluents of wastewater treatment plants, surface water, groundwater and drinking water [4][5][6]. Considering that in many areas, surface water is the main source for drinking water, the potential adverse impact of NSAIDs on water resources have gathered considerable attention [7][8][9][10][11][12]. In 2011, the World Health Organization (WHO) published a report on pharmaceuticals in drinking-water which reviewed the risks to human health associated with exposure to trace concentrations of pharmaceuticals in drinking-water, raising the fear that the continuous input of pharmaceuticals may pose a potential risk for organisms living in both terrestrial and aquatic environments [13][14][15].

Naproxen, ketoprofen and piroxicam, are frequently consumed NSAIDs [16][17][18],

which have been detected in environmental samples, with up to 33.9 g L -1 (naproxen) in the effluent of the secondary settler of a municipal waste water treatment plant [19][20][21][22][23]. Once in receiving waters, possible adverse effects such as reducing lipid peroxidation by bivalves were reported for naproxen [24,25], and sometimes leading to the accumulation of intermediates more toxic than the parent compound [26,27]. The co-toxicity of naproxen with other pharmaceuticals was also studied, that toxicity of mixture was considerable, even at concentrations for which the single substances showed no or only very slight effects [28]. Reported EC 50 as low as 21.2 g L -1 for the ToxAlert ® 100 test and 35.6 g L -1 for the Microtox ® test was obtained for naproxen [23].

Considering the hazards of persistent pharmaceuticals in the environment, various technologies for removing them have been studied. Ozonation treatment, utilizing the high redox potential of O 3 (Eº = 2.07 V/SHE) [29], can be effective against chlorineresistant pathogens, and is applied as a useful tool for plant operations to help control taste and odor, color, and bacterial growth in filtration beds used in purification of drinking water and wastewater [30][31][32][33][34]. With wide-scale adoption of ozonation for water treatment in both North America and the E.U., the study of the removal of M -1 s -1 , and k OH of 9.6 × 10 9 M -1 s -1 for naproxen [38]. The second-order rate constant for ketoprofen was determined by O 3 as 0.4  0.07 M -1 s -1 , and k OH (Fenton process) as 8.4  0.3 × 10 9 M -1 s -1 [39]. The ozone oxidation kinetics of piroxicam are unknown

Ozone applied for water treatment can increase biodegradable organic carbon levels (BDOC), producing readily bio-degradable substrates for down-stream bacteria and biofilm growth [40]. To control post-O 3 BDOC, water treatment facilities have employed biologically-active filtration media. Granular activated carbon (GAC) is one popular support medium that has been shown to remove a wide-range of organic contaminants [41], and has ample surface area for biofilm attachment along with the ability to adsorb some of the influent biodegradable organic matter or organic materials released by microorganisms [42]. Both aqueous pollutants and ozonation by-products are adsorbed on the solid support medium and oxidized by supported microorganisms into environmentally acceptable metabolites such as carbon dioxide, water and additional biomass. As expected, most investigated pollutants so far have shown excellent removals by combination of ozone and GAC application [43,44].

The objective of this study was to observe the oxidation kinetics for 3 emerging aquatic pollutants of concern (the NSAIDs: piroxicam, ketoprofen, and naproxen) under varying ozone treatment regimes, and to both quantitatively and qualitatively assess the pathways for intermediates formation. from Florida Lake Watch water chemistry summary.

Ozonation

Ozone stock solution (20-30 mg O 3 L -1 ) was produced with a plasma-arc ozone generator (RMU16-04, Azcozon) utilizing compressed, purified oxygen (moisture removed through anhydrous CaSO 4 ). The temperature of the ozone stock solution was maintained at 6°C or less in an ice bath through a water-jacketed flask containing 10 mM phosphate buffered solution (pH 6). Ozone dosing was performed by injecting the ozone stock solution (0-4 mg L -1 ) via a digital titrator (Titronic basic) into a 100 mL amber boston-round bottle, continuously stirred, and immediately capped to prevent ozone degassing. At specific reaction times, indigo solution was added to quench the residual O 3 . For select samples H 2 O 2 was added 30 seconds prior to the addition of ozone stock solution (1 mg L -1 ), with continuous mixing.

Ozone concentration was determined according to the standard colorimetric method (4500-O 3 ) with indigo trisulfonate at l = 600 nm (ε = 20000 M -1 cm -1 ) [45]. All

BAC Bio-filtration

Biological activated carbon (BAC) testing, with GAC media sampled from an active bio-filtration facility (Tampa, FL), was conducted using rapid, small-scale column tests to predict its performance. The sampled filtration media was added to a 5

Total organic carbon (TOC)

Carbon mineralization in oxidized samples was monitored by total organic carbon content, as measured with a Teledyne Tekmar Phoenix 8000 UV persulfate TOC analyzer. A non-dispersive infrared detector (NDIR) was used to measure CO 2 .

Calibration of the analyzer was attained by dilution of Teledyne Instruments-Tekmar certified standard solution (800 ppm), standards for total carbon (TC) and inorganic Chapter 7: Pharmaceuticals cytotoxicity evolution and removal with ozonation and biofiltration 178 carbon (IC), respectively. Reproducible TOC values with ±2% accuracy were found using the non-purgeable organic carbon method.

Microbial toxicity

Cytotoxicity of the NSAIDs and their oxidized intermediates in treated solutions

was assessed with a commercially-available bio-assay using bioluminescent marine bacteria V. fischeri (Microtox, Modern Water), according to manufacturer's specifications. The reduction in measured luminescence (RLU) is reported as inhibition (%) in cell viability after sample exposures of 5 and 15 min at 15°C. The bioluminescence measurements (GloMax 20/20 Luminometer, Promega) were realized in solutions oxidized with varying degrees of ozonation, and on a blank (C 0 = 0 mg L -1 of O 3 ).

Electrospray ionization mass spectrometry (ESI-MS)

The intermediates produced during the ozonation of NSAIDs were determined by an electro-spray-ionization-mass spectrometry (ESI-MS) system (AccuTOF JEOL; 90 eV). The needle voltage was 2000 V. The temperature of the orifice, de-solvation chamber and interface were 80, 250 and 300 °C. Samples were diluted 10 times in MeOH (0.1% formic acid), while 20 L of this was injected in a stream of MeOH (0.1% formic acid, v/v), flowing at a rate of 200 L min -1 .

Results and Discussion

Removal efficiency by ozonation/AOP (O 3 /H 2 O 2 ) of NSAIDs in surface water and Type II lab water

The treatment efficiency of ozonation highly depends on the chemical structure of the target compounds, as ozone is known to favor compounds with unsaturated double bonds or moieties with electron donation potential [46]. For instance, different removal efficiencies of pharmaceuticals were reported for the same compound in river water as compared to distilled water with ozonation [47,48]. Advanced oxidation processes with the addition of hydrogen peroxide to promote hydroxyl radical reactions may help to improve contaminant elimination during ozonation, however like all unit processes, ozonation requires optimization before any treatment effect can be noticed.

For the optimization of ozonation/AOP for the target NSAIDs (initial concentration of 2 mg L -1 ), the following parameters were varied: water matrix (Type II lab water, lake water), ozone dose (0, 0.5, 1, 1.5, 2, 3, 4 mg L -1 ), and the mole ratios of To achieve sufficient reaction between pollutants and ozone, NSAIDs solutions were firstly sampled at different oxidized times after adding an initial 2 mg L -1 O 3 dose.

Results confirmed 2 min was adequate to ensure >90% oxidation of all 3 organic compounds in Type II lab water (Fig. 7.1).

As expected, increasing the initial ozone dose contributed to greater oxidation of selected NSAIDs (contact time = 2 min). The trend of increasing removal efficiency at increasing ozone dose for NSAIDs in surface water was similar to that of Type II lab water (Fig. 7.2). However, a lower removal rate was obtained, due to background oxidant scavengers in the surface water. At an ozone dose of 4 mg L -1 , the removal rate was 95%, 99% and 96% in Type II lab water (Fig. 7.2. A), while 84%, 90%, and 77% removal was observed in surface water for ketoprofen, naproxen and piroxicam (Fig. 7.2. B), respectively. In the range of ozone dose (from 0.5 mg L -1 to 2 mg L -1 ) applied in Type II lab water, the degradation rate increased more than 40%, while in the range of 2 mg L -1 to 4 mg L -1 , the removal rate increased less than 6%. Based on the results, 2 mg L -1 could be selected as the optimal oxidant dose for remaining ozone exposures to achieve >90% of the NSAIDs.

Kinetic of ozonation of piroxicam in Type II lab water

The absolute rate constant (k PIR,O3 ) of piroxicam degradation by O 3 was determined by accepted competition kinetics methods [49]. The reference compound, bisphenol A (BPA, k BPA : 2.7 × 10 6 M -1 s -1 ), was selected due to its known reaction rates with ozone under acidic condition, and with  OH [50]. The ozonation treatment was performed on both compounds in equal molar concentration (6 M) and under the same operating conditions (ozone dose = 0, 0.25, 0.5, 0.75, 1, 1.5 mg L -1 , pH = 6.0, V = 150 mL), while mechanically stirring. At acidic pH, ozone decomposition to  OH becomes negligible [51]. Concentrations of both the reference and probe compounds remaining in solution were analyzed by HPLC. Under direct ozonation, the absolute rate constant was calculated by: ln

[ ] [ ] / ln [ ] [ ] (7.1)
where the subscripts 0 and n are the ozone dose of the reaction.

The resulting linear relationship allows for the determination of the absolute rate constant for oxidation of piroxicam with ozone, by the slope of the intergrated inectic equation (y PIR = 1.22 × k BPA, R 2 = 0.98). The value of k PIR,O3 was determined to be 3.3 ( 0.1) × 10 6 M -1 s -1 .

Sequential ozonation and biofiltration

With an initial O 3 dose of 1 mg L -1 , the biofiltration was set up to treat the solution oxidized by ozonation at different EBCT while measuring both degradation of NSAIDs and associated toxicity. The EBCT presents the extent of solution contact with the biofilm-supporting GAC filtration bed. Biofiltration was able to improve NSAIDs removal rates following ozonation by 50%, 17%, and 43%, at 5 min of EBCT for ketoprofen, naproxen and piroxicam, respectively. The removal efficiency was better than that of the application of H 2 O 2 and O 3 at ratio of 1, with the exception of naproxen solutions. At an EBCT of 15 min, the total removal rate of combined Chapter 7: Pharmaceuticals cytotoxicity evolution and removal with ozonation and biofiltration 184 ozonation/biofiltration achieved 93%, 88% and 92% for ketoprofen, naproxen and piroxicam, respectively. As the results showed, an EBCT of 5 min is effective contact time for ketoprofen and piroxicam while 10 min was most effective for naproxen (Fig. The structures produced from ketoprofen have been identified by literatures of Salgado [59] via photodegrdation, Kosjek also via phototransformation [60], and

Toxicity Evaluation

Considering that in the array of intermediates formed during ozonation of NSAIDs in surface waters, some by-products will be more or less pharmaceuticallyactive than others. It is critical for water treatment plant operators to be able to assess formation of cytotoxic products with fluctuating influent and ozone oxidation conditions. In addition, for plants employing BAC filtration to quench residual toxicity and oxidants following ozone and AOPs, a rapid bioassay, like Microtox, can be used to assess multi-barrier treatment efficiency, and is known to indicate the toxic potency of a broad spectrum of compounds with different modes of action. After an initial ozone dose of 2 mg L -1 , Figure 7.7 depicts the evolution of cytotoxicity with increasing contact time. The trend of decreasing biolumiscence inhibition is evident, except at t = 20 s where there was an inhibition peak for all the three compounds. Evolution of toxicity of NSAIDs treated by ozonation at different ozone dosages is shown in Figure 7.8. The contact time for all ozone doses was 2 min before quenching. The toxicity decreased with the higher ozone doses applied in each water matrix containing NSAIDs. While at the ozone dose of 1 mg L -1 , an increase in toxicity for both piroxicam and ketoprofen occurred in both water matrices. At this dose, significant concentrations of toxic byproducts accumulated in the solution that were not eliminated, likely to be hydroxylated benzophenone, catechol, benzoic acid, and some alkyl groups [63]. The toxicity in Type II lab water decreased faster than in surface water, most likely due to the slower oxidation kinetics in surface water with increased oxidant scavenging by other dissolved solutes.

The effect of H 2 O 2 and O 3 on inhibition of luminescence by V. fischeri bacteria in NSAIDs solutions was also studied. As shown in Figure 7.9, the inhibition curves for the compounds treated in Type II lab water decreased with the application of higher toxicity evolution for the three compounds selected, it was evident that naproxen exhibits higher toxicity to V.fischeri than the other selected NSAIDs, which can be explained by the potential for more aromatic by-products present in the solution (Fig. However, solution toxicity was observed to decrease until an EBCT of 10 min, with another increase at 15 min of EBCT. The inhibitory effects of ketoprofen decreased up to 8 min EBCT, then increased; however, the observed level of inhibition was always lower than the value produced by O 3 alone. The increasing inhibition of bioluminescence at longer EBCT was also confirmed by Reungoat et.al [64], indicating that increasing the contact time during biofiltration would not improve the water quality further.

In combination with the efficiency of degradation at different EBCT, good removal rates and lower toxicity were achieved at 8 min for all three compounds. Due to the expected benefits to operating costs and observed rates of NSAID degradation and toxicity removal, ozonation followed by BAC treatment for polishing drinking water, can provide effective and efficient barriers to wastewater-derived, pharmaceuticallyactive organic contaminants in surface water. As an important parameter influencing the process efficiency, a series of catalyst concentrations applied in EF was firstly operated at a low current intensity (i.e. 100 mA).

The best removal rate was obtained with 0.1 mM Fe 2+ for ketoprofen and naproxen, while 0.2 mM was needed for piroxicam. The degradation rate was significantly slowed In contrast when monitoring the mineralization rate for AO process, pH was not significantly influencing the NSAID molecules mineralization rate. Same mineralization removal trends were obtained for ketoprofen and naproxen. However, the mineralization rate was better at pH 3, followed by at pH 9.0 and 5.4 with no much difference for piroxicam.

Afterwards, effect of bubbling compressed air through the solution in AO process at pH of 3 (higher removal rate) was then performed. It showed that the air bubbling influenced efficiency, the removal rate was lower than pH of 3.0, but higher than other pH applied in this research. All the degradation kinetics well fitted to a pseudo-first order reaction.

The percentage of TOC removal can reach to above 90% at 2 hour electrolysis time of 1000 mA applied intensity. The trends of evolution of mineralization of current efficiency (MCE) with electrolysis time decreased with increasing current intensity.

There was an obvious difference between current density of 100 and 300 mA, but not too much with the upper current values.

The EF process with BDD or Pt anode has better removal rate than AO with BDD anode in degradation as the results showed. While in the mineralization part, the EF-BDD has the best removal rate but followed by EF-Pt or AO-BDD for different pollutants treated.

Optimization of the ozonation/biofiltration treatments

The experiments using ketoprofen, naproxen and piroxicam of 2 mg L -1 in both lab (de-ionized) and surface water were operated for the optimization of the ozonation/biofiltration treatments.

The effect of contact time as well as efficient ozone doses requested to reach the best removal of three compounds in lab water was studied. The results showed that 2 min was enough to ensure >90% oxidation of all the three pharmaceutical compounds in lab water, and afterwards, 2 min was applied in all ozone experiments as contact time.

The optimization of ozone dose was applied in both type II lab and surface water in the Chapter 8 General Discusion 204 experiments. As expected, the increasing initial ozone dose contributed to greater oxidation in both lab water and surface water, but a lower removal rate in surface water, due to the presence of background oxidant scavengers (natural organic matters). In the range of ozone dose from 0.5 mg L -1 to 2 mg L -1 , the degradation rate increased more than 40%, while less than 6% in the range of 2 mg L -1 to 4 mg L -1 in type II lab water.

Based on the results, 2 mg L -1 was selected as the optimal oxidant dose with >90% removal rate.

In and 92% for ketoprofen, naproxen and piroxicam, respectively at an EBCT of 15 min.

As the results showed, an EBCT of 5 min is an efficient contact time for ketoprofen and piroxicam while 10 min for naproxen, due to not much improvement of removal rate was obtained afterwards. Otherwise, the increasing solution temperature helped to improve the removal efficiency in ozonated surface water.

Kinetic study for the degradation

The absolute rate constant of the oxidation by electrochemically generated hydroxyl radicals was determined by using competition kinetics method. The p-Chapter 8 General Discusion 206 hydroxybenzonic acid (p-HBA) was selected as standard competitor. The values were determined as (2.8  0.1) × 10 9 M -1 s -1 , (3.67 ± 0.03)  10 9 M -1 ·s -1 and (2.19  0.01) × 10 9 M -1 s -1 for ketoprofen, naproxen and piroxicam, respectively. The absolute rate constant of piroxicam reacted with O 3 was determined as (3.3  0.1) × 10 6 M -1 s -1 .

Pathway of the mineralization of the pharmaceutials

For the investigation of electrochemical oxidation on the compounds selected, the identification of the intermediates formed during the mineralization was performed at a lower current intensity (i.e. 50 to 100 mA) with Pt as anode. It was observed that the aromatic intermediates were formed at the early stage of the electrolysis in concomitance with the disappearance of the parent molecule. For the evolution of main carboxylic acids, the similar trends were obtained but EF-BDD had a quicker removal rate than EF-Pt. Oxalic and acetic acids were persistent during the whole processes in all the compounds oxidized solutions.

For piroxicam, inorganic ions such as ammonium, nitrate, and sulfate ions were identified and quantified by ion chromatography during the mineralization. About 70% of the nitrogen atoms were transformed into NO 3 -ions, whereas only about 25% NH 4 + ions were formed to a lesser extent. For sulfur atoms, about 95% converted into SO 4

2ions at the end of the electrolytic treatments. Similarly, EF-BDD has a higher releasing inorganic ions concentration than EF-Pt.

Based on the identified aromatic intermediates and carboxylic acids as endproducts before mineralization, plausible mineralization pathways were proposed. In total, the reaction happens by addition of  OH on the aromatic rings (hydroxylation) or by H atom abstraction reactions from the side chain propionic acid group. These

Toxcity evolution of the solution treated

The evolution of effluent toxicity during AOPs treatments was monitored by Microtox ® method with exposure of Vibrio fischeri luminescent bacteria to the oxidized solutions.

For EAOPs, experiments were conducted over 120 min electrolysis times at two current intensities. The toxicity (as % luminescence inhibition) increased quickly at the early treatment time, and then decreased below its initial percentage. This is due to the degradation of primary intermediates and formation to secondary/tertiary intermediates that can be more or less toxic than previous intermediates. Then toxic intermediates are removed by oxidation. It was observed no much inhibition difference between treatments, while luminescence inhibition lasted longer for smaller current intensities values, which was attributed to  OH formation rate as function of current intensity value.

When ozonation is combined with biofiltration system, the results indicated a decreasing biolumiscence inhibition for ozone contact time experiments for all the three compounds, except an inhibition peak at 20 seconds. The toxicity decreased with the higher ozone doses applied in each water matrix but an increasing value at the ozone dose of 1 mg L -1 for both piroxicam and ketoprofen was noticed. At this sampling solution oxidized, more toxic byproducts may be accumulated in the solution that were not eliminated, as hydroxylated benzophenone, catechol, benzoic acid, and some alkyl groups identified in intermediates part. The toxicity decreased faster in lab water than in surface water. This difference is likely due to the pollutants oxidation rate slowed down by other dissolved solutes (mainly natural organic matter).

Chapter 8 General Discusion 208

When ozonation is combined with H 2 O 2 treatment, the luminescence inhibition of the combination application was significantly lower than with ozone applied alone.

At ozone/biofiltration treatments, the evolution of toxicity decreased till 10 min but with a slow increase afterwards, meaning that increasing the application time of biofiltration would not improve the water quality furthermore. With the increasing bacteria of high temperate, the toxicity decreased in the temperature from 0 to 35 degree.

In all the processes, the oxidized naproxen solution has higher inhibition value than other two as the toxicity evolution showed, which also can be concluded that more aromatic by-products present in the solution, which raises the toxicity.

Perspective for the future works

Beside the emphasis on the optimization of the AOPs, the elucidation of degradation pathway and the evolution of effluent toxicity, the improvements for AOPs to produce safe water for the future work have been summarized as follows.

1.

As mentioned above (see chapter 2), most investigations are done at labscale. For a practical view and commercial uses, much more work is necessary to switch from batch work to a large scale to find out the efficiency and ecotoxicity of the processes.

2.

Regarding most researches on model aqueous solutions or surface waters, more focus can be put in actual wastewaters from sewage treatment plants or effluents from pharmaceutical industrial units.

3.

The rational combination of AOPs and other process can be a step towards the practical application in water treatments plants. The attention should be paid to the economical (biofiltration) and renewable energy (solar light), better removal efficiency, and lower ecotoxicity risk of complex pollutants during the oxidation.

4.

More point of views, such as technical, socioeconomic and political one, can be applied for the assessment of AOPs. Also, these aspects are useful for the improvement of sustainability of the wastewater management.

Conclusion

The removal of the nonsteroidal anti-inflammatory drugs ketoprofen, naproxen and piroxicam from tap water was performed by EAOPs such as EF and AO. The effect of operating conditions on the process efficiency, such as catalyst (Fe 2+ ) concentration, Chapter 8 General Discusion 209 applied current intensity value; nature of anode material, bulk solution pH, and air bubbling was studied. The effectiveness of degradation by these AOPs was also studied by determining the intermediates generated and the toxicity of degradation products was evaluated. One can conclude that:

1.

The fastest degradation rate of ketoprofen and naproxen by EF was reached with 0.1 mM of Fe 2+ (catalyst) concentration, while 0.2 mM iron was requested for piroxicam. Further increase in catalyst concentration results in decrease of nonsteroidal anti-inflammatory drugs oxidation rate due to enhancement of the rate of the parasitic reaction between Fe 2+ and  OH.

2.

The degradation curves by hydroxyl radicals within electrolysis time followed pseudo-first-order reaction kinetics. Increasing current density accelerated the degradation processes. The oxidation power and the removal ability was found to follow the sequence AO-BDD < EF-Pt < EF-BDD, indicating higher oxidation power of BDD anode compared to Pt anode.

3.

Solution pH in AO affects greatly the oxidation efficiency of the process for all the three compounds. The value of pH 3 allows reaching the highest nonsteroidal anti-inflammatory drugs degradation rate.

4.

The absolute (second order) rate constant of the oxidation reaction by  OH was determined as (2.8  0.1) × 10 9 M -1 s -1 , (3.67 ± 0.03)  10 9 M -1 ·s -1 , and (2.19  0.01) × 10 9 M -1 s -1 by using competition kinetic method for ketoprofen, naproxen and piroxicam, respectively.

5.

High TOC removal (mineralization degree) values were obtained using high current intensity, and the highest mineralization rate was obtained by EF-BDD setup. The mineralization current efficiency (MCE) decreased with increasing current intensity, due to the side reaction and energy loss on the persistent byproducts produced, such as oxalic and acetic acids.

6.

Intermediates identified showed aromatic intermediates were oxidized at the early stage, followed by the formation of short chain carboxylic acids from the cleavage of the aryl moiety. The remaining TOC observed can be explained by the residual TOC related to persistent oxalic and acetic acids present already in solution at trace level even in the end of treatments.

7.

A plausible oxidation pathway for each compound by hydroxyl radicals was proposed based on the identification by HPLC. Finally the obtained results of degradation, mineralization, evolution of the intermediates and solution toxicity show that the EAOPs, in particular electro-Fenton process with BDD anode and carbon felt cathode, are able to achieve a quick elimination of the pharmaceuticals from water, could be applied as an environmentally friendly technology.

The removal efficiency, intermediates formed and evolution of toxicity toward V.

fischeri for ketoprofen, naproxen and piroxicam after ozone/O 3 /H 2 O 2 /BAC treatments in lab and lake water was monitored for ketoprofen, naproxen and piroxicam. Results

showed:

1.

2 min is an efficient contact time for ozone reaction with the pollutants.

The removal rates increase with increasing O 3 dose, O 3 /H 2 O 2 , and EBCT in ozone/AOP/BAC application, albeit a lower oxidation rates obtained in the sampled surface water than in organics-free lab water.

2.

The intermediates produced during the oxidation were identified and pathways for the mineralization were proposed. Inhibition of bacterial luminescence percentages declined with higher O 3 dose, O 3 /H 2 O 2 , and limited longer EBCT, for all 3 oxidized pharmaceutical solutions. Of the EAOPs and ozonation/biofiltration system, all the process could achieve >90% removal under the optimized condition. Under the best conditions, however, almost 100% removal achieved. The best treatment results were obtained with Chapter 8 General Discusion 211 the EF process, which under the optimal pH equal to 3 and catalyst (Fe 2+ ) concentration around 0.1 mM for three compounds. For higher current intensity the removal efficiencies were less time dependent and essentially it was not worth increasing the current over 300 mA, as the benefit increase not significantly with a contact time of up to 40 min (degradation) and 4 h (mineralization) electrolysis time.

Regarding ozonation, this process gave excellent results of the removal of pharmaceuticals leading to >90% in 2 min at the ozone dose of 2 mg L -1 . At less dose of 1 mg L -1 of ozone, coupling with H 2 O 2 addition or biofiltration application, the removal was also sufficient to reach more than 90%. In any case the necessity of coupling treatment by biofiltration would imply an additional step in the global treatment scheme.

On the basis of the results of the present study it is hypothesized that the performance of electrochemical oxidation is better than ozonation/biofiltration system with regard to the TOC abatement, detection of intermediates and evolution of solution toxicity (except 4 mg L -1 O 3 achieved similar toxic value). During oxidation they accumulate in the solution and oxidize further, simultaneously removal of a primarily present pollutant.

I

  Parole chiave: Processi di Ossidazione Avanzata; Electro-Fenton, Ossidazione Anodica, Ozonizzazione, Biofiltrazione; Ketoprofen, Naproxene, Piroxicam. time half maximal effective concentration for 50% reduction of the response during exposition to a drug (mg L -median lethal dose required to kill 50% of the members of a tested population after a specified test duration (mg L -1 ) Pharmaceuticals with different physicochemical and biological properties and functionalities already have been largely consumed over the last 50 years. These compounds are most notably characterized by their more or less specific biological activity and low mocro-biodegradability feature. As the fate of pharmaceuticals in environment shows, most of them are discarded in their original chemical structures or metabolites via toilet (human only can metabolize a small percentage of the medicines), or production facilities, hospitals, and private household into the municipal sewers. Others from solid waste landfill or manure waste could enter into the water cycle, due to their nonadsorbed polar structure [1-3]. The traditional wastewater treatment plants are mostly not designed to deal with polar micropollutants such as pharmaceuticals. With the respect of pharmaceutical characteristic being resistent to microbial degradation, low removal percentages are performed in the secondary treatment in traditional water treatments. Such final effluents containing residual pharmaceuticals are discharged into natural surface water bodies (stream, river or lake). Low removal efficiency of pharmaceuticals by conventional wastewater treatment plants requests for more efficient technologies and nowadays research on advanced oxidation processes (AOPs) have become a hot topic. AOPs, rely on the destruction of pollutants by highly reactive oxidant species, such as hydroxyl radical (  OH), ion superoxide (O 2 -

Chapter 1 General Introduction 3 classified

 3 in this context. As researches in different water matrix showed, ozonation,

Fig. 1 . 1 .

 11 Fig. 1.1. Chemical structure of ketoprofen

3 Fig. 1 . 2 .

 312 Fig. 1.2. Chemical structure of naproxen

Fig. 1 . 3 .

 13 Fig. 1.3. Chemical structure of piroxicam

Fig. 2 . 1 .Table 2 . 1 . 2 :

 21212 Fig. 2.1. General structure of NSAIDsIn Table2.1, it is shown a classification of NSAIDs according to their chemical structure. This table also shows the most frequently detected pharmaceuticals in environment.

Chapter 2 : 12 Fig. 2 . 2 .

 21222 Fig. 2.2. Pathway for the occurrence of pharmaceuticals in aqueous environment

2 :

 2 by direct electrochemistry (anodic oxidation, AO) or indirectly through electrochemically generation of Fenton's reagent. In the first case  OH are generated heterogeneously by direct water discharge on the anode while in the last case  OH are generated homogeneously via Fenton's reaction (electro-Fenton, EF). Both processes are widely applied to the treatment of several kind of wastewater with an almost Chapter Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes. A review 21 mineralization efficiency in most cases. They can be applied in a variety of media and volumes; also can eliminate pollutants in form of gas, liquid, and solid. The use of electricity for water treatment was first suggested in 1889[START_REF] Guohua | Electrochemical technologies in wastewater treatment[END_REF]. Since then, many electrochemical technologies have been devised for the remediation of wastewaters[START_REF] Robinson | Remediation of dyes in textile effluent: a critical review on current treatment technologies with a proposed alternative[END_REF][START_REF] Martinez-Huitle | Electrochemical oxidation of organic pollutants for the wastewater treatment: direct and indirect processes[END_REF][START_REF] Rajkumar | Electrochemical treatment of industrial wastewater[END_REF], like anodic oxidation (AO), electro-Fenton (EF), photoelectro-Fenton (PEF), and sonoelectro-Fenton [102], providing valuable contributions to the protection of the environment through implementation of effluent treatment and production-integrated processes. The non-selective character of  OH helps to prevent the production of unwanted by-products that could minimize waste, making them as promising technologies to treatment of bio-refractory compounds in waters[103,[START_REF] Sires | Remediation of water pollution caused by pharmaceutical residues based on electrochemical separation and degradation technologies: A review[END_REF].

Chapter 2 :

 2 Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes. A review 23 treatment of pollutants, the kinetic of both processes being mass-transport controlled [107].

Figure 2 .

 2 Figure 2.3 shows a brief scheme of the main processes which should be considered to understand an anodic oxidation process.

Chapter 2 : 4 Fig. 2 . 4 .

 2424 Fig. 2.4. Proposed electro-oxidation degradation pathway of diclofenac (Adapted from ref [125] with Copyright from 2009 Elsevier).

Fig. 2 . 5 .

 25 Fig. 2.5. Effect of supporting electrolyte on TOC removal (electrolyte concentration: 0.1 M, ketoprofen: 5 mM, initial pH: 6.00, T: 25 °C, applied current density: 8.8 mA cm -2 , ( ) BDD-NaCl, (*) BDD-Na 2 SO 4 , (■) DD-NaNO 3 , (•) Pt-NaCl, (▲) Pt-Na 2 SO 4 .

Chapter 2 :

 2 Bi 2 MoO 6 can absorb visible light near 460 nm and it is a visible-light driven photocatalyst for O 2 evolution from an aqueous solution. Results showed that ibuprofen and naproxen both can be degraded via photoelectrocatalytic process under visible light irradiation. The degradation rates of these molecules in the combined process were larger than the sum of photocatalysis and anodic oxidation. The ibuprofen and naproxen were also efficiently mineralized in the combined process. Hu et al. [138] developed a novel magnetic nanomaterials-loaded electrode for photoelectrocatalytic treatment. The degradation experiments were performed in a quartz photo reactor with 1.0 × 10 -3 mol L -1 diclofenac. Magnetically attached TiO 2 /SiO 2 /Fe 3 O 4 electrode was used as the working electrode, a platinum wire and a saturated calomel electrode as the counter electrode and reference electrode, respectively. A 15 W low pressure Hg lamp with a major emission wavelength of 253.7 nm was used. The result of degradation efficiency with different techniques indicated that after 60 min UV irradiation, 59.1% of diclofenac was degraded, while efficiency reached 77.3% by employing TiO 2 /SiO 2 /Fe 3 O 4 electrode. When applied + 0.8 V and UV irradiation simultaneously on the magnetically attached TiO 2 /SiO 2 /Fe 3 O 4 electrode, the degradation efficiency of diclofenac was improved to 95.3% after 45 min treatment, but the COD removal efficiency was only 47.8% after 45 min, less than half of the degradation efficiency, due Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes. A review 34 to the slow mineralization of diclofenac and difficult removal intermediates were quickly formed during the photo-electrochemical processes.

  anti-inflammatory pharmaceuticals) were monitored during the anodic oxidation treatment. Results obtained demonstrated that in the removal of emerging pollutants in actual matrixes, electrical current density in the range 20-100 A m -2 did not show influence likely due to the mass transfer resistance developed in the process when the oxidized solutes are present in such low concentrations. Removal rates fitted well to first order expressions, being the average values of the apparent kinetic constant for the electro-oxidation of naproxen 4.4  10 -2 ± 4.5  10 -4 min -1 and for ibuprofen 2.0  10 -2

Chapter 2 :

 2 Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes. A review 36 materials have been proposed for the anodic oxidation of analgesic and antiinflammatory pharmaceuticals looking for new more accurate analytical techniques based on the electrochemical behavior of a given analgesic and anti-inflammatory pharmaceutical on a particular anode surface. Accordingly, these works focused more on the description of electrodic characterization techniques than on bulk electrolysis results. Good examples are the studies about the oxidation of hispanone with Pt-Ni

Chapter 2 :Chapter 2 :Chapter 2 :Chapter 2 :

 2222 Photoelectrocatalysis (PEC); a working electrode: TSF (magnetic TiO 2 /SiO 2 /Fe 3 O 4 loaded), a counter electrode: Pt, and a reference electrode: a 15 W low pressure Hg lamp emitting at 253.7 nm

25 )

 25 Then the generated strong oxidant radical (  OH) can either dehydrogenate unsaturated compounds (RH) or hydroxylate aromatic pollutants (Ar) or other compounds having unsaturated bonds until their overall mineralization (conversion into CO 2 , H 2 O and inorganic ions). The oxidation of organic pollutants by EF process can be visualized in the catalytic cycle of Fig. 2.6b. In EF process, several operating parameters involved in process (Fig. 2.6a), such as O 2 feeding, stirring rate or liquid flow rate, temperature, solution pH, applied current (or potential), electrolyte composition, and catalyst and initial pollutant concentration influence the degradation and/or mineralization efficiency. The optimized works have been done to find best experimental conditions, which are operating at high O 2 or air flow rates, high stirring or liquid flow rate, temperatures in the range of 25-40 °C, solution pH near 3.0, and optimized Fe 2+ or Fe 3+ concentration (0.05-0.2 mM) to obtain

Chapter 2 : 45 Fig. 2 . 6 .

 24526 Fig. 2.6. (a): Sketch of a bench-scale open and stirred two electrode undivided tank reactor with a 60 cm 2 carbon-felt cathode fed with compressed air utilized for the EF treatment of organic solutions and (b): Schematic representation of the main reactions involved in the EF process in a divided cell. RH is an unsaturated compound that undergoes dehydrogenation, while Ar is an aromatic pollutant that is hydroxylated.

Photoelectro- 2 :

 2 Photoelectro-Fenton and solar photoelectro-Fenton at constant current density were studied by Skoumal et al.[START_REF] Skoumal | Electro-Fenton, UVA photoelectro-Fenton and solar photoelectro-Fenton degradation of the drug ibuprofen in acid aqueous medium using platinum and borondoped diamond anodes[END_REF]. The degradation of ibuprofen solution at pH 3.0 was performed in a one-compartment cell with a Pt or BDD anode and an O 2 diffusion cathode. It was found the induced sunlight strongly enhanced generation of  OH via PEF reaction, ascribed to a quicker photodegradation of Fe(III) complexes induced by the UV intensity supplied by sunlight. Mineralization rate was increased under UVA

Fig. 2 . 7 .

 27 Fig. 2.7. Proposed reaction scheme for the initial degradation of ibuprofen by EF and PEF. The sequence includes all aromatics detected, along with hypothetical intermediates within brackets. Pt (  OH) and BDD (  OH) represent the hydroxyl radical

  electrochemical treatment for a post-biological treatment in a flow cell. The electrochemical experiment contained the working electrode (graphite felt), which was separated from the two interconnected carbon-graphite plate counter electrode compartments by cationic exchange membranes. A good homogeneity of the potential distribution in the three dimensional working electrode was obtained when the graphite felt was located between two counter electrodes. The saturated calomel electrode as reference electrode was positioned in the middle of the felt. The electrolyte solution (0.05 M Na 2 SO 4 containing the insecticide phosmet) was percolated the porous electrode with a constant flow rate. For biological treatment, activated sludge issued from a local wastewater treatment plant was used at 30 °C and pH 7.0.

  mostly consumed and detected in environment, was discussed. From the focus of recent researches, it is clear that the most frequently removed NSAIDs by EAOPs are ibuprofen, paracetamol and diclofenac. The elucidation of the reaction pathways, byproducts generated during the treatment and their toxicities are another important consideration of electrochemical treatments. Aromatic intermediates produced from pharmaceutical residues in primary stage have significant influence on increase/decrease toxicity of solution, after while the short chain carboxylic acids generated in following steps could influence the TOC abatement. This technology was largely investigated at lab-scale; the next steps are: design of a pilot-scale reactor, investigation of the Chapter 2: Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes. A review53

Chapter 3 :

 3 Degradation of anti-inflammatory drug ketoprofen by electro-oxidation: comparison of electro-Fenton and anodic oxidation processes 76 In AO, heterogeneous hydroxyl radicals M(  OH) are generated by electrochemical discharge of water (Eq. (3.1)) or OH -(Eq. (3.2)) on a high O 2 evolution overvoltage anode (M). In the case of the boron doped diamond (BDD) film anode,  OHs are physisorbed and therefore more easily available compared, for example, to Pt anode on which  OHs are chemisorbed [25]. M + H 2 O → M(  OH) ads + H + + e - (3.1) M + OH -→ M(  OH) ads + e - (3.2) In contrast, homogeneous hydroxyl radicals (  OH) are generated by electro-Fenton process in the bulk solution via electrochemically generated Fenton's reagent (mixture of H 2 O 2 + Fe 2+ ), which leads to the formation of the strong oxidant from Fenton's reaction (Eq. (3.3)):

  0 M H 2 SO 4 , and was measured with a CyberScan pH 1500 pH-meter from Eutech Instruments, and an adequate concentration of FeSO 4 7H 2 O was added to initial solutions as source of Fe 2+ as catalyst. The currents of 100-2000 mA were applied for degradation and mineralization kinetics, by-product determination and toxicity experiments. The current and the amount of charge passed through the solution were measured and displayed Chapter 3: Degradation of anti-inflammatory drug ketoprofen by electro-oxidation: comparison of electro-Fenton and anodic oxidation processes 78 continuously throughout electrolysis by using a DC power supply (HAMEG Instruments, HM 8040-3).

Chapter 3 :

 3 Degradation of anti-inflammatory drug ketoprofen by electro-oxidation: comparison of electro-Fenton and anodic oxidation processes 79

Chapter 3 :

 3 Degradation of anti-inflammatory drug ketoprofen by electro-oxidation: comparison of electro-Fenton and anodic oxidation processes 80Catalyst concentration (i.e. Fe 2+ ) is an important parameter influencing process efficiency, particularly in the case of Fe 2+ as catalyst[17, 28]. Figure3.1 shows the degradation of a 101 mg L -1 (0.198 mM) ketoprofene in aqueous solution of pH 3, as function of time in electro-Fenton experiments using Pt/carbon felt cell at a current intensity of 100 mA with different catalyst concentrations ranging from 0.05 to 1 mM. At optimum pH condition (pH = 2.8-3.0), Fenton process take place according to equation(3.3) [17, 29, 34] to generate  OHs that react with ketoprofen. Thus the rate of  OH generation is controlled by the rate of the electrochemical generation of Fe 2+ from Eq. (3.4).

Figure 3 .

 3 Figure 3.1 shows that decay of concentration of ketoprofen was fastest for 0.1 mM Fe 2+ concentration. The degradation rate decreased with increasing Fe 2+ concentration up to 1 mM. The degradation was significantly slowed down with 1.0 mM Fe 2+ ; 80 min were necessary for completed oxidation of ketoprofen while 50 min were enough with 0.1 mM Fe 2+ . There was no much considerable change in the oxidative degradation rate for Fe 2+ concentration values between 0.1 and 0.2 mM, while the concentration of 0.05 mM implied a slower degradation rate compared to 0.1 mM.

Chapter 3 : 81 Fig. 3 . 1 .

 38131 Fig. 3.1. Effect of Fe 2+ (catalyst) concentration on the degradation kinetics of ketoprofen (C 0 : 0.198 mM) in tap water medium by electro-Fenton process with Pt anode at 100 mA and pH 3. [Fe 2+ ]: 0.05 mM ( ); 0.1 mM (); 0.2 mM (×); 0.5 mM (); 1.0 mM (▲); [Na 2 SO 4 ]: 50 mM; V: 0.25 L.

8 ) 3 :Fig. 3 . 2 . 3 :

 83323 Fig. 3.2. Effect of current intensity on the degradation kinetics of ketoprofen in tap water medium by different electrochemical processes: 100 mA ( ); 300 mA (×); 500 mA (); 750 mA (); 1000 mA (▂); 2000 mA (▲). C 0 : 0.198 mM; [Na 2 SO 4 ]: 50 mM; V: 0.25 L; electro-Fenton: [Fe 2+ ]: 0.1 mM; pH: 3.0; Anodic oxidation at pH 7.5.

Chapter 3 :Fig. 3 . 3 .Chapter 3 :

 3333 Fig. 3.3. Effect of pH and air bubbling on the degradation kinetics and mineralization degree of ketoprofen in tap water medium by AO at 300 mA: pH = 7.5 (); pH = 3 without introduced air (×); pH = 10 (▲); pH = 3 (); C 0 : 0.198 mM; [Na 2 SO 4 ]: 50 mM; V: 0.25 L.

3 : 3 . 3 . 3

 3333 0 /[KP] t ) and Ln ([p-HBA] 0 /[p-HBA] t ) provides a linear relationship, then the absolute rate constant of oxidation of ketoprofen with  OH can be calculated from the slope of the intergrated kinectic equation, which was well fitting (R 2 = 0.999). The Chapter Degradation of anti-inflammatory drug ketoprofen by electro-oxidation: comparison of electro-Fenton and anodic oxidation processes 86 value of k KP was then determined as 5.4 ( 0.1) × 10 9 M -1 s -1 . This value is lower than that reported by Real and al.[46] (8.4 ( 0.3) × 10 9 M -1 s -1 ), obtained during photo-Fenton treatment of ketoprofen. We did not find any other data in the literature for comparison. Effect of current intensity on the mineralization of ketoprofen aqueous solutins The mineralization degree is considered as an indicator of the efficiency of the treatment by AOPs. To investigate the effects of applied current intensity on the mineralization degree of ketoprofen aqueous solution, several experiments were performed in similar experimantal condition. The EF and AO treatments of 250 mL, 0.198 mM ketoprofen solution (corresponding to 38.4 mg L -1 TOC) with 0.1 mM Fe 2+ at pH 3.0 were comparatively tested for the different systems to clarify their relative mineralization power. A range of current intensity 100 mA -2000 mA was investigated.

  3.6).

Figure 3 .

 3 Figure 3.4a shows that, EF-Pt reached 91% TOC removal at 300 mA and 94% at 2000 mA, while EF-BDD reached 97% TOC removal at 300 mA and and almost 100% TOC removal at 2000 mA at the end of electrolysis. The great mineralization power of EF-BDD is related to the production of supplementary, highly reactive BDD(  OH) on the cathode compared to Pt anode. In contrast, AO-BDD reached 89% and 95% TOC removal at at 300 and 2000 mA at the end of electrolysis. Higher mineralization degrees obtained by EF process can be explained by the quicker destruction of ketoprofen and by-products with homogeneous  OH generated from Fenton's reaction (Eq. (3.3)). The oxidation reaction takes place in the mass of hole volume of the solution, while in AO,

Chapter 3 :Fig. 3 . 4 .

 334 Fig. 3.4. Effect of applied current on the mineralization efficiency (in terms of TOC removal) (a), and MCE (b) during treatment of 0.198 mM ketoprofen in tap water medium by EAOPs: 100 mA ( ); 300 mA (×); 500 mA (•); 750 mA (); 1000 mA (▂); 2000 mA (▲). [Na 2 SO 4 ]: 50 mM; V: 0.25 L. EF: [Fe 2+ ]: 0.1 mM; pH: 3.0. AO: pH 7.5.

Fig. 3 . 5 . 3 - 3 :Fig. 3 . 6 .Chapter 3 : 1 OH 1 Fig. 3 . 7 . 3 :

 353336311373 Fig. 3.5. Time course of the concentration of the main intermediates accumulated during degradation of ketoprofen in tap water medium with EF-Pt: benzophenone (); phenol ( ); 3-hydroxybenzoic acid (▲); benzoic acid (+); catechol (•); pyrogallol (×); hydroquinone ( ); ketoprofen (-). C 0 : 0.198 mM; [Na 2 SO 4 ]: 50 mM; V: 0.25 L. Electro-Fenton: [Fe 2+ ]: 1 mM; pH: 3.0; current density: 60 mA.

Chapter 3 :Fig. 3 . 8 .

 338 Fig. 3.8. Evolution of the solution toxicity during the treatment of ketoprofen aqueous solution by inhibition of marine bacteria, Vibrio fisheri luminescence (Microtox® test) during ECPs of KP in tap water medium: (▲): EF-BDD (100 mA); (×): EF-BDD (300 mA); (): EF-Pt (100 mA); (): EF-Pt (300 mA). C 0 : 0.198 mM; [Na 2 SO 4 ]: 50 mM; V: 0.25 L. EF: [Fe 2+ ]: 0.1 mM; pH: 3.0.

Chapter 3 : 1 .

 31 Degradation of anti-inflammatory drug ketoprofen by electro-oxidation: comparison of electro-Fenton and anodic oxidation processes[START_REF] Almeida | Solar photoelectro-Fenton degradation of paracetamol using a flow plant with a Pt/air-diffusion cell coupled with a compound parabolic collector: Process optimization by response surface methodology[END_REF] The fast degradation rate of ketoprofen by electro-Fenton was displayed at 0.1 mM of Fe 2+ (catalyst) concentration. Further increase in catalyst concentration results in decrease of oxidation rate due to enhancement of the rate of the wasting reaction between Fe 2+ and  OH.

(4. 6 )

 6 This extra oxidant production on the anode surface enhances the decontamination Chapter 4: Electro-Fenton removal of naproxen from aqueous medium: effect of anode material and operating conditions 103 of organic solutions which possess much greater degradation ability than similar advanced oxidation and Fenton processes alone.

Chapter 4 : 4 7H 2 O

 442 Electro-Fenton removal of naproxen from aqueous medium: effect of anode material and operating conditions 104 surrounding the counter electrode cantered in the cell, either as a 4.5 cm high Pt cylindrical mesh anode or a 24 cm 2 DD thin-film anode (double side coated on niobium substrate from CONDIAS, Germany). Compressed air was bubbled through the solution with a flow rate of 1 L min -1 . Solution was agitated continuously by a magnetic stirrer (800 rpm) to ensure mass transfer during the whole process. A DC power (HM 8040-3) was used to monitor electrochemical cell and carry out electrolyses at constant current. 0.05 M Na 2 SO 4 was induced to the solution as supporting electrolyte. As well known for electro-Fenton process, the best parameter of pH for the medium was adjusted to 3.0 by H 2 SO 4 with a CyberScan pH 1500 meter. An adequate dose of FeSO was added into initial solutions as catalyst.

  luminescence (%) of bioluminescent marine bacteria V. fischeri (Lumistox LCK 487, Hach Lange France SAS) by Microtox ® method. The value of the inhibition of the luminescence (%) was measured after 15 min of exposition of bacteria to treated solutions at 15°C. The bioluminescence measurements were performed on solutions Chapter 4: Electro-Fenton removal of naproxen from aqueous medium: effect of anode material and operating conditions 105 electrolyzed at several constant current intensities (I = 100, 300 mA), and on blank (C 0 = 0 mg L -1 naproxen).

  (4.1), (4.2), (4.4), and (4.5)), the influence of current intensity ranging from 100 to 2000 mA was determined for EF processes with Pt (EF-Pt) or DD (EF-DD) anodes versus carbon felt cathode by monitoring the degradation and mineralization of 0.1λ8 mM naproxen (Fig. 4.1.A).

  (4.1) and (4.5)) and regeneration of Fe 2+ (Eq. (4.4)) to promote the  OH generation (Eq. (4.3)). The degradation of 0.1λ8 mM naproxen was achieved at electrolysis time of 40 and 30 min at 300 mA current intensity, in contrast to 10 and 5 min at 2000 mA current intensity, under EF-Pt and EF-DD processes, respectively (Fig. 4.1.A). The monitoring of the mineralization process shows that the naproxen mineralization efficiency by EF process rapidly increased with increasing current intensity and then reached a steady state value afterwards (Fig. 4.1.

Figure 4 . 1 .Chapter 4 :material and operating conditions 109 Fig. 4 . 1 .

 41410941 Figure 4.1. shows the evolution of MCE curves as function of electrolysis time at different current intensity. It can be seen from this figure that MCE values decreased with increasing current intensity and the lower current intensity achieved the highest MCE value in all EF processes (Fig. 4.1. ). There was an obvious difference on MCE value between current density of 100 and 300 mA. However, no big difference from current density of 300 to 2000 mA was noticed. The lower MCE value of higher current intensity can be the completion between formation of H 2 O 2 (Eq. (4.1)) with parasitic

Figure 4 . 2 .

 42 Figure 4.2.A shows that high molecular weight aromatic intermediates were almost degraded in less than 60 min and lower molecular weight aromatic intermediates such as benzoic acids were removed within 140 min electrolysis time. 5dihydroxynaphthalene and 2-naphthol were produced firstly, and then disappeared quickly, followed by phenol, 1-naphthalenacetic and 3-hydroxybenzoic acids. The concentration of most of these intermediates was less than 0.017 mM. Other intermediates such as catechol, benzoic acid, phthalic acid, pyrogallol, phthalic anhydride and hydroquinone reach their highest concentration between 20 and 40 min electrolysis time, then decreased gradually within the electrolysis time till 140 min.

Chapter 4 :Fig. 4 . 2 .Chapter 4 : 4 . 3 . 5

 4424435 Fig. 4.2. Time course of the concentration of the main intermediates (A) and short chain carboxylic acids ( ) accumulated during degradation of naproxen in tap water mediumμ electro-Fenton process with Pt as anode; A (aromatic derivatives)μ 3-hydroxybenzoic acid (○); 1-naphthalenacetic ( ); phenol ( ); 1,5-dihydroxynaphthalene ( ); 2naphthol ( ); catechol (•);benzoic acid (×); phthalic acid ( ); pyrogallol ( );

Fig. 4 . 3 .

 43 Fig. 4.3.General reaction sequence proposed for the mineralization of naproxen in aqueous medium by  OH (electro-Fenton with Pt anode). The compounds displayed in the pathway proposed had been detected as by-products from literature[18, 57 .

Fig. 4 . 4 .

 44 Fig. 4.4. Evolution of the inhibition of Vibrio fisheri luminescence (Microtox® test) during electro-Fenton processes; EF-Pt (•); EF-DD ( ); 100 mA (line); 300 mA (dash line); C 0 = 0.1λ8 mM; [Na 2 SO 4 = 50 mM; V = 0.25 L; [Fe 2+ = 0.1 mM; pH = 3.0.

Fig. 4 . 5 .

 45 Fig. 4.5. Energy cost of electro-Fenton processes; EF-Pt (line); EF-DD (dash line); 100 mA ( ); 300 mA (•); 1000 mA (▲); C 0 = 0.1λ8 mM; [Na 2 SO 4 = 50 mM; V = 0.25 L; [Fe 2+ = 0.1 mM; pH = 3.0.

Chapter 4 :

 4 Electro-Fenton removal of naproxen from aqueous medium: effect of anode material and operating conditions[START_REF] Song | Electrochemical degradation of azo dye C.I. Reactive Red 195 by anodic oxidation on Ti/SnO 2 -Sb/PbO 2 electrodes[END_REF]

4. 6

 6 mm (i.d.) at 40° C and coupled with a L-2400 UV detector selected at optimum wavelengths of 240 nm. Mobile phase was consisted of a 69:29:2 (v/v/v) methanol/water/acetic acid mixtures at a flow rate of 0.2 mL min -1 . Carboxylic acid compounds produced during the electrolysis were identified and quantified by ionexclusion HPLC using a Supelcogel H column (φ = 4.6 mm × 25 cm), column at room temperature at = 210 nm. 1% H 3 PO 4 solution at a flow rate of 0.2 mL min -1 was performed as mobile phase solution. The identification and quantification of byproducts were achieved by comparison of retention time and UV spectra with that of authentic substances.

5 :

 5 198 mM, 45.6 mg L -1 ) solutions of 50 mM Na 2 SO 4 in 250 mL solution The effect of different pH Chapter Electrochemical oxidation of naproxen in aqueous medium by the application of a boron-doped diamond anode and a carbon felt cathode 130 conditions (from 3 to 10) at 300 mA current intensity on naproxen degradation and mineralization was evaluated. According to the degradation curves display on figure 5.1.A, higher naproxen removal rate was obtained at pH 3 than with other pH conditions (i.e. pH 7.5 and 10). However, the naproxen removal rates at pH 7.5 and 10 are close but significantly low compare to that of pH 3. A part from the effect of pH, the influence of air bubbling on the process efficiency was also monitored under the fastest and slowest degradation rate, respectively obtained at pH 3 and 10. Air bubbling flow rate was shown to have a significant impact on naproxen degradation rate at the better pH value of 3 (Fig.5.1.A).

Figure 5 . 1 .

 51 Figure 5.1.B shows that the mineralization rate has the same degradation features as naproxen at different pH. The quickest TOC removal rate was obtained at pH 3.0, yielding about 96% TOC removal after 4 hours electrolysis. Comparatively, it was only 77%, 68% at pH 7.5 and 10, respectively. TOC removal percentage was 92% and 75% without air bubbling at pH 3 and 10, respectively. The MCE results indicate that better efficiency can be reach in the early stage of electrolysis. Then, the MCE values decrease till to reach similar current efficiencies after about 4 hours treatment time for all experimental conditions.

Chapter 5 :Fig. 5 . 1 .

 551 Fig. 5.1. Effect of pH and air bubbling on the degradation kinetics (A) and mineralization degree ( ) of naproxen in tap water medium by AO at 300 mAμ pH = 3 (); pH = 3 without air bubbling (×); pH = 7.5 (); pH = 10 ( ); pH = 10 without air bubbling (▲); dash lineμ MCE (%). C 0 μ 0.1λ8 mM; [Na 2 SO 4 μ 50 mM; Vμ 0.25 L.

Fig. 5 . 2 .

 52 Fig. 5.2. Effect of applied current on the mineralization efficiency (in terms of TOC removal percentage) and MCE during treatment of 0.1λ8 mM naproxen in tap water medium by EAOPsμ 100 mA (); 300 mA (•); 1000 mA (▲); EF-DDμ solid line; AO-DDμ dash line. [Na 2 SO 4 μ 50 mM; Vμ 0.25 L. EFμ [Fe 2+ μ 0.1 mM; pHμ 3.0. AOμ pHμ 7.5.

9 )Chapter 5 : 134 Table 5 . 1 .

 9513451 Fe 3+ + e -→ Fe2+ (5.10) Electrochemical oxidation of naproxen in aqueous medium by the application of a boron-doped diamond anode and a carbon felt cathode Apparent rate constants of degradation of naproxen at different currents intensities in tap water medium by electrochemical processes. k app = 7.79 × 10 -1 (R 2 = 0.998) k app = 1.86 × 10 -1 (R 2 = 0.988) 2000 k app = 9.11 × 10 -1 (R 2 = 0.999) k app = 4.17 × 10 -1

Table 5 . 2 .Chapter 5 :Chapter 5 :

 5255 OH were identified by comparison of their retention time (t R ) with that of standards compounds under the same HPLC condition, during experiments performed at a low current density by EF-BDD at 50 mA. The intermediates identified were list in table 5.2. It was expected that the aromatic intermediates were formed at the early stage of the electrolysis in concomitance with the disappearance of the parent molecule. The attack of  OH on naproxen happened by addition of  OH on the benzenic ring (hydroxylation) or by H atom abstraction on side chain leading to its oxidation or mineralization (as 2-naphthol, 1,5-dihydroxynaphthalene and 1-naphthalenacetic). These intermediates were then oxidized to form polyhydroxylated products that underwent finally oxidative ring opening reactions (3-hydroxybenzoic acid, phthalic, phthalic anhydride), leading to the formation of catechol, hydroquinone and pyrogallol. General by-products of the mineralization of naproxen in aqueous medium by  OH (electro-Fenton with DD anode) Electrochemical oxidation of naproxen in aqueous medium by the application of a boron-doped diamond anode and a chain carboxylic acids as the final products of the processes were detected during the mineralization of naproxen by EAOPs. The experiments were operated under the optimum conditions by EF-DD and AO-DD at 50 mA to capture the most intermediates. The predominant acids produced in the first stage were glycolic, Electrochemical oxidation of naproxen in aqueous medium by the application of a boron-doped diamond anode and a carbon felt cathode 136 succinic and malic acids, which could be transferred into acetic, oxalic and formic acids.

Chapter 5 :Fig. 5 . 3 .

 553 Electrochemical oxidation of naproxen in aqueous medium by the application of a boron-doped diamond anode and a carbon felt cathode 137 Time course of the concentration of the main carboxylic acid intermediates accumulated during EAOPs treatment of naproxen in tap water medium; acetic (•); oxalic (▲); formic (); glycolic (x); malic ( ); succinic ( ). Current densityμ 50 mA; C 0 μ 0.1λ8 mM; [Na 2 SO 4 μ 50 mM; Vμ 0.25 L. Electro-Fentonμ [Fe 2+ μ 0.1 mM; pHμ 3.0; AOμ pHμ 7.5.

Fig. 5 . 4 .Chapter 5 :

 545 Fig. 5.4. Evolution of the solution toxicity during the treatment of naproxen aqueous solution by inhibition of marine bacteria, Vibrio fisheri luminescence (Microtox® test) during EAOPs in tap water mediumμ ()μ EF-DD (100 mAμ line; 300 mAμ dash line); ()μ AO-DD (100 mAμ line; 300 mAμ dash line). C 0 μ 0.1λ8 mM; [Na 2 SO 4 μ 50 mM; Vμ 0.25 L. EFμ [Fe 2+ μ 0.1 mM; pHμ 3.0; AOμ pHμ 7.5.

2 -Chapter 6 :

 26 was measured by ionic chromatography. The evolution of toxicity was monitored by the inhibition of luminescence of bacteria Vibrio fisheri by Microtox method during the mineralization, showing a decreasing toxicity of piroxicam solution after treatments. As results showed, electro-Fenton process with BDD anode was found efficient on the elimination of piroxicam as an ecologically optional operation. Keywords: Piroxicam; Anodic Oxidation; Electro-Fenton; Hydroxy Radical; Toxicity Evolution; Rate Constant; Mineralization. Removal of piroxicam from aqueous solution: comparison of anodic oxidation and electro-

Chapter 6 :

 6 Removal of piroxicam from aqueous solution: comparison of anodic oxidation and electro-Fenton processes performances 146 O 2 (g) + 2H + + 2e -→ H 2 O 2 (6.1)

H 2 O 6 :

 26 2 was produced in situ from the reduction of dissolved O 2 in the solution. The Chapter Removal of piroxicam from aqueous solution: comparison of anodic oxidation and electro-Fenton processes performances 148 concentration of O 2 in the solution was maintained by continuously bubbling compressed air through a frit at 1 L min -1 . A period of 10 min before electrolysis was sufficient to reach a stationary O 2 level. Solutions were vigorously stirred by a magnetic PTFE stirrer during the treatment to ensure the mass transport toward electrodes. All the experiments were conducted at room temperature with 0.05 M Na 2 SO 4 introduced as supporting electrolyte. The current and the amount of charge passed through the solution were measured and displayed continuously throughout electrolysis by using a DC power supply (HAMEG Instruments, HM 8040-3).

Chapter 6 :Fig. 6 . 1 .

 661 Fig. 6.1. Effect of catalyst (Fe 2+ ) concentration on the degradation and decay kinetics of piroxicam in tap water by electro-Fenton with DD anode. 0.05 mM (■); 0.1 mM (•); 0.2 mM (▲); 0.5 mM (▼); 1 mM ( ); C 0 = 0.08 mM; [Na 2 SO 4 = 50 mM; V = 0.25 L; current intensity = 100 mA; pH = 3.0.

Chapter 6 :Fig. 6 . 2 .

 662 Fig. 6.2. Influence of pH on anodic oxidation processes with DD anode of piroxicam in tap water. pH 3(■); pH 3 with no air bubbled (•); pH 5.5 (natural solution value) (▲); pH λ (▼); C 0 = 0.08 mM; [Na 2 SO 4 = 50 mM; V = 0.25 L; current intensity = 100 mA.

Chapter 6 :

 6 Removal of piroxicam from aqueous solution: comparison of anodic oxidation and electro-

Fig. 6 . 3 . 5 . 5 . 6 . 3 . 2 .Chapter 6 :

 63556326 Fig. 6.3. Effect of current intensity on the degradation and decay kinetics for piroxicam in tap water by electro-Fenton/anodic oxidation process. Current intensity variedμ 100 ( ); 300 (•); 500 ( ); 750 (■); 1000 (▼); the corresponding kinetic analyses assuming a pseudo-first-order decay for piroxicam in the insert panels. C 0 = 0.08 mM; [Na 2 SO 4 = 50 mM; V = 0.25 L. For electro-Fentonμ pH = 3.0. For anodic oxidationμ pH = 5.5.

Fig. 6 . 4 .

 64 Fig. 6.4. Effect of iron concentration and pH on the mineralization and MCE for piroxicam in tap water by electro-Fenton/anodic oxidation with DD anode. Aμ iron concentration varied in electro-Fenton process, 0.05 mM (■); 0.1 mM (•); 0.2 mM (▲); 0.5 mM (▼); 1 mM ( ); μ pH varied in anodic oxidation process, pH 3(■); pH 3 with no air bubbled (•); pH 5.5 (▲); pH λ (▼); insert figure indicates MCE. C 0 = 0.08 mM; [Na 2 SO 4 = 50 mM; V = 0.25 L; current intensity = 100 mA. For electro-Fentonμ pH = 3.0. For anodic oxidationμ pH = 5.5.

Figure 6 . 4 A 6 :Chapter 6 :Fig. 6 . 5 .Chapter 6 :

 6466656 Figure 6.4 A shows the effect of iron concentration on the mineralization of 0.08 mM piroxicam (corresponding to 15.4 mg L -1 TOC) by EF with DD anode with 50mM Na 2 SO 4 at pH 3.0 under a current intensity of 100 mA. Most piroxicam was mineralized during the first 2 h electrolysis and mineralization rate order was the same as the one for piroxicam degradation rate (Fig.6.1). TOC removal with 0.2 mM Fe 2+ in EF process reaches λ8.7% after 6 h electrolysis time. A peak value was reach with 26.5% of MCE after 60 min electrolysis (Fig.6.4A). MCE showed a high value at the beginning 2 h, and then decreased to a similar level afterwards for different iron concentration. According to the obtained results, 0.2 mM Fe 2+ was chosen as the optimum catalyst concentration under these experimental conditions and was used in the rest of the study.Meanwhile, the effect of pH on piroxicam mineralization in AO was also

Figure 6 .Chapter 6 :Fig. 6 . 6 .

 6666 Fig. 6.6. Time-course of inorganic ions concentration during EAOPs of piroxicam in tap waterμ EF-DD (×); EF-Pt (■); AO-DD (O); C 0 μ 0.08 mM; [KCl μ 50 mM; current intensityμ 100 mA; Vμ 0.25 L. For electro-Fentonμ [Fe 2+ μ 0.1 mM; pHμ 3.0. For anodic oxidationμ pH = 5.5.

Chapter 6 :Fig. 6 . 7 . 6 . 3 . 5 . 6 :Fig. 6 . 8 .Chapter 6 :

 6676356686 Fig. 6.7. Evolution of the concentration of intermediates generated during the EAOPs of piroxicam in tap water. Carboxylic acidsμ glycolic (■), oxamic (O), oxalic (▲), glyoxylic (▼), fumaric ( ), malonic (◀), acetic (▶), succinic (•), maleic ( ), malic (x); C 0 μ 0.08 mM; [Na 2 SO 4 μ 50 mM; current intensityμ 100 mA; Vμ 0.25 L. For electro-Fentonμ [Fe 2+ μ 0.1 mM; pHμ 3.0.

7. 1

 1 Introduction Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly used medication among pharmaceutical compounds for relieving mild and moderate pain with 70 million prescriptions each year in the U.S. (2011 Consumers Union of United States, Inc). With such consumption, a large part of the original drug and its metabolite are discarded to solid waste disposal sites or flushed (human body only metabolizes a small percentage of drug) into municipal sewers in excrement [1-3]. Meanwhile,

Chapter 7 :

 7 Pharmaceuticals cytotoxicity evolution and removal with ozonation and biofiltration 177 experiments were conducted in triplicate at an ambient temperature of 24±1°C. Dilution factors were assessed when analyzing data.

Chapter 7 :

 7 Pharmaceuticals cytotoxicity evolution and removal with ozonation and biofiltration 179H 2 O 2 to O 3 (0, 0.3, 0.5, 1). Residual ozone was quenched immediately following the prescribed contact time.

Fig. 7 . 1 .Fig. 7 . 2 .Concentration (mg L - 1 )O 3 /H 2 O 2 BFig. 7 . 3 . 7 : 2 BChapter 7 : Pharmaceuticals cytotoxicity evolution and removal with ozonation and biofiltration 183 Fig. 7 . 4 .

 71721327372718374 Fig. 7.1. Removal percentage of three drugs selected by ozonation at different ozone contact time in Type II lab water; C 0 =2 mg L -1 ; O 3 doseμ 2 mg L -1 ; Vμ 100 mL.

Chapter 7 : Pharmaceuticals cytotoxicity evolution and removal with ozonation and biofiltration 185 Fig. 7 . 5 . 7 . 3 . 4 Chapter 7 :

 7185757347 Fig. 7.5. Effect of E CT on degradation of NSAIDs in Lake radford surface water by ozonation/ AC; dash line inserted as the removal at O 3 alone (1 mg L -1 ) on NSAIDs; ketoprofen (■); naproxen (•); piroxicam (▲); C 0 μ 2 mg L -1 ; O 3 doseμ 1 mg L -1 ; Vμ 100 mL; Ozone contact timeμ 2 min.

Fig. 7 . 6 . 7 :

 767 Fig. 7.6. Pathway proposed for the oxidation of NSAIDs selected by ozonation/AOP.

7. 5 )Chapter 7 : Pharmaceuticals cytotoxicity evolution and removal with ozonation and biofiltration 190 Fig. 7 . 7 .Fig. 7 . 8 . 2 BFig. 7 . 9 .

 571907778279 Fig. 7.7. Evolution of the inhibition of marine bacteria, Vibrio fisheri luminescence during ozonation in Type II lab water at increasing contact time with O 3 ; ketoprofenμ (■); naproxen (•); piroxicam (▲); C 0 μ 2 mg L -1 ; O 3 doseμ 2 mg L -1 ; Vμ 100 mL.

Figure 7 . 7 :

 77 Figure 7.10 reveals a higher toxicity at this EBCT than when to piroxicam and naproxen solutions where treated with O 3 only. At this short contact time with bacteria

Fig. 7 . 10 .7. 4 ConclusionsChapter 7 : 8 . 1 . 1 . 1 .

 710478111 Fig. 7.10. Evolution of the inhibition of marine bacteria, Vibrio fischeri luminescence during ozonation/BAC at different EBCT; dash line indicates the inhibition (%) of ozone alone (1 mg L -1 ) on NSAIDs; ketoprofenμ (■); naproxen (•); piroxicam (▲); C 0 : 2 mg L -1 ; O 3 dose: 1 mg L -1 ; V: 100 mL; Ozone contact timeμ 2 min.

Fig. 8 . 1 .

 81 Fig. 8.1. Electrochemical oxidation processes with carbon felt as cathode and DD (a) or Pt (b) as anodes.

  Fe 2+ ; due to side reaction of iron with  OH (Eq. (8.1)) as wasting reaction:Fe 2+ +  OH → Fe 3+ + OH -(8.1) With 0.1 mM Fe 2+ , 50 min were sufficient for the complete removal of both ketoprofen and naproxen. The time required for complete removal of 0.08 mM prioxicam was 30 min with 0.2 mM Fe 2+ . Accordingly, the optimized iron concentration for each compound was used in the rest of the experiments.Due to the inconsistent removal values reported in the literature for AO process, the effects of pH and introduction of compressed air on the treatment efficiency were studied at an applied current intensity of 300 mA. Firstly, pH values of 3.0, 7.5 (natural pH) and 10.0 for ketoprofen and naproxen, while 3.0, 5.5 (natural pH) and 9.0 for piroxicam were tested in the oxidation processes. It was shown that, pH influenced significantly the nonsteroidal anti-inflammatory (NSAID) molecules degradation efficiency in AO process. The best degradation rate of ketoprofen and naproxen was achieved at pH 3.0, followed by pH 7.5, which was slightly better than pH 10. Similar results were obtained regarding the degradation of piroxicam. The removal rate followed the order of pH 3.0 > 5.5 > 9.0. It may due to at acidic condition, H 2 O 2 is easily produced from (Eq. (8.2)): O 2 (g) + 2H + + 2e -→ H 2 O 2 (8.2) In addition, O 2 gas can be reduced to the weaker oxidant as HO 2 -under alkaline condition (Eq. (8.3)): O 2 (g) + H 2 O + 2e -→ HO 2 -+ OH (8.3)

Chapter 8 General Discusion 205 Fig. 8 . 2 .

 20582 Fig. 8.2. Saturated filter columns with varying volumes of sampled AC media.

  intermediates were then oxidized to form polyhydroxylated products that underwent finally oxidative ring opening reactions, leading to the formation of aliphatic compounds. Mineralization of short-chain carboxylic acids constituted the last step of the process as showed by TOC removal data. For the assessment of biological effect of the ozonation/biofiltration, intermediates derived from target compounds during ozone/AOP processes in type II lab were analyzed subject to a close examination of their chemical structures with ESI (+)/MS analysis. According the intermediates formed and mechanism, the oxidation Chapter 8 General Discusion 207 mainly happens by electrophilic substitution on an O-O-O (O 3 ) attack at the unsaturated electro-rich bonds, involving oxidative ring opening and leading to the formation of aldehyde moieties and carboxyl groups by cleavage. Furthermore, the  OH radicals and O-O-O continue to oxidize intermediates to form organic acids and keto acids by loss of a CH group, such as methyl group and saturated group. Then short chain carboxylic acids were formed as final mineralization products. Oxidation pathways of the three compounds were proposed based on the intermediates formed. It well confirmed both direct and indirect oxidations happen simultaneously, and oxidants attack more than one position in one molecule.

Chapter 8 General Discusion 210 8 .

 8 The evolution of the toxicity of treated solutions highlighted the formation of more toxic intermediates at early treatment time, while it was removed progressively by the mineralization of aromatic intermediates. The evolution of the toxicity was in agreements of the intermediates produced during the mineralization for the pollutants by EAOPs.

3 .

 3 The best management practice could be obtained for ozone/AOP/BAC under the consideration of removal rate and level of residual cytotoxicity, as ozone doses at 2 mg L -1 , a O 3 /H 2 O 2 of 0.5 and 8 min empty bed contact time with flow-up filtration. The discussed results were in agreement with previous studies showing enhanced removal of advanced oxidation by-products by following O 3 treatment with BAC filtration.

Table 2 . 2 .

 22 Basic information of selected NSAIDs.

	NSAIDs	Formula	Mass (g mol -1 )	CAS No.	pKa	Solubility (mg L -1 )	log Kow	log Koc	Ref.
	Aspirin	C 9 H 8 O 4		180.0 50-78-2		3.50 4600 1.20	1.0	[31,3 2,39]
	Diclofenac	C 14 H 11 Cl 2 NO 2	296.2 15307-79-6 4.91 2	4.51	1.9	[33-35]
	Ibuprofen	C 13 H 18 O 2		206.3 15687-27-1 4.15 21	4.51	2.5	[33-35]
	Ketoprofen	C 16 H 14 O 3		254.3 22071-15-4 4.45 51	3.12	2.5	[32, 33]
	Mefenamic acid	C 15 H 15 NO 2 241.3 61-68-7		5.12 20	5.12	2.7	[33, 36]
	Naproxen	C 14 H 14 O 3		230.3 22204-53-1 4.15 144	3.18	2.5	[32, 33]
	Paracetamol C 8 H 9 NO 2	151.2 103-90-2	9.38	1290 0	0.46	2.9	[37, 38]
	Data of solubility at 20°C

Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes. A review 15

  Aspirin, 2-acetoxybenzoic acid, is one of the most popular pain killers, this compound, as well as its derivatives, is known to exhibit high toxicity to a wide range of aquatic organisms in water bodies[39, 40].

	Diclofenac, 2-[2-(2,6-dichlorophenyl)aminophenyl] ethanoic acid, commonly
	used in ambulatory care, has a highest acute toxicity

Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes. A review 17

33 mg L -1 compared Chapter 2: with 66.4 mg L -1 in acute toxicity for naproxen by Daphnia magna and Ceriodaphnia dubia (48 h/21days).

Chapter 2: Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes. A review 19Table 2 . 3 .

 23 The detected concentration and frequency of NSAIDs in WWTP influent/effluent, surface water and their toxicity data.

	Drug	WWTP influent ( g L -1 )	WWTP effluent ( g L -1 )	Remo val rate	Surface water	Acute mg L -1 ) toxicity (EC 50	Acute mg L -1 ) toxicity (LC 50	Ref.
		&		&				Daphnia	Daphnia
		Frequency	Frequency	%	( g L -1 )	Algae	Algae
		of detection	of detection			Fish	Fish
	Aspirin		100/100		0.05-1.51/ 93	81.0	< 0.05/ 100	88, 107, -	141.0, -, 178	[39, 66, 71]
	Diclofenac 0.10-4.11/96	0.04-1.95/ 86	34.6	0.001-0.07/ 93	5057, 2911, 532	22.4, 14.5, -	[39, 71-75]
	Ibuprofen	0.17-83.50/100	95/89 <	74.2	96 0.20/ n.d.-	38,

Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes. A review 20 2.4 Advanced Oxidation Processes on anti-inflammatory and analgesic drugs

  WWTPs usually do not reach complete removal of pharmaceuticals and therefore behave as an important releasing source of pharmaceuticals into environment. The implementations of sustainable technologies are imposed as possible solutions for the safe reclamation of high-quality treated effluent.

	Chapter 2: (AOPs) are therefore particularly useful for removing biologically toxic or non-
	degradable molecules such as aromatics, pesticides, dyes and volatile organic
	compounds potentially present in wastewater [83-88], getting more and more interests
	compared to conventional options, being treated as promising powerful and
	environmentally friendly methods for treating pharmaceuticals and their residues in
			1.62/ 82	31.1	< 0.33/ -	248, 16, 32,	64.0, -, -	[71, 74, 78, 79]
	Mefenamic acid	0.14-3.2/50	0.09-2.4/75	40.0	-/20	20, 4.33 -	-	[71, 72, 32]
	Naproxen 1.79-611/96	0.17-33/96	81.6	n.d-0.04/ 93	15, 22, 35	43.5, 320, 560	[39, 63, 71-73]
						41,	9.2,	[62, 80,
	Paracetamol -/100	6.9/100	40.0 10/89	2549,	134,	67, 81,
						258	378	82]

wastewater

[START_REF] Isarain-Chavez | Degradation of pharmaceutical beta-blockers by electrochemical advanced oxidation processes using a flow plant with a solar compound parabolic collector[END_REF][START_REF] Hussain | COD reduction of waste water streams of active pharmaceutical ingredient -Atenolol manufacturing unit by advanced oxidation-Fenton process[END_REF][START_REF] Abdelmelek | Removal of Pharmaceutical and Personal Care Products from Reverse Osmosis Retentate Using Advanced Oxidation Processes[END_REF]

. The destruction reaction involves different oxidant species, like hydroxyl radicals (  OH) and other strong oxidant species (e.g. O 2

 , HO 2



, and ROO  ) produced in situ in reaction media. Hydroxyl radical (  OH), produced via hydrogen peroxide, leaving -green‖ chemicals oxygen gas and water as by-products, has a high standard reduction potential (E⁰ (  OH/H2O) = 2.8 V/SHE), which is known as the second strongest oxidizing agent just after fluorine. It can highly react with a wide range of organic compounds, regardless of their concentration. A great number of methods are classified under the broad definition of AOPs, as wet oxidation, ozonation, Fenton process, sonolysis, homogeneous ultraviolet irradiation, and heterogeneous photo catalysis using semiconductors, radiolysis and a number of electric and electrochemical methods

[START_REF] Brillas | Electro-Fenton process and related electrochemical technologies based on Fenton's reaction chemistry[END_REF]

. AOPs are able to destruct the target organic molecules via hydroxylation or dehydrogenation, and may mineralize all organics to final mineral products as CO 2 and H 2 O

[START_REF] Brillas | Electro-Fenton process and related electrochemical technologies based on Fenton's reaction chemistry[END_REF][START_REF] Almeida | Solar photoelectro-Fenton degradation of paracetamol using a flow plant with a Pt/air-diffusion cell coupled with a compound parabolic collector: Process optimization by response surface methodology[END_REF]

.

Chapter 2: Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes. A review 24 Fig. 2.3. A

  simple description of the mechanisms occurred during anodic oxidation of a pollutant. (Adapted from ref

	Anode
		Direct Electrolyses	Mediated
	e -	S i	S i	electrolyses with hydroxyl radicals
		S i+1	S i+1			Mediated electrolyses via hydroxyl radicals
			Mred	S i	with other oxidants produced from salts
		H 2 O				contained in the waster
	e -			Mox		S i+1
		OH•
				O 2	S i	Mediated electrolyses via hydroxyl radicals
		2H + + O 2				with ozone
		Oxygen evolution		O 3		S i+1
	e -	Mred	S i	H 2 O	S i	Mediated electrolyses via hydroxyl radicals
						with hydrogen peroxide
		Mox	S i+1	H 2 O 2		S i+1
		Mediated electrolyses with oxidants
		produced from salt contained in the
		waste

Chapter 2: Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes. A review 26

	account that conductive-diamond is not a unique material, but many types of materials
	are included into this denomination with significantly different behaviors [118],
	depending on the substrate (Ti, p-Si, Nb, etc), doping compound (N, F) and
	concentration level, sp 3 -sp 2 ratio, etc. This explains some contradictory results shown in
	literature when generalizations are done. BDD is the most common conductive-diamond
	electrode and the only type used in the studies shown in this work. The reaction of
	heterogeneously formed  OH at a high efficiency anode (M) from water oxidation is
	commonly represented by Eq. (2.4), indicating the occurrence of hydroxyl radicals as
	free species close to the anode surface.
	M + H 2 O → M (  OH) + H + + e -	(2.4)

Chapter 2: Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes. A review 27 used

  as anode for comparison purposes. It was found that anodic oxidation with Pt had much lower oxidizing power and yielded poor mineralization.

	After that initial work, Brillas et al. [122] studied degradation of diclofenac in
	aqueous medium by anodic oxidation using an undivided cell with a Pt or BDD anode.
	It was demonstrated that diclofenac was completely depleted by AO with BDD even at
	the very high concentrations assessed (175 mg L -1 ). Only some carboxylic acids were
	accumulated in low concentrations and oxalic and oxamic were found to be the most
	persistent acids. Comparative treatment with Pt gives poor decontamination and great
	amounts of malic, succinic, tartaric and oxalic acids. The reaction of diclofenac
	followed pseudo-first-order kinetics. For BDD, TOC and drug decays were enhanced
	with increasing current, although efficiency in terms of the use of current decreased
	significantly due to the promotion of side reactions, such us oxidation of BDD(  OH) to
	O 2 (Eq. (2.5)), production of hydrogen peroxide (Eq. (2.6)) and destruction of hydrogen
	peroxide by hydroxyl radicals (Eq. (2.7)).
	2 BDD(  OH) → 2 BDD + O 2 (g) + 2H + + 2e -	(2.5)
	2 BDD(  OH) → 2 BDD + H 2 O 2		(2.6)
	H 2 O 2 + BDD(  OH) → BDD(HO 2	 ) + H 2 O	(2.7)
	1 g L -1 in aqueous medium within the pH range 2.0-12.0. Current efficiency increased
	with raising drug concentration and temperature and decreased with current density,
	showing a typical response of a diffusion controlled process. In this work, Pt was also

Chapter 2: Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes. A review 28

	(SO 4	-)  +  OH•  HSO 5	-	(2.13)
	PO 4	3-+  OH•  (PO 4 2-)•+ OH -	(2.14)
	(PO 4	2-) + (PO 4	2-)  P 2 O 8 4-	(2.15)
	(PO 4	2-) +  OH•  HPO 5	2-	(2.16)
	2 SO 4	2-	→ S 2 O 8	2-+ 2e -	(2.8)
	2 PO 4	3-	→ P 2 O 8	4-+ 2e -	(2.9)
	3 H 2 O → O 3 (g) + 6 H + + 6e -	(2.10)
				It is worth to take into account that they can be produced by direct electron
	transfer (as indicated in the previous equations) or by the action of hydroxyl radicals as
	shown below (Eqs. (2.11)-(2.13) for peroxosulfates) and (Eqs. (2.14)-(2.16) for
	peroxophosphates) [112].
	SO 4	2-+  OH•  (SO 4	-)  + OH -	(2.11)
	(SO 4	-)  + (SO 4	-)   S 2 O 8 2-	(2.12)

Chapter 2: Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes. A review 30 clearly

  .5, was obtained from the results shown in that work, indicating that the oxidation of ketoprofen follows a pseudo-first-order kinetic and that kinetic rate is dependent on the nature of the electrolyte. The high mineralization in the

	presence of SO 4	2-could be explained by in situ generation of S 2 O 8	2-and sulfate radical
	as shown in Eqs. (2.9), (2.12) and (2.13) [127].
	The oxidants are either consumed for the degradation of ketoprofen molecule or
	coupled with water molecule to form peroxomonosulfuric acid (H 2 SO 5 ) which in turn
	can produce H 2 O 2 [128].

Table 2 . 4 .

 24 Anodic oxidation (AO) process applied on anti-inflammatory and analgesic

	drugs
	Pharmaceutical	Anodic	oxidation	Matrix	Results obtained	Ref.
	investigated	and	and	likely
		processes
	Aspirin	Pt or steel as	Water	The progressive oxidation	[119]
		cathode, plates of Pt		increased	biological
		or carbon fiber as		availability.
		anodes. 0.1 NH 2 SO 4
		or 0.1 N NaOH as
		supporting
		electrolyte
		concentration (SEC)
	Diclofenac	Pt/stainless steel and		AO with Pt: 1) acidified	[122]
		BDD/stainless steel		the solution, lead to good
		cells, added 0.05 M		mineralization degree; 2)
		Na 2 SO 4 without pH		gave poor decontamination
		regulation or in		at low contents of the
		neutral		buffer		drug; 3) high amounts of
		medium with 0.05 M		malic, succinic, tartaric,
		KH 2 PO 4 + 0.05 M		oxalic	acids,	NH 3	+
		Na 2 SO 4 + NaOH at		produced. AO with BDD:
		pH 6.5, 35°C			1) the solution became
						alkaline, only attained
						partial mineralization; 2)
						total mineralization of low
						contents of the drug; 3)
						increased	current
						accelerated the degradative
						process, but decreased its
						efficiency; 4) produced
						small extent of some
						carboxylic acids but a

Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes. A review 38

				larger persistence of oxalic
				and oxalic acids, NH 3	+ and
				NO -	released.	The
				diclofenac decay always
				followed a pseudo first-
				order reaction; aromatic
				intermediates identified as
				2-hydroxyphenylacetic
				acid,	2,5-
				dihydroxyphenylacetic
				acid, 2,6-dichloroaniline
				and	2,6-
				dichlorohydroquinone
				(Fig. 2.5); chloride ion was
				lost in all cases.
	BDD or Ti/Pt/PbO 2	COD removed between 60
	as	anodes	and	and 95% and TOC varying
	stainless steel foils	from 48 to 92% in 6 h
	as cathodes, 0.035 M	experiments, with higher
	Na 2 SO 4 as SEC, at	values obtained with the
	22-25 °C		BDD	electrode;	both
				electrodes gave a similar
				results in general current
				efficiency	and
				mineralization	current
				efficiency for 20 mA cm -2

Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes. A review 49

  2.8).

	N H Paracetamol CH 3 Chapter 2: OH O	O H	N H	O	. OH CH 3	OH OH OH O Hydroquinone CH 3 O H O H O O	H 3 H	H C OH OH O O	O	H 3	H 3 C	C	O H	O H OH	O CH 3 CH 2	CH 3
						O H		OH						H 3	C	OH
							O	O							O H	CH 3
							O
																	+
						H 2	N	CH 3		H 3	C		NH 2		NH4	NO3
						Acetamide



1 Fig.

2

.8. Proposed degradation pathway for paracetamol (Adapted

[START_REF] De Luna | Acetaminophen degradation by electro-Fenton and photoelectro-Fenton using a double cathode electrochemical cell[END_REF]

with permission from Copyright 2012 Elsevier).

2.5.2.

3 Application of electro-Fenton related processes for removal of pharmaceuticals from aqueous solutions

  It is not only the additional generation of  OH by sonolysis from reaction to accelerate the destruction process, but also the bubbles produced in solution help the transfer of reactants Fe 3+ and O 2 toward the cathode for the electrogeneration of Fe 2+ and H 2 O 2 , as well as the transfer of both products to the solution increasing

Sonoelectro-Fenton (SEF) processes, have received intensive attention recently

[102]

. Ultrasounds applied to aqueous solutions leads to the formation of cavitation bubbles; a fast pyrolysis of volatile solutes takes place and water molecules also undergo thermal decomposition to produce H + and  O; then reactive radicals formed from water decomposition in gas bubbles, together with thermal decomposition, due to the acoustic energy concentrated into micro reactors, enhancing the reaction with  OH by ultrasound irradiation.  OH production in Fenton's reaction,

Removal of residual anti-inflammatory and analgesic pharmaceuticals from aqueous systems by electrochemical advanced processes. A review 51 generated

  For thermal plasma, the energy of this plasma is extremely high enough to break any chemical bond, so that this type of plasma can significantly removes most organic, while the cold plasma easily generate electric discharges under reduced pressure, such as high-energy electrons,  OH,  H, O  , and O 2 H 2 O 2, accelerating the degradation rate of organics. However, excessive energy is required for expensive and complex accessories application.

	-, as well as long-
	lived active molecules such as O 3 , H 2 O 2 , excited-state neutral molecules, and ionic

e - (2.27) Electrochemical peroxidation (ECP), is a proprietary process that utilizes sacrificial iron electrodes for Fe 2+ electro generation and  OH formed from Fenton's reaction with added or cathodically generated H 2 O 2 [187, 189] Fe → Fe 2+ + 2e - (2.28) With voltage applied to steel electrodes, Fe 2+ is produced, and then the presence H 2 O 2 (added or cathodically generated) leads to the formation of  OH from the Fenton's reaction (Eq. (2.24)). The major advantage of ECP process is the reaction above that allows the recycle of Fe 3+ /Fe 2+ (Eq. (2.28)). Plasma can be defined as the state of ionized gas consisting of positively and negatively charged ions, free electrons and activated neutral species (excited and radical). It is classified into thermal (or equilibrium) plasma and cold (or nonequilibrium) plasma. species, which can oxidize organic pollutants. Plasma-assisted treatments, with the addition of Fe 2+ or Fe 3+ to the aqueous medium, can produce extra  OH with extra Chapter 2:

77

  The pharmaceutical-ketoprofen(2-[3-(benzoyl) phenyl] propanoic acid, (C 16 H 14 O 3 ), sodium sulfate (supporting electrolyte), anhydrous Na 2 SO 4 (99%), and acetic acid (glacial p.a. C 2 H 4 O 2 ) were supplied by Sigma-Aldrich. Sulfuric acid (ACS

	reagent grade, 98%), Iron (II) sulfate heptahydrate (catalyst, 99%), 4-p-
	hydroxybenzonic acid (as competition substrate in kinetic experiments), methanol (for
	HPLC analysis grade), aromatic intermediates: benzophenone (C 13 H 10 O), phenol
	(C 6 H 6 O), 3-hydroxybenzoic acid (C 7 H 6 O 3 ), benzoic acid (C 7 H 6 O 2 ), catechol (C 6 H 6 O 2 ),
	pyrogallol (C 6 H 6 O 3 ), hydroquinone (C 6 H 6 O 2 ) and carboxylic acids: acetic (C 2 H 4 O 2 ),
	glyoxylic (C 2 H 2 O 3 ), oxalic (C 2 H 2 O 4 ), formic (CH 2 O 2 ), glycolic (C 2 H 4 O 3 ) acids were
	purchased from Acros Organics in analytical grade. All other products were obtained
	with purity higher than 99%.

Ketoprofen solutions of concentration 0.198 mM were prepared in tap water, and all other stock solutions were prepared with ultra-pure water obtained from a Millipore

Table 3 .

 3

1. Apparent rate constants of degradation of KP at different current intensities in tap water medium by electrochemical processes.

Table 4 .

 4

	Naproxen	Formulaμ C 14 H 14 O 3	Structure
	Mass (g mol -1 )μ 230.3	CAS No.μ 22204-53-1
	Log Kocμ 2.5	Log Kowμ 3.18
	Solubility (at 20°C)μ 144 mg•L -1	Concentration WWTPsμ < 32 g L -1 in [10-12

1. asic physicochemical parameters of naproxen

[8, λ .

Naproxen, 6-methoxy-α-methyl-2-naphthalene acetic acid, is widely used as human and veterinary medicine

[13 .

This compound occurs frequently in wastewater treatment plants (WWTPs) effluents (λ6% of occurrence) and surface water [14-16 (Table

4

.1). The detected concentrations are more than 10 times than the threshold value suggested by the European Medicine Agency (EMEA) [17 . Chronic toxicity higher than its acute toxicity was also confirmed by bioassay tests

[18 ,

which may due to the stability of the chemical structure (i.e., naphthalene ring) (

Table 4

 4

	.1). Other researchers

more efficient processes for the complete removal of pharmaceuticals present in wastewater after conventional treatments [23-27 . Among these processes, advanced oxidation processes (AOPs) are attracting more and more interests as an effective

Electro-Fenton removal of naproxen from aqueous medium: effect of anode material and operating conditions 102 method

  [28-31 , which are mostly used for removing biologically toxic or recalcitrant molecules. Such processes, may involve different oxidant species produced by in situ reactions, particularly hydroxyl radicals (  OHs) and other strong oxidant species (e.g.

	O 2	-, HO 2	 , and ROO  ). Hydroxyl radical (  OH) is a strong oxidizing agent (E⁰ = 2.8 vs.
	ENH at pH 0), able to react with a wide range of organic compounds in a non-selective
	oxidation way, causing the organic pollutant's ring opening, regardless of their
	concentration [32, 33 .
			Among AOPs, electrochemical advanced oxidation processes (EAOPs) are being
	regarded as the most perspective treatments for removing persistent organic
	micropollutants [11, 12, 34-37 . Generally, EAOPs can be carried out directly (forming
	of to a superoxide ion (O 2	-) to generate H 2 O 2 continuously. The process can occur in
	homogeneous or heterogeneous systems and has been known as a powerful process for
	organic contaminants (Eqs. (4.1)-(4.4)) [42, 43 .
	O 2 (g) + 2H + + 2e -	→ H 2 O 2	(4.1)
	Fe 2+ + H 2 O 2 + H +	→ Fe 3+ + H 2 O +  OH	(4.2)
	Fe 3+ + H 2 O 2 → Fe 2+ + HO 2	 + H +	(4.3)
	Fe 3+ + e -	→ Fe 2+	(4.4)
			On the other hand, supplementary  OHs can be formed at the anode surface from
	oxidation of water (Eqs. (4.5) and (4.6)) directly without addition of chemical
	substances [44 .
	H 2 O →  OH ads + H + + e -	(4.5)
	OH -	→

 OH at the anode) or indirectly (using the Fenton's reagent partially or completely generated from electrode reactions) by electrochemical oxidation through reduction electrochemically monitored Fenton's reaction

[38 .

Electro-Fenton (EF) treatment [3λ, 40, 41 , is improved from classical Fenton's reagent process, with a mixture of iron salt catalyst (ferrous or ferric ions) and hydrogen peroxide (oxidizing agent), producing hydroxyl radicals in which the reaction is catalysed via a free radical chain. A suitable cathode fed with O 2 or air reduce dioxygen  OH ads + e -

Electro-Fenton removal of naproxen from aqueous medium: effect of anode material and operating conditions 106

	Chapter 4: Consequently, an optimal 0.1 mM of ferrous ion concentration has been used for
	the further experiments.
	1 mM is the best
	concentration in our experimental conditions. It can be seen from Eqs. (4.2) and (4.3)
	that with the increase of ferrous ion concentration, more  OH and HO 2	 could be
	produced which enhance the removal rate of naproxen. However, if higher ferrous ion
	concentration is added, these extra ions will be reacting with  OH (see Eq. (4.8)), and
	therefore leads to lower naproxen removal efficiency [46, 47 .
	Fe 2+ +  OH → Fe 3+ + OH -	(4.8)

Table 4 . 2 .

 42 Apparent rate constant of naproxen oxidation by  OH at different concentration of ferrous ion in tap water medium by EF process.

	Fe 2+	0.05 mM	0.1 mM	0.2 mM	0.5 mM	1 mM
	k app & R 2
	y = ax	y = 0.116  x y = 0.135  x y = 0.107  x y = 0.076  x y = 0.074  x
	R 2	0.λλ1	0.λλ8	0.λ8λ	0.λ87	0.λλ2
	K app (min -1 ) 0.116	0.135	0.107	0.076	0.074

Electro-Fenton removal of naproxen from aqueous medium: effect of anode material and operating conditions 107 supplementary

  , highly reactive DD(  OH) produced at the anode surface compared with Pt anode[48 . The oxidation rate of naproxen at 1000 mA current intensity is almost 3 times higher than that of 300 mA current intensity.

4.1.A).

The apparent rate constants k app of naproxen oxidation by EF process at current intensity of 300 mA and 1000 mA are presented in Table

4

.3. From the results, it is clear that removal of naproxen by EF-DD process has a higher rate than that of EF-Pt process.

The great mineralization power of EF-DD is related to the production of Chapter 4:

Table 4 . 3 .

 43 Apparent rate constants for oxidative degradation of naproxen at 300 mA and 1000 mA current intensity by EF process with DD or Pt anodes.

		Processes	Current 300 mA	1000 mA
		EF-Pt		y = 0.147  x / R 2 = 0.λλ6 y = 0.451  x / R 2 = 0.λλ7
		K app (min -1 )		0.1λ0	0.5λ3
		EF-DD		y = 0.185  x / R 2 = 0.λ81 y = 0.77λ  x / R 2 = 0.λλλ
		K app (min -1 )		0.185	0.77λ
	On the other hand, the mineralization reaction of naproxen can be written as
	followsμ
	C 14 H 14 O 3 + 64  OH → 14 CO 2 + 3λ H 2 O	(4.λ)
	The mineralization current efficiency (MCE in %) is an indicator for
	acknowledgement of the capacity of current intensity application, can be calculated by
	following formula at a given electrolysis time t (h) as [4λ μ
	MCE =	nFVs TOC exp 4.32 ×10 7 mIt	× 100	(4.10)

Electro-Fenton removal of naproxen from aqueous medium: effect of anode material and operating conditions 110 this

  hypothesis, the pseudo-first-order rate law can be applied to naproxen and p-H A decay[54 . From these pseudo-first-order kinetic law expressions, the following equation can be obtained to calculate the absolute rate constant for oxidation of naproxen by  OH.

	72% 96% 0% 24% 48% 72% 96% [N ]0 [N ]t where the subscripts 0 and t indicate the reagent concentrations at time t = 0 (initial 40% 0 1 2 3 4 5 6 7 8 0% 8% 16% 24% 32% 40% EF-BDD EF-Pt B Chapter 4: kN k Ln / Ln [ ]0 [ ]t (4.11) MCE (%) concentration) and at any time of the reaction. TOC removal efficiency Ln([NAP 0 /[NAP t ) and Ln([p-H A 0 /[p-H A t ) provides a linear relationship,
	24% 48%		MCE (%)	32% 16% 24%
				8%
				0%	0	1	2	3	4	5	6	7	8
	0%
	0	1	2		3	4		5	6	7	8
					Time (hour)

Electrochemical oxidation of naproxen in aqueous medium by the application of a boron-doped diamond anode and a carbon felt cathode 129 C

  14 H 14 O 3 + 64  OH → 14 CO 2 + 39 H 2 O 2(5.3)

	Chapter 5:
	1-1A). n is the number of
	electrons consumed per molecule mineralized as 64, the total mineralization reaction of
	naproxen asμ

Electrochemical oxidation of naproxen in aqueous medium by the application of a boron-doped diamond anode and a carbon felt cathode 132 chapter

  4). Figure5.2 shows that TOC removal rate increased with increasing current density for both EF-BDD and AO-BDD. In AO-BDD, this is due to higher amount of BDD(  OH) formed at anode surface from water discharge when higher current density

	Chapter 5:
	is applied [15]:
	BDD + H 2 O → DD(  OH) + H + + e -	(5.6)
	EF shows better TOC removal rate compared to AO process. . EF-BDD provided
	better results than AO-BDD. The TOC abatement of 4 h electrolysis reached to an
	almost total mineralization, with TOC reduction by 94.6, 96 and 97.3% for EF-BDD,
	whereas 68.8, 77 and 92.7% for AO-BDD, at 100, 300, and 1000 mA current density,
	respectively. The MCE curves showed an opposite tendency for TOC decay with
	current density, decreased as current density increased. Highest value of MCE was
	achieved as 42.6% and 24.9% for EF-BDD and AO-BDD within 1.5 h treatment at 100
	mA current density, respectively. The lower MCE obtained at longer electrolysis time,
	deceleration of mineralization rate could be assocaited to the wasting reactions by
	oxidation of BDD(  OH) to BDD and reaction of H 2 O 2 giving weaker oxidant [28, 29]:
	2BDD(  OH) →2 DD + O 2 + 2H + + 2e -	(5.7)
	H 2 O 2 +  OH → HO 2	-+ H 2 O	(5.8)

1 mM (see B A Chapter 5:

as result of formation of short chain carboxylic acids (Fig.

5

.2), hardly oxidizing by products or complex compounds accumulated in the solutions vs. electrolysis time, which wasted the  OH and BDD(  OH). Meanwhile, under the higher current density,

Electrochemical oxidation of naproxen in aqueous medium by the application of a boron-doped diamond anode and a carbon felt cathode 133

  15 H 13 N 3 O 4 S, cas number: 9012-00-4), anhydrous sodium sulfate (99%, Na 2 SO 4 ) and acetic acid (C 2 H 4 O 2 ) were supplied by Sigma-Aldrich. Sulfuric acid (98%, H 2 SO 4 ), iron (II) sulfate heptahydrate (FeSO 4 7H 2 O), p-Hydroxybenzoic acid (p-HBA, C 7 H 6 O 3 ), methanol (CH 3 OH), carboxylic acids: acetic (C 2 H 4 O 2 ), glyoxylic (C 2 H 2 O 3 ), oxalic (C 2 H 2 O 4 ), formic (CH 2 O 2 ), glycolic (C 2 H 4 O 3 ) acids, as well as ammonium nitrate, sodium nitrate, nitrite, and sulfate were purchased from Fluka, Merck, and Acros Organics in analytical grade. All other products were obtained with purity higher than 99%.

Chapter 7: Pharmaceuticals cytotoxicity evolution and removal with ozonation and biofiltration 174 pharmaceuticals

  by ozonation has significant practical benefit. Anthropogenic organic contaminants, like NSAIDs, are often simultaneously directly-oxidized by aqueous O 3 , and indirectly-oxidized by  OH. Conditions which favor the production of highly reactive species such as hydroxyl radicals (  OH) include high pH (O 3 /OH OH as 8.4 × 10 9 M -1 s -1 [37]. Huber et al. observed a k O3 value of 2 × 10 5

	-) and addition
	of hydrogen peroxide (O 3 /H 2 O 2 ) [35, 36].
	The potential removal efficiency of NSAIDs with ozonation can be assessed by
	reported rate constants for both direct (k O3 ) and indirect (k OH ) oxidation. Benitez et al.
	studied the apparent rate constants of aqueous pharmaceuticals, and found that, for
	naproxen, the k O3 value varies with pH (2.5-9), ranging between 2.62 × 10 4 and 2.97 ×
	10 5 M -1 s -1 , and k

Table 7 . 1 .

 71 NaH 2 PO 4 ), and hydrogen peroxide 30% solution (H 2 O 2 ) were purchased from Sigma-Aldrich, or Macron Chemicals and used as received.NSAIDs solutions with the concentration of 2 mg L -1 were prepared in laboratory-grade Type II or surface water (SW), and all other stock solutions were prepared with Type II water. Achieving desired pH of test solutions required different ratios of NaH 2 PO 4 and Na 2 HPO 4 . Chemical identification and structures of selected NSAIDs.

	Finally, bench-scale biological filtration was

Pharmaceuticals cytotoxicity evolution and removal with ozonation and biofiltration 176

	Solubility	51	144	23
	(mg L -1 at 20
	°C)
	7.2.2 Surface Water Sampling
	The surface water samples were collected from Lake Bradford, Tallahassee, FL,
	USA (Latitude 30.40 N and longitude -84.34 W). The physicochemical data were
	obtained from published reports, or measured according to Standard Methods [45]. The
	water sample was filtered through a 0.2 m micropore membrane before using. The
	basic character of surface water is is listed in Table 7.2.

Table 7 . 2 .

 72 Physicochemical properties of Lake radford water.

	Color (Pt-Co cu)	127 b	pH	6.7
	Total P (mg L -1 )	0.03 a	Alkalinity (mg L -1 as CaCO 3 ) 4.6
	Total N (mg L -1 )	0.61 a	Conductance (S cm -1 at 25	25 b
			°C)
	Cl (mg L -1 )	5.6 b	TOC	3.8 mg/L
	a from water quality report for selected lakes and streams, Leon County Public Works; b

Pharmaceuticals cytotoxicity evolution and removal with ozonation and biofiltration 180 water

  The research of Huber et al. confirmed that ≥ 2 mg L -1 , there may be other species competing with NSAIDs for the selective and nonselective oxidants, therefore requiring a higher oxidant dose to achieve the desired level of elimination.

	ozone dose applied in wastewater effluent could oxidize more than 90% naproxen and
	other pharmaceuticals [38].
	Figure 7.3 shows the effect of AOP (O 3 /H 2 O 2 ) on degradation of NSAIDs by
	different molar ratio of H 2 O 2 and O 3 , with the ozone dose fixed at 1 mg L -1 (which
	applied alone at 1 mg L -1 in ozonation showed in dash line). Theoretically, 1 mole O 3
	yields 0.7 mole  OH, while 1 mole O 3 /H 2 O 2 produced 1 mole  OH. The results of the
	O 3 /H 2 O 2 bench-scale testing validated the theory that while the efficiency of O 3 /H 2 O 2
	treatment is higher than in the sampled surface water, there are secondary reactions
	which contribute to observed contaminant oxidation. The degradation rates at a molar
	ratio of 1 were 96%, 98%, and 98% in Type II lab water, while 81%, 83%, and 76% was
	observed in surface water for ketoprofen, naproxen and piroxicam, respectively. It is
	obvious that addition of H 2 O 2 highly improved the removal rate of NSAIDs compared
	with ozone application alone. For Type II lab water, there is no much difference among
	H 2 O

2

and O 3 of 0.3 to 1 on the degradation rate, meanwhile, for surface water, the removal rate increased obviously with increasing ratio. It can be seen that in surface Chapter 7:

Chapter 7: Pharmaceuticals cytotoxicity evolution and removal with ozonation and biofiltration 187

  Quintana via biodegradation[61]. Naproxen's oxidative transformation pathways can be found in the literature of Hsu via the indirect photolysis of naproxen[62] with  OH.

		O H		OH						OH							O	OH	O	OH
		O M/Z: 138, C 7 H 6 O 3		O M/Z: 165, C 8 H 6 O 4 O O H		C M/Z: 163, C 10 H 10 O 2 H 3 O	O	CH 3 M/Z: 131, C 5 H 8 O 4 OH	O M/Z: 123, C 7 H 6 O 2
																			O H	CH 3
		OH								OH								O
	O H 3 M/Z: 263, C 14 H 14 O 5 C O O		O	CH 3		O H 3	C	CH 3 O M/Z: 295, C 14 H 14 O 7 O O O H OH		H 3	C	M/Z: 174, C 11 H 10 O 2 CH 3 O M/Z: 187, C 13 H 14 O O	OH	O H	OH M/Z: 160, C 10 H 8 O 2
																			OH
																	O		H 3	C	OH
		OH															H 3	C	O	CH 3	M/Z: 217, C 13 H 12 O 3	O H
	O				CH 3											M/Z: 231, C 14 H 14 O 3	O	OH	M/Z: 144, C 10 H 8 O
	H 3	C			O
																			H 3	C
	With these published pathways as a guide, the following ozone transformation pathways OHOH OH O H M/Z: 263, C 14 H 14 O 5 O M/Z: 187, C 12 H 10 O 2
	O are proposed. H 3	C		O H		OH	O	CH 3			O				O	OH	O	O	O
	M/Z: 164, C 5 H 8 O 6 O H H OH O O O CH 3	malic acid OH O M/Z: 265, C 14 H 16 O 5 C OH H 3	O	OH		M/Z: 143, C 6 H 7 O 4 OH O H O M/Z: 165, C 7 H 10 O 5 O OH	O	O H	O M/Z: 132, C 4 H 4 O 5 O O OH C H 3 M/Z: 265, C 14 H 16 O 5	M/Z: 165, C 9 H 9 O 3 CH 3 O OH OH
																	Ring opening
		O	O		OH	OH				O		O		OH	O	O	OH
	O	M/Z: 255, C 16 H 14 O 3 O O M/Z: 287, C 16 H 14 O 5 Ring opening OH CH 3 O O 3 CH 3	O M/Z: 383, C 16 H 14 O 11 O O O O O O H O H O OH O OH O O O O O O	OH CH 3 OH CH 3 O Ring opening O H OH O	CH 3 OH M/Z: 287, C 16 H 14 O 5 O O OH O CH 3 M/Z: 287, C 16 H 14 O 5 O3, -C2	O3, -C2 O M/Z: 263, C 14 H 14 O 5 O O O	OH CH 3 O3, -C2
		O H OH	O		OH	O3, OH	O H	O H	O	OH	O3, -CH2	O H OH	O H	O	O	OH	O O3, -C4H4	O	O	OH
	O H M/Z: 308, C 15 H 16 O 7 O M/Z: 278, C 10 H 14 O 9 O H O O O OH O O OH OH O3, -C5H2 Ring opening CH 3 CH 3 OH OH M/Z: 359, C 14 H 14 O 11 OH O O OH O O O O O H O3, -C4 H O3, OH M/Z: 255, C 16 H 14 O 3 Ring opening	O	CH 3	O M/Z: 263, C 14 H 14 O 6 O O O O H O3, -C2 M/Z: 287, C 16 H 14 O 5	CH 3 CH 3 OH O3, -C4H6 M/Z: 234, C 12 H 10 O 5 O M/Z: 256, C 10 H 8 O 8 CH 3 OH O OH O O H O O O Ring opening O3, -C4H4
	A: Ketoprofen.

Pharmaceuticals cytotoxicity evolution and removal with ozonation and biofiltration 189 H

  2 O 2 to O 3 from 0.3 to 0.5. In all cases, luminescence inhibition was lower than with O 3 alone at a 1 mg L -1 dose. The application of AOP in surface water showed slightly lower inhibition than in Type II lab water at H 2 O 2 to O 3 of 0.3 for all three compounds. While increased inhibitions was observed in naproxen solutions with a higher molar ratio of 0.3, which indicated that for naproxen in surface water, the ratio of H 2 O 2 to O 3 of 0.3 could achieve better removal efficiency of NSAIDs, and leaving with lower residual toxicity. For piroxicam in surface water, there was peak inhibition at a ratio of 0.5 (O 3 /H 2 O 2 ), then the curve decreases. The toxic value was lower than that in Type II lab water at any ratio of O 3 /H 2 O 2 or ozone alone, which means the application of AOP, is most efficient for removal of piroxicam and its toxic intermediates. With the exception of O 3 /H 2 O 2 at a ratio of 1, the inhibition percentage of ketoprofen surface water solutions was lower than in Type II lab water with O 3 application. From the observed

dose of H 2 O 2 , whereas, naproxen's cytotoxicity dropped sharply from mole ratio of Chapter 7:

Chapter 8 General Discusion 203

  The applied current intensity is other main parameter for EAOPs oxidation, and the experiments were set-up with varying current intensity in the experiments. Oxidative degradation rate and mineralization of the solution increased by increasing applied current. The main reason is at higher current intensity, the enhancement of electrochemical reactions (Eqs. (8.3)-(8.6)) generating more heterogeneous M(  OH) and at higher extent from Eq.(8.4), and high generation rate of H 2 O 2 from Eq. (8.5). Fe 2+ + H 2 O 2 → Fe 3+ +  OH + OH - (8.7)

	M + H 2 O → M(  OH) ads + H + + e -	(8.4)
	O 2 + 2 H + + 2 e -→ H 2 O 2	(8.5)
	Also, iron can be regenerated (Eq. (8.6)) with a higher rate to produce more  OH
	(Eq. (8.7)):
	Fe 3+ + e -→ Fe 2+	(8.6)

  sequential O 3 /H 2 O 2 part, different mole ratios of O 3 /H 2 O 2 molar ratios (ozone dose fixed at 1 mg L -1 ) were applied in experiments. The efficiency of O 3 /H 2 O 2 in type II lab water was higher than in the surface water. It is obvious that addition of H 2 O 2 highly improved the removal rate compared with ozone application alone. An improved value at O 3 /H 2 O 2 of 1 was obtained of 33%, 55% and 28% for ketoprofen, naproxen and piroxicam, respectively. Due to the secondary reactions with natural organic matters in surface water, the removal rate increased obviously with increasing ratio in surface water, but not much in type II lab water. TOC values were measured for surface water after mineralized by ozone and O 3 /H 2 O 2 . About 20% of the mineralization rate can be achieved at O 3 dose of 4 mg L -1 and more than 20% at mole ratio of O 3 /H 2 O 2 at 1. The results were higher than the data from other related literatures with a low TOC removal in the application of ozone/O 3 and H 2 O 2 .

Acknowledgements

Ling Feng is a Doctoral research fellow of the Erasmus Mundus Joint Doctorate programme ETeCoS 3 (Environmental Technologies for Contaminated Solids, Soils and Sediments) under the grant agreement FPA no. 2010-0009. Acknowledgements Ling Feng is a Doctoral research fellow of the Erasmus Mundus Joint Doctorate programme ETeCoS 3 (Environmental Technologies for Contaminated Solids, Soils and Sediments) under the grant agreement FPA no. 2010-0009. Acknowledgements The authors would like to thank the European Commission for providing financial support through the Erasmus Mundus Joint Doctorate Programme ETeCoS 3 (Environmental Technologies for Contaminated Solids, Soils and Sediments) under the grant agreement FPA n°2010-000λ. Acknowledgement The authors would like to thank the European Commission for providing financial support through the Erasmus Mundus Joint Doctorate Programme ETeCoS 3 (Environmental Technologies for Contaminated Solids, Soils and Sediments) under the grant agreement FPA n°2010-0009. Acknowledgements Ling Feng is a Doctoral research fellow of the Erasmus Mundus Joint Doctorate programme ETeCoS 3 (Environmental Technologies for Contaminated Solids, Soils and Sediments) under the grant agreement FPA no. 2010-0009. Acknowledgments Ling Feng is a Doctoral research fellow of the Erasmus Mundus Joint Doctorate programme ETeCoS 3 (Environmental Technologies for Contaminated Solids, Soils and Sediments) under the grant agreement FPA no. 2010-0009. Chapter 7: Pharmaceuticals cytotoxicity evolution and removal with ozonation and biofiltration

I am so honored to have this opportunity to study in the Laboratoire Géomatériaux et Environnement under the grant agreement FPA no. 2010-0009 of Erasmus Mundus Joint Doctorate programme ETeCoS 3 (Environmental Technologies for Contaminated Solids, Soils and Sediments).

I am very grateful to my thesis advisor Mehmet Oturan for his insight,

Pharmaceuticals cytotoxicity evolution and removal with ozonation and biofiltration

The work was presented in the paper:

In preparation