<figure><img src="image_1.png" /></figure>

RESEARCH ARTICLE

OPEN ACCESS

# Non-Thermal Plasma Oxidation Processes for the Removal of Pharmaceuticals in Water: Diclofenac and Diclofenac/Carbamazepine Mixture

Manoj P. Rayaroth<fnref n="1" />,² | Olivier Aubry<fnref n="1" /> | Hervé Rabat<fnref n="1" /> | Eloi Marilleau³ | Yvan Gru⁴,⁵ | Dunpin Hong<fnref n="1" /> | Pascal Vaudin⁶ | Pascal Brault<fnref n="1" />

**Correspondence:** Olivier Aubry (olivier.aubry@univ-orleans.fr)

**Received:** 14 February 2025 | **Revised:** 24 March 2025 | **Accepted:** 27 March 2025

**Funding:** This study has been supported by Conseil Régional Centre-Val de Loire with grant #2021-00144786 for project Perturb'Eau.

**Keywords:** advanced oxidation processes | DBD | non-thermal plasma | reactive nitrogen species | toxicological analyses of degradation products

## ABSTRACT

The Non-Thermal Plasma (NTP) process was studied for the removal of pharmaceutical pollutants (diclofenac (DCF) and carbamazepine (CBZ)) from water. In the individual treatment, at 0.2 W, showed 86% DCF and 63% CBZ degradation in 40 min, forming hydroxylated and nitro-products. The same degradation efficiency was achieved for each compound in the mixed pollutant systems, and a complete degradation was attained after 90 min. By comparing the intermediate products, the formation of nitro-products was higher in the mixed systems compared to their individual solutions treatment. The study concluded that NTP efficiency should be evaluated on pollutant mixtures rather than single compounds. Complementary biological analyses revealed the potential cell toxicity induced by generated products, highlighting the pertinence for toxicological analyses.

## 1 | Introduction

Pharmaceutical pollution has become a growing concern worldwide over the last few decades due to extensive production and usage [1–4]. Wastewater treatment plants (WWTPs) are sometimes inefficient at completely removing pharmaceuticals. Therefore, environmental matrices, especially water resources, can be easily contaminated by pharmaceuticals. Consequently, water sources might have mixed contamination from a wide variety of pharmaceutical compounds [5–7].

Advanced oxidation processes (AOPs) are the most promising method for the removal of organic compounds including pharmaceutical ones [8–12]. However, the use of high concentrations of chemicals, energy requirements, and the

necessity of changing the experimental conditions especially pH step back the AOPs from large-scale applications. Non-thermal plasmas (NTPs) processes are one of the methods in AOPs for the in situ generation of reactive oxygen species (especially *OH and many neutral species such as O₃, and H₂O₂*) which can oxidize organic contaminants and nitrogen species. Therefore, compared to other AOPs, NTP does not require additional chemicals in water and can be initiated at neutral pH conditions and in energy-efficient process [13–17]. NTPs from dielectric barrier discharges (DBDs) have been utilized in the degradation of pharmaceutical compounds like tetracycline, carbamazepine, sulfa drugs, NSAIDs, etc [18–20]. However, most studies have tested only one compound excepted for few studies including one by Bilea et al. [21].

<footnote n="1">¹GREMI, UMR 7344, CNRS, Université d'Orléans, Orléans, France | ²Department of Chemistry, School of Sciences, GITAM (Deemed to be) University, Visakhapatnam, India | ³INOVALYS Vannes, Saint-Avé, France | ⁴INOVALYS Nantes, Nantes Cedex 3, France | ⁵INOVALYS Tours, Tours Cedex, France | ⁶N2Cox, UMR 1069, INSERM, Faculty of medicine, University of Tours, Tours Cedex, France</footnote>

<footnote>This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.</footnote>

<footnote>© 2025 The Author(s). *Plasma Processes and Polymers* published by Wiley-VCH GmbH.</footnote>
As far as real pharmaceutical-contaminated water is considered, one cannot predict the performance of a process or the exact degradation behavior of pollutants by studying a single pollutant in a mixed contaminated system. Therefore, this study aims to propose the pertinence of the NTP process in the treatment of a solution containing a pharmaceutical mixture. Hence, it is expected that this study can provide an insight on the removal of contaminants from real contaminated water. To gain an understanding of the removal of these mixed pollutants, two different pharmaceutical compounds, such as diclofenac (DCF) and carbamazepine (CBZ), were selected with different physicochemical properties, particularly solubility and structures are selected (Supporting Information, Table S1).

DCF is a nonsteroidal anti-inflammatory drug commonly used by people both as an oral drug and as topical gel, and it is consequently found in municipal and hospital wastewater [22, 23]. On the other hand, CBZ is an antiepileptic drug detected in municipal and domestic wastewater [24–26]. According to recent surveys, the approximate annual consumption of DCF and CBZ is 1014 and 940 tons, respectively [27]. As a result, the surface water, groundwater, and even drinking water can be contaminated with DCF and CBZ [28]. Biological treatment processes and other conventional methods do not satisfactorily remove these contaminants from these sources [27]. The cumulative impact of both these contaminants is quite high compared to their individual effect [29]. In addition, the metabolites of these contaminants are likely to cause more severe environmental impacts and are more persistent. Hence, the remediation of such a mixed contaminant system will have significant environmental relevance.

These processes for treating water generate degradation or transformation products that will be more and more present in natural water. Their fate and their impact become a concern, concentrating attention since last few years [30]. Studies reporting toxicological analyses of degradation products are mostly based with in silico assessments [31–34]. Some are closer to physiology using prokaryote cells, yeast, phytoplankton [35–38], and few with human cells or whole vertebrates [39, 40].

Therefore, the present work was conducted with, the key objectives of: 1) studying the degradation of diclofenac in an aqueous matrix by varying the operational parameters and water quality parameters, 2) comparing the degradation of DCF in pure water and with the presence of CBZ, 3) identifying and comparing the intermediate products evolution in mixed contaminant systems and 4) *In vitro* assessment evaluating the toxicity of degradation products using brain human cells.

## 2 | Materials and Methods

Highly pure diclofenac, carbamazepine, and formic acid were purchased from sigma Aldrich®, France. Acetonitrile (HPLC grade a) were procured from Fisher scientific, France. Ultrapure water collected from BARNSTEAD SMART2PURE (Thermo scientific®) system was used to prepare the aqueous solution. For the toxicity tests, α-MEM medium (22571), Fetal Bovine Serum (r10270-106), Penicillin-Streptomycin mix (15140) and HEPES (15630), MEM powder (41500-018), NaHCO₃

(25080-094) from Gibco® have been used. CellTiter-Glo® Lunminescent Cell Viability Assay (G7570) and GloMax® Discover Microplate Reader (GM3000) were provided by Promega®.

## 3 | Experiment and Analysis

### 3.1 | Degradation Studies

A DBD reactor consisted of a multiple needle-to-plate configurations embedded in a Polyvinyl Chloride (PVC) vessel (internal diameter 110 nm) was used (Fig S1). Air is used as the working gas in all the studies and is supplied through 12 needles with a total flow rate of 100 sccm (Bronkhorst® EL-Flow flow meters). The specified volume (40 mL) of the water sample spiked with 5 mg.L⁻¹ of DCF is introduced into the reactor and positioned between the dielectric and needle electrodes. To study the degradation of mix, 5 mgL⁻¹ each of DCF and CBZ were mixed in water and introduced into the reactor. Other components of the reactor include HV pulse generator (NANOGEN 3®) powered by a high voltage power supply system (TECHNIX®). A detailed description of the reactor and the procedure for the calculation of dissipated power are given in the previous studies [41, 42]. The equivalent electric diagram and a typical applied HV pulse of 1 µs in width are given in the supporting file S3. The dissipated power was determined from the Lissajous curve using a suitable capacitor (Cm, 2 nF) placed in series in the circuit after the reactor, enabling the calculation of the dissipated power.

When electric current flows through the reactor, the electric charge that accumulates in the capacitor Cm can be determined by measuring the voltage across the capacitor (Um) according to the equation:

$$Q(t) = C_m \times U_m(t) \quad (1)$$

The voltage at the discharge is close to that of the power supply, UHV, since the value of Cm is much bigger than the equivalent capacitance of the reactor. Two HV probes (TESTEC® HVP-2739 and Tektronix® P6015A) were connected to an oscilloscope (LeCroy® WaveJet 354 A) to record the voltage curves, UHV and Um.

The dissipated energy during a cycle in the reactor is equal to the area of the diagram obtained with the Q-UHV plot, which is obtained by following the evolution of the capacitor charge Q(t) as a function of the value of the high voltage UHV(t). The instantaneous power p(t) in J.s⁻¹ is defined by equation (Eqn):

$$p(t) = U_{HT}(t) \times \left( \frac{dC_m U_m}{dt} \right) \quad (2)$$

After integration over one period, the average discharge power (P in W) is given by the following equation:

$$P = \frac{1}{T} \int_{0}^{T} p(t) \cdot dt = f \times \int_{0}^{T} U_{HV}(t) \cdot C_{m} \cdot dU_{m} = f \times \int_{0}^{T} U_{HV}(t) \cdot dQ_{m} \quad (3)$$
<table><caption>TABLE 1 | The chromatographic conditions for the separation of DCF, CBZ and their degradation products.</caption><thead><tr><th>Time (min)</th><th>0.5–10</th><th>10.5–13</th><th>13.5–20</th></tr></thead><tbody><tr><td>Composition of mobile phase acetonitrile (%)</td><td>5</td><td>70</td><td>5</td></tr></tbody></table>

with *f* the pulse repetition rate in Hz.”

## 3.2 | Analysis

A high-performance liquid chromatography (HPLC; SHIMADZU® LC 2040 C 3D plus) coupled with a photodiode array detector (PDA) was used in the analysis of DCF and CBZ in the water sample. A gradient elution of 0.1% formic acid (A) and Acetonitrile (B) was performed to get a better separation of each component (Table 1).

The degradation efficiency and Energy yield (EY, in g.(kWh)⁻¹) were calculated from the concentration obtained from HPLC by inserting it into the Equations 4 and 5 respectively.

$$ \% \text{ Degradation} = \left( 1 - \frac{C_t}{C_0} \right) \times 100 \quad (4) $$

$$ \text{EY} = \frac{(C_0 - C_t) \times V}{\Delta t \times P} \quad (5) $$

Where C₀ and Ct are the initial and final concentration, respectively in g.L⁻¹, V is the volume of the solution in L, t is the treatment time in hours, and P is the power in kW.

A high-resolution mass spectrometer (Bruker®, Impact II Q-TOF) was used to analyze intermediate products. The analytical procedure for identifying and proposing the structure of these intermediates is detailed in previous studies [41]. An LC-MS (Shimadzu® LC-MS 2020) employing the single ion monitoring (SIM) method was used to track the formation and decay of degradation products. An Accumet AB200 pH/conductivity meter (Fischer Scientific®) was used to measure pH and conductivity. Additionally, a MultiDirect (Lovibond®) photometer was employed to measure the concentration of nitrite and nitrate ions formed during oxidation.

## 3.3 | Cell Viability Assessment

8-MG-BA cells (Accession Number: CVCL_1052) were seeded at 25.000 cells/mL in 96-well white cell culture plates and maintained at 37°C and 5% CO₂ atmosphere in α-MEM medium supplemented with 10% decomplemented Fetal Bovine Serum, 1% Penicillin-Streptomycin mix, and 1% HEPES. 24 h later, cells were exposed with NTP-treated water described in the “Degradation studies” section. For that one medium per condition was reconstituted from NTP-treated water with 1% MEM powder, 2.66% NaHCO₃, 1% Penicillin-Streptomycin mix, and 1% HEPES. Cells were exposed for 48 h before measuring their viability using the CellTiter-Glo® Luminescent Cell Viability Assay and GloMax®

Discover Microplate Reader. Eight measures per condition were taken and raw data were analysed with Prism - GraphPad 10 software. Normality was tested and rejected, so a non-parametric test using a Kruskal-Wallis test multiple comparison with the control condition was chosen. Differences between control and sample to be analysed are accepted if the *p*-value (probability that chance explains the difference) ≤ 0.05.

# 4 | Results and Discussions

## 4.1 | Degradation of DCF

To evaluate the process efficiency, the effects of applied voltage and presence of ions (CO₃²⁻ or Cl⁻) in the water matrix, were studied.

## 4.2 | Effect of Voltage

Applied voltage is an important parameter in NTP process; the discharge is strongly affected by this parameter. To study this effect, the degradation efficiency was examined at three applied HV such as 8, 10, and 12 kV. The degradation efficiency is shown in Figure 1. The dissipated power was 0.05, 0.20, and 0.60 W at the HV 8, 10, and 12 kV, respectively. The degradation efficiency was 35% with the applied voltage of 8 kV, which was increased to 50% and 61.5% with the rise of HV to 10 kV and 12 kV, respectively, after 5 min of treatment. Moreover, the energy yields were 17.8, 3.8, and 2.6 g.(kWh)⁻¹ for the applied voltages, 8, 10, and 12 kV, respectively. Considering both the energy yield and the degradation efficiency, an applied voltage of 10 kV (0.20 W) was chosen for further experiments.

The degradation of DCF by NTP can be explained by the generation of reactive oxygen and nitrogen species (ROS and RNS) by the plasma. The electrical discharge excited the water molecule (H₂O*) and underwent the following reactions (Reactions 6–8) [18, 43].

The discharge from the NTP process contains high-energy electrons (1-20 eV) [44–47] which collide with the gas molecules forming dissociated, excited, or ionized species in the gas phase. Subsequently, reactive species such as reactive oxygen (·OH, ¹O₂, O₂⁻ and O₃), and nitrogen species (NO₂*, NO₃*,) were produced in the plasma in the gas phase. The diffusion of these to the aqueous phase resulting the formation of other species such as hydrogen peroxide (H₂O₂), nitrite (NO₂⁻), and nitrate (NO₃⁻). The concentration of nitrate and nitrite ions at several times is shown in Figure 2. The pollutants can be degraded by any of these reactive species including electrons and H⁺ (Reactions 6-24). Besides these radical-based reactions, the pollutants can also be degraded by physical effects such as physical effects such as ultraviolet radiation, heat and shock wave [44–47].

$$ \mathrm{H_2O*} + \mathrm{H_2O} \rightarrow \mathrm{H} + \mathrm{OH} + \mathrm{H_2O} \quad (6) $$

$$ \mathrm{H_2O*} + \mathrm{H_2O} \rightarrow \mathrm{O} + \mathrm{H_2} + \mathrm{H_2O} \quad (7) $$

$$ \mathrm{H_2O*} + \mathrm{H_2O} \rightarrow \mathrm{O} + 2 \mathrm{H} + \mathrm{H_2O} \quad (8) $$

$$ \mathrm{e}^{-} + \mathrm{H_2O} \rightarrow \mathrm{H} + \mathrm{OH} + \mathrm{e}^{-} \quad (9) $$

$$ \mathrm{e}^{-} + \mathrm{H_2O} \rightarrow \mathrm{OH} + \mathrm{H}^{-} \quad (10) $$
$$e^{-} + H_{2}O^{+} \rightarrow \cdot OH + H^{\cdot} \quad (11)$$

$$H^{\cdot} + H_{2}O^{+} \rightarrow \cdot OH + H_{2} \quad (12)$$

$$H^{\cdot} + H_{3}O^{+} \rightarrow \cdot OH + H_{2} + H \quad (13)$$

$$e^{-} + O_{2} \rightarrow 2 O^{\cdot} + e^{-} \quad (14)$$

$$O^{\cdot} + O_{2} + M \rightarrow O_{3} + M \quad (15)$$

$$\cdot OH + \cdot OH \rightarrow H_{2}O_{2} \quad (16)$$

$$N_{2} + O^{\cdot} \rightarrow \cdot NO + \cdot N \quad (17)$$

$$N_{2} + e^{-} \rightarrow 2N \quad (18)$$

$$\cdot N + O^{\cdot} + M \rightarrow \cdot NO + M \quad (19)$$

$$\cdot N + H^{\cdot}O^{\cdot} \rightarrow \cdot NO + \cdot H \quad (20)$$

$$\cdot N + O_{3} \rightarrow \cdot NO + O_{2} \quad (21)$$

$$\cdot NO + ROS \rightarrow \cdot NO_{2} \quad (22)$$

$$\cdot NO_{2} + ROS/\cdot N \rightarrow \cdot NO_{3}/N_{2}O_{5}/N_{2}O \quad (23)$$

$$ROS/RNS + H_{2}O \rightarrow \begin{array}{l} \text{neutral species (H}_{2} \\ \text{O}_{2}, \text{HNO}_{2}, \text{HNO}_{3}\dots) \end{array} \quad (24)$$

## 4.3 | Degradation of DCF in Pure and Tap Water

To study the degradation behavior of DCF, its concentration was monitored over time. The time-dependent concentration of DCF during the degradation is displayed in Figure 3A. It was found that the concentration of DCF decreased rapidly up to 15 min and then slowed down. Finally, 86% of the DCF was degraded after 40 min of treatment. The pH and conductivity of the solution remained about the same during the treatment, likely due to the lower initial concentration of pollutants (Figure 3B and 3C).

pH and conductivity behaviors depend on the water matrix. In pure water, pH decreased (from 5.3 to 4.6) as a function of the treatment time with a slight rise of the conductivity. The observed decrease of pH corresponds to a rise of nitrate and nitrite ions in solution, as observed Figure 2. The rise of the conductivity corresponds to a rise of the pH (ions H₃O⁺ in solution) and to the formation of by-products. Nevertheless, the variations remain low due to a low initial diclofenac concentration even for the highest degradation efficiency.

In tap water, lower variations for pH and conductivity were observed, which corresponded to lower diclofenac degradation, only 50% for the longest treatment time studied. pH and conductivity remain highly dependent on the tap water characteristics, the produced species playing minor effects in this case.

<figure><img src="image_2.png" /><figcaption>**FIGURE 1** | Effect of HV on the degradation of DCF. Experimental conditions: [DCF] = 5 mgL⁻¹, treatment time 5 min (bar graph represents the % degradation and star symbol represents the EY).</figcaption></figure>

<figure><img src="image_3.png" /><figcaption>**FIGURE 2** | The concentration of nitrate ions (A) and nitrite ions (B) during the NTP oxidation of pure water. Frequency 500 Hz, pulse width 1 µs, applied HV 10 kV, applied power 0.2 W, needle to surface distance 5 mm.</figcaption></figure>
<figure><img src="image_4.png" /><figcaption>**FIGURE 3** | Degradation (A), changes in pH (B), and conductivity (C) during the NTP treatment of DCF in pure and tap water. Experimental parameters: Frequency 500 Hz, pulse width 1 µs, applied HV 10 kV, applied power 0.2 W, needle to surface distance 5 mm, [DCF]₀ = 5 mg. L⁻¹.</figcaption></figure>

<figure><img src="image_5.png" /><figcaption>**FIGURE 4** | The degradation of DCF with adding concentrations of Cl⁻ and CO₃²⁻; Experimental parameters, [DCF]: [ions] = 1:10, Frequency 500 Hz, pulse width 1 µs, applied HV 10 kV, applied power 0.2 W, needle to surface distance 5 mm, Time of treatment 20 min. The used tap water has the initial Cl ion concentration of 19.36 mg.L⁻¹ and initial bicarbonate concentration of 256.9 mg.L⁻¹.</figcaption></figure>

The practicability was investigated by performing the degradation in tap water spiked with 5 mg.L⁻¹ of DCF. It was noted that the degradation efficiency was significantly reduced in tap water. In this case the DCF was degraded slowly, reaching only

57% degradation after 40 min. The lower degradation efficiency in tap water can be attributed to the presence of background ions, especially carbonate ions, present in this water [48].

To get a further understanding on the influence of the coexisting matrices in the real contaminated water on removal, degradation was monitored with the addition of most common inorganic ions such as Cl⁻ and CO₃²⁻. The concentration of the DCF to inorganic ion ratio was fixed at 1:10, and the degradation efficiency after 20 min of treatment was calculated (Figure 4). The graph indicates that degradation decreased from 64% to 20% after 20 min with the addition chloride ions. In the case of carbonate ions, the reduction was even stronger, and only 2% of the initial DCF was degraded. The inhibitor effects of the ions can be explained by their scavenging of reactive species, resulting in the formation of less reactive secondary chlorine and carbonate radical species [48, 49]. Thus, the reduced degradation efficiency in tap water can be thus proposed due to the interference of coexisting matrices during the oxidation.

## 4.4 | Product Analysis and the Degradation Mechanism

Product identification is a crucial step in any of the oxidation-based treatment techniques. The information obtained from HPLC is limited to the standard peaks only, and there are many
<table><caption>TABLE 2 | The m/z values and the respective elemental composition of the product formed during the oxidation of DCF.</caption><thead><tr><th>Product</th><th>m/z</th><th>Ionization mode</th><th>Elemental composition</th><th>Type of product</th></tr></thead><tbody><tr><td>DCF</td><td>294.0094</td><td>ESI-</td><td>C<sub>14</sub>H<sub>11</sub>Cl<sub>2</sub>NO<sub>2</sub></td><td></td></tr><tr><td>P1</td><td>312.0189</td><td>ESI+</td><td>C<sub>14</sub>H<sub>11</sub>Cl<sub>2</sub>NO<sub>3</sub></td><td>Hydroxylated product</td></tr><tr><td>P2</td><td>249.0115</td><td>ESI-</td><td>C<sub>13</sub>H<sub>10</sub>Cl<sub>2</sub>N</td><td>Decarboxylated product</td></tr><tr><td>P3</td><td>322.9990</td><td>ESI-</td><td>C<sub>14</sub>H<sub>10</sub>Cl<sub>2</sub>N<sub>2</sub>O<sub>3</sub></td><td>Nitrosated product (three isomers)</td></tr><tr><td>P4</td><td>322.9975</td><td>ESI+</td><td>C<sub>14</sub>H<sub>8</sub>Cl<sub>2</sub>N<sub>2</sub>O<sub>3</sub></td><td>Nitrosation/Cyclisation</td></tr><tr><td>P5</td><td>338.9941</td><td>ESI-</td><td>C<sub>14</sub>H<sub>10</sub>Cl<sub>2</sub>N<sub>2</sub>O<sub>4</sub></td><td>Nitrated product</td></tr><tr><td>P6</td><td>295.0159</td><td>ESI+</td><td>C<sub>12</sub>H<sub>8</sub>Cl<sub>2</sub>N<sub>4</sub>O</td><td>Nitration and rearrangement</td></tr></tbody></table>

<figure><img src="image_6.png" /><figcaption>FIGURE 5 | The tentative degradation pathway of DCF by NTP.</figcaption></figure>

other product peaks need to be identified (supporting information Fig S4). Mass spectrometric studies were performed to gain insight into the structure of the intermediate products. High-resolution mass spectrometry (HRMS) analysis provided the exact mass, isotopic pattern, and fragmentation pattern corresponding to the product peaks. The various steps involved in product identification using HRMS are detailed elsewhere [41]. Table 2 shows the exact mass, elemental composition, and MS/MS fragmentation of DCF and its intermediate compounds.

The structure of the intermediate compound was proposed by comparing the elemental composition, MS/MS fragments, and mass difference with those of the parent compound. The DCF was detected in negative ionization mode, and its elemental composition was found to be C₁₄H₁₁Cl₂NO₂ (m/z 294.0094). An intermediate product with m/z 312.0189 (P1) was identified in positive ionization mode with an elemental composition of C₁₄H₁₁Cl₂NO₃. By comparing these data, it became evident that the intermediate has one additional oxygen atom compared to

DCF, resulting in a molecular weight difference of 16. Hence, it is proposed that the product is a hydroxylated derivative of DCF.

The elemental composition of the product, P2 (m/z 249.0115, C₁₃H₁₀Cl₂N), lacked one carbon and one hydrogen, and two oxygen atoms less compared to DCF, indicating a decarboxylation from DCF.

Another product, detected in negative ionization mode, was P3, identified with an elemental composition of C₁₄H₁₀Cl₂N₂O₃ (m/z 322.9990). The product comprised of an additional N and O atom and one H atom less compared to DCF, suggesting it is a nitroso product. Two species of P3 with the same m/z, elemental composition, and fragmentation pattern were identified, indicating isomers formed by the attack of RNs at various possible positions in the DCF.

The product, P4 (m/z 322.9975), was identified, in the positive ionization mode, with an elemental composition of
<figure><img src="image_7.png" /><figcaption>**FIGURE 6** | The evolution of intermediate products with m/z (A) P1, (B) P2, (C) P5 and (D) P6 in pure and tap water and mixed pollutants. Experimental parameters: Frequency 500 Hz, pulse width 1 µs, applied HV 10 kV, applied power 0.2 W, needle to surface distance 5 mm, [DCF] = 5 mg. L⁻¹.</figcaption></figure>

<figure><img src="image_8.png" /><figcaption>**FIGURE 7** | Degradation of DCF and CBZ in separate (A) and the mixed solutions (B). Experimental parameters: Frequency 500 Hz, pulse width 1 µs, applied HV 10 kV, applied power 0.2 W, needle to surface distance 5 mm, [DCF] = [CBZ] = 5 mg. L⁻¹.</figcaption></figure>

C₁₄H₈Cl₂N₂O₃. This product has two H atoms less than P3. Three isomeric products of P4 were identified by the HRMS.

The product, P5 (C₁₄H₁₀Cl₂N₂O₄), was identified in negative mode. P5 has an additional N atom and two O atom compared to DCF, indicating a nitro product.

The product P6 (m/z 295.0159, elemental composition of C₁₂H₈Cl₂N₄O) was identified in positive mode with fewer C atoms and three additional N atoms compared to DCF.

The structures of the products are shown in Figure 4. Based on the analysis of the intermediate products, it is proposed that

both reactive oxygen (ROS) and reactive nitrogen (RNs) species are involved in the degradation and transformation of DCF. The hydroxylated and nitro products are formed by the attack of ROS and RNS on DCF. The product with P6 is formed by the decarboxylation of the DCF induced by ROS shown in Figure 5 which is a tentative degradation pathway of DCF by NTP.

## 4.5 | Monitoring of Intermediate Products in Pure and Tap Water

The fate of the intermediate products was investigated by monitoring the products at specific time intervals. No additional
<figure><img src="image_9.png" /><figcaption>**FIGURE 8** | The evolution of intermediate products with m/z (A) P1, (B) P2, (C) P5, and (D) P6 under different time interval in DCF alone and mix of DCF and CBZ. Experimental parameters in pure water: Frequency 500 Hz, pulse width 1 µs, applied HV 10 kV, applied power 0.2 W, needle to surface distance 5 mm, [DCF] = [CBZ] = 5 mg. L⁻¹.</figcaption></figure>

intermediate products were observed in tap water compared to that detected in pure water. A SIM technique using the LC-MS technique was utilized to monitor the intermediates. The products P1, P2, P5, and P6 were detected in all treated solutions and hence selected to represent product decay. A comparison of the intensities of each selected product in pure and tap water is given in Figure 6. As evident from the figure, the product intensities do not exhibit decay within the selected timeframe. The product P1 is formed by the reaction of *OH with DCF. The concentration of P1 increased over time, likely due to the continuous reaction. Similarly, the nitration of DCF (P5 and P6) occurred as time progressed, which is evident from the product formation. However, P1 can also degrade due to reactive species formed during the NTP processes, leading to a decrease in product intensity over time. On the other hand, degradation may reach saturation if all the DCF is converted into intermediates and the reactive species are insufficient for further degradation. However, it was found that the concentration of P2 (the decarboxylated product) did not vary with treatment time. This may be due to the rapid decarboxylation rate of DCF and its low reactivity (or even lack of reactivity) toward reactive species. In addition, the peak intensities of the intermediate products are higher in tap water. This likely arises from the reduced reactivity of the intermediates with reactive species in the presence of co-existing ions in tap water.

## 4.6 | Degradation of DCF in the Mixed Contaminants With Carbamazepine

Before to investigating mixed systems, the degradation of DCF and CBZ was evaluated in separate batch experiments. As shown in Figure 7A, under identical experimental conditions,

86% of DCF degraded in pure water after 40 min, while only 63% of CBZ degraded within the same treatment time. After this, the degradation of the pharmaceutical mixture was assessed by spiking a concentration of 5 ppm of CBZ and DCF each in pure water (Figure 7B). Similar efficiency degradations were achieved in the mixed system (85% for DCF and 60% for CBZ).

A comparison of the independent and mixed systems reveals that DCF degrades faster than CBZ under these conditions. These differences can be attributed to variations in either the reactivity of the generated species with the pollutants or the physicochemical properties of the pollutants themselves.

The bimolecular rate constant for the reaction of CBZ with *OH is 4.63 × 10⁹ M⁻¹ s⁻¹ [50] is lower than that for DCF (9.29 × 10⁹ M⁻¹ s⁻¹ [51]). Thus, DCF reacts more with the *OH than CBZ. In addition, the octanol-water partition coefficient, log(K<sub>ow</sub>) for CBZ and DCF are 1.51 and 1.9, respectively [52]. A higher log (K<sub>ow</sub>) value indicates a tendency for DCF to reside closer to the liquid surface, potentially granting it greater access to reactive species generated in the plasma. Based on this combined analysis, DCF undergoes faster degradation than CBZ in this system.

In addition, the evolution of intermediates of DCF in the presence of CBZ has been investigated and is shown in Figure 8. The intensities of the product due to *OH reactions (P1 and P2) decreased in the mixed contaminant system. Even though DCF has a higher bimolecular rate compared to CBZ, the intermediate product likely shows less reactivity towards the reactive species. Hence, instead of degrading as observed in DCF alone, these products may accumulate in the solution. This is the
<figure><img src="image_10.png" /><figcaption>**FIGURE 9** | The evolution of intermediate products with m/z (A) 253, (B) 251, (C) 282 (D) 300, (E) 296, and (F) (241) under different time interval during the degradation of CBZ in single and mixed pollutants. Experimental conditions in pure water: Frequency 500 Hz, applied HV 10 kV, applied power 0.2 W, needle to surface distance 5 mm, [DCF] = [CBZ] = 5 mg. L⁻¹.</figcaption></figure>

reason for the increased concentration (peak intensity) of P1 and P2 in the mix. However, the intermediate species produced from reactions with RNSs (P5 and P6) appear unaffected by the presence of CBZ. This indicates that RNSs effectively react with DCF regardless of the interfering matrices.

Figure 9 presents the trends of intermediate products (m/z values 251, 253, 241, 282, 296, and 300) formed during CBZ degradation. Their structures are provided in the same figure. Products with m/z values of 251, 253, 241, and 271 were attributed to reactive oxygen species (ROS) with DCF, while those with m/z values of 282, 296, and 300 were formed by reactions with reactive nitrogen species (RNS) and DCF. Detailed data is presented in the previous study [41].

From Figure 9, it is possible to note that the intensities of products with m/z values of 253, 251, 241, and 300 show no significant change between the CBZ solution and the mixture (DCF + CBZ). This suggests that ROS generated in the plasma were distributed in the liquid medium, allowing a part of these species can react with CBZ. Furthermore, the reaction of ROS with CBZ within the liquid medium appears independent of DCF presence.

However, the intensities of the nitro-products for both CBZ (with m/z values 282 and 296) and DCF (m/z 339) were higher in the mixture compared to their individual solutions.

## 4.7 | Evaluation of Cell Toxicity

To evaluate the toxicity of degradation products after NTP treatment, cell viability was measured using 8-MG-BA cells derived from human glioblastoma. This cell line is a glial cell model since it expresses glial marker as glial fibrillary acidic protein (GFAP) and vimentin [53]. Using human brain cells is consistent with the tropism of CBZ, an antiepileptic, and DCF, drug targeting wide tissues including brain cells.

Figure 10A and 10B show the toxicity results for the diclofenac solutions and the diclofenac/carbamazepine mixtures presented in this present work (applied power of 0.2 W and for two treatment time: 20 and 40 min). The results of the biological tests of the treated solutions were systematically compared to the initial solutions without plasma treatment (w/o plasma) ones. We noted that for the DCF treatments, the results indicated no difference of cell viability according any tested NTP conditions (Figure 10A).
<figure><img src="image_11.png" /><figcaption>**FIGURE 10** | Viability of 8MG-BA cells after 48h00 exposure with NTP untreated contaminated water (W/O plasma) and with NTP treated contaminated water (power and duration in brackets), expressed with international unit of luminescence. (A) DCF and (B) CBZ/DCF mixture. ns: nonsignificant \*: *p* < 0.05.</figcaption></figure>

For DCF/CBZ mixtures a significative diminution of cell viability, compared with the control condition, was obtained only by NTP treatment with 0.2 W and 20 min of duration (Figure 10B). The variations of viability of the cells for DCF + CBZ mix could be explained by the concentrations of the produced species during the plasma treatment. In the treatment of DCF + CBZ mixture, for a treatment time of 20 min, the intensities of the nitro-products for both CBZ (with m/z values 282 and 296, Figures 8C and 8E respectively) and DCF (m/z 339, Figure 7C) in the mixture compared to their individual solutions.

For a treatment time of 40 min, no difference of cell viability was observed (Figure 10B). For this treatment time, the intensities of the nitro-products for both CBZ (with m/z values 282 and 296) in the mixture and in the individual solutions are the same as well as m/z 339 (from DCF degradation) at a lower level. Nevertheless, the identification of products responsible for toxicity after treatment is delicate and requires very thorough work in terms of detection and identification.

5 | Conclusions

NTP process effectively degraded the diclofenac in pure and tap water. Both reactive oxygen and nitrogen species (ROS and RNS) participated in the transformation of DCF, resulting the formation of hydroxylated and nitration products in pure water, tap water, and mixed contaminant systems. The intermediate products identified in all the matrices were the same, and no additional products were detected. However, the rate of decay of the intermediate products was significantly slower in tap water. This is due to the interference from the inorganic ions in the tap water, which reduces the degradation efficiency in tap water. In addition, the concentration (in terms of intensity) of intermediates is high in the tap water due to the limited availability of the reactive species for the further reaction.

Furthermore, a study with a pollutant mixture of DCF and carbamazepine (CBZ) revealed that DCF underwent faster degradation compared to CBZ due to its lower hydrophobicity. The degradation efficiency of these pollutants was not significantly affected by their copresence. However, the hydroxylation of DCF was slightly retarded by the presence of CBZ, while the formation of nitro-products was enhanced in the mixed contaminant system.

The toxicity of the treated solutions has been evaluated with biological assays. Cell viability was measured using 8-MG-BA cells derived from human glioblastoma. Results show no toxicity induced by the degradation compounds of DCF in the experimental conditions. The presence of CBZ with DCF during NTP treatments has an impact on cell viability and induces cell toxicity for one of the two experimental conditions. Indeed, the duration of the treatment plays a role with less induced toxicity associated with a longer NTP treatment. The viability cells seems to be linked to the limitation of nitro-products in the treated solution. The identification of products responsible for toxicity after treatment is delicate and requires very thorough work in terms of detection and identification. The results heavily depend on the equipment used and also require studying the effects of all detected products on toxicity, which also depends on concentration levels. Toxicity tests like those used in this study thus allow for addressing the overall toxicity issue of a treatment and can help in adjusting the operational conditions *in fine*.

Therefore, this study highlights the importance of detailed investigations when using oxidative water treatment processes for systems containing multiple pollutants. These investigations should consider the potential impact of water matrix composition and interactions between contaminants on the degradation efficiency and product formation.

Acknowledgments

This study has been supported by Conseil Régional Centre-Val de Loire with grant #2021-00144786 for project Perturb'Eau.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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**Supporting Information**

Additional supporting information can be found online in the
Supporting Information section.