*Article* **Presence and Reduction of Anthropogenic Substances with UV Light and Oxidizing Disinfectants in Wastewater—A Case Study at Kuopio, Finland**

**Jenni Ikonen 1,\*, Ilpo Nuutinen 2, Marjo Niittynen 1, Anna-Maria Hokajärvi 1, Tarja Pitkänen 1,3, Eero Antikainen <sup>2</sup> and Ilkka T. Miettinen <sup>1</sup>**


**Abstract:** Anthropogenic substances are a major concern due to their potential harmful effects towards aquatic ecosystems. Because wastewater treatment plants (WWTPs) are not designed to remove these substances from wastewater, a part of the anthropogenic substances enter nature via WWTP discharges. During the spring 2019, the occurrence of anthropogenic substances in the municipal wastewater effluent in Kuopio, Finland, was analysed. Furthermore, the capacity of selected disinfection methods to reduce these substances from wastewater was tested. The disinfection methods were ozonation (760 mL min<sup>−</sup>1) with an OxTube hermetic dissolution method (1), the combined usage of peracetic acid (PAA) (<5 mg L−1) and ultraviolet (UV) disinfection (12 mJ/cm2) (2), and the combined usage of hydrogen peroxide (H2O2) (<10 mg L−1) and UV disinfection (12 mJ/cm2) (3). The substances found at the concentrations over 1 μg L−<sup>1</sup> in effluent (N = 3) were cetirizine (5.2 <sup>±</sup> 1.3 <sup>μ</sup>g L<sup>−</sup>1), benzotriazole (BZT) (2.1 <sup>±</sup> 0.98 <sup>μ</sup>g L<sup>−</sup>1), hydrochlorothiazide (1.7 <sup>±</sup> 0.2 <sup>μ</sup>g L<sup>−</sup>1), furosemide (1.6 <sup>±</sup> 0.2 <sup>μ</sup>g L<sup>−</sup>1), lamotrigine (1.5 <sup>±</sup> 0.06 <sup>μ</sup>g L<sup>−</sup>1), diclofenac (DCF) (1.4 <sup>±</sup> 0.2 <sup>μ</sup>g L−1), venlafaxine (1.0 <sup>±</sup> 0.13 <sup>μ</sup>g L−1) and losartan (0.9 <sup>±</sup> 0.2 <sup>μ</sup>g L−1). The reduction (%) with different methods (1, 2, 3) were: cetirizine (99.9, 5.0, NR = no removal), benzotriazole (67.9, NR, NR), hydrochlorothiazide (91.1, 5.9, NR), furosemide (99.7, 5.9, NR), lamotrigine (46.4, NR, 6.7), diclofenac (99.7, 7.1, 16.7), venlafaxine (91.3, NR, 1.1), losartan (99.6, 13.8, NR). Further research concerning the tested disinfection methods is needed in order to fully elucidate their potential for removing anthropogenic substances from purified wastewater.

**Keywords:** anthropogenic substances; disinfection; wastewater

#### **1. Introduction**

Emerging anthropogenic pollutants are a permanent global challenge to freshwater quality and safety [1–3]. A major group of emerging pollutants in the aquatic environmental consists of pharmaceuticals [4]. After being used for human or animal medication [5], pharmaceuticals are mainly excreted in urine and faeces as such or as metabolites [6]. Subsequently, they are distributed in the environment via wastewater treatment plants (WWTPs) [7] where they pass through various treatment processes and, therefore, are easily transferred to the receiving waters. In Finland, the legislation does not require the removal of anthropogenic substances from wastewater before discharge into the environment and most of the treated wastewaters are discharged to the receiving waters without disinfection. The Water Framework Directive (WFD) [8] aimed to improve the status of all European

Niittynen, M.; Hokajärvi, A.-M.; Pitkänen, T.; Antikainen, E.; Miettinen, I.T. Presence and Reduction of Anthropogenic Substances with UV Light and Oxidizing Disinfectants in Wastewater—A Case Study at Kuopio, Finland. *Water* **2021**, *13*, 360. https://doi.org/10.3390/w13030360

**Citation:** Ikonen, J.; Nuutinen, I.;

Academic Editor: Amin Mojiri Received: 18 December 2020 Accepted: 27 January 2021 Published: 30 January 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Union (EU) inland waters, coastal waters, and groundwater by 2015. The deadline has been extended until 2027 at the latest under the WFD derogation rules.

In the future, the use of pharmaceuticals is likely to increase due to the ageing population. Unless efforts are made to reduce emissions, more pharmaceutical residues will end up in the environment. To compare the effectiveness of different wastewater treatment methods, more research data on the existence and harmfulness of these substances in the environment is needed. EU Member States are required to monitor the concentrations of 45 substances or groups of substances in the aquatic environment [9]. These substances are listed in the directive 2013/39/EU (amending Directives 2000/60/EC and 2008/105/EC as regards priority substances in the field of water policy). Moreover, some of the substances are listed as priority hazardous substances. Furthermore environmental quality standards (EQS) are included in the directive for these 45 substances or groups of substances that EU Member States are required to monitor. The concentrations of the substances in water or biota must not exceed the EQS set for them. With the aim of achieving good surface water chemical status, the revised EQS for existing priority substances should be met by the end of 2021 and the EQS for newly identified priority substances by the end of 2027.

At the WWTPs pharmaceuticals may transform, retain in sewage sludge, or end up in receiving water. In a recent risk assessment study concerning Finnish surface waters, the calculated environmental risk was assessed by a so called risk component; or risk quotient (RQ). A risk quotient > 1 was found for 29 of the evaluated substances, suggesting that these substances potentially pose a risk in Finnish surface waters. Four substances: diclofenac (DCF) (0.022 μg L<sup>−</sup>1), azithromycin (0.0015 μg L<sup>−</sup>1), ciprofloxacin (0.034 μg L<sup>−</sup>1), and 17α- ethinylestradiol (0.00018 μg L−1) concentrations measured in Finnish surface waters exceeded concentrations assessed as harmful [10].

As the pharmaceuticals and other anthropogenic substances are not properly removed in current WWTP processes, alternative, tentatively more efficient removal options such as novel disinfection methods to remove these substances from wastewater have been studied. For example in Mexico, Mejía-Morales et al. studied a post treatment with advanced oxidation process (AOP) based on an ultraviolet (UV)/H2O2/O3 system in hospital wastewaters [11]. In addition, various other methods have been tested to remove inorganic and organic impurities from water such as porous ceramic disk filter (PVDF) ultrafiltration membrane [12] and porous ceramic disk filter coated with Fe/TiO2 nano-composites [13]. Here we studied the efficiency of three disinfection methods, i.e., ozonation (760 mL min<sup>−</sup>1) with OxTube mixing; a combination of peracetic acid (PAA) (<5 mg L−1) and UV disinfection (12 mJ/cm2), and a combination of hydrogen peroxide (<10 mg L−1) and UV disinfection (12 mJ/cm2) in order to reduce the amount of anthropogenic substances in treated wastewater. This study was one part of a project in which we studied the removal of certain microbes and chemicals in different water matrices with different disinfection methods.

#### **2. Materials and Methods**

Treated wastewater samples (N = 3) were collected from the municipal WWTP of the city of Kuopio (Lehtoniemi WWTP) in the spring of 2019. The wastewater that was used in the tests was from the channel where purified wastewater is discharged into the surface water. The population of the service area of the Lehtoniemi WWTP is 90,697; and the total population of the city of Kuopio is 118,000. The disinfection methods tested herein were an ozone purification process with the OxTube hermetic dissolution method, a combination of the usage of PAA (<5 mg L<sup>−</sup>1) and UV disinfection (12 mJ/cm2) processes, and a combination of hydrogen peroxide (<10 mg L−1) and UV disinfection (12 mJ/cm2) processes. A wide set of chemical substances were analysed (N = 121). Wastewater samples were taken before and after each disinfection treatment. All wastewater samples were frozen and stored at −20 ◦C and subsequently sent to a commercial laboratory (Eurofins Environment Testing Finland Oy, Lahti) for analysis. Analysed substances are listed in the Table S1. The substances were analysed with the U.S. Environmental Protection Agency

(EPA) method 1694. Method 1694 is used for determination of pharmaceuticals and personal care products (PPCPs) in multi-media environmental samples by high-performance liquid chromatography combined with tandem mass spectrometry (HPLC/MS/MS) using isotope dilution and internal standard quantitation techniques [14].

#### *Experimental Design*

All disinfection experiments were carried out in the Savonia Water laboratory (Savonia University of Applied Sciences, Kuopio, Finland). The experimental design is shown in the Supplementary Material (Figure S1). First, a 1000-litre food-grade plastic container was filled with 500 L of wastewater. The treated wastewater was mixed with an electric motor-operated water mixer to ensure the homogeneity of the sample water. After the wastewater was disinfected, it was collected into a plastic container with a capacity of 45 L (Curtec Ltd., Denmark). The pipe material used was a plastic water pipe with an inner diameter of 15 mm (Uponor Aqua Pipe, PEX 15/18 mm polyethylene, PE) and the connectors were acid-resistant stainless steel water pipe fittings (various manufacturers).

For the pumping of the tested wastewater, a 24 V resistance-adjustable gear pump designed for drinking water systems in boats with a maximum flow of 26 L min−<sup>1</sup> (Marco UP/Em, Castenedolo, Italy,) was used. Acid-resistant steel valves (EGO, stainless) were used in the test system due to the oxidizing peroxide chemicals used in the experiments.

For the supply of peroxide chemicals (PAA and H2O2) (Lamor water technology, Finland), a chemical pump (Grundfos DDA 12-10 AR-PP/E/C-F-31U2U2FG, Bjerringbro, Denmark) with proven chemical supply and adjustability for a wide feed rate between 12 mL h−<sup>1</sup> and 12 L h−<sup>1</sup> was obtained. A rotameter (Kobold, Germany) with a flow scale of 100 to 1000 L h−<sup>1</sup> was obtained to measure the water flow. A tube UV lamp (Wedeco Aquada 1, Xylem, Herford) was used in the disinfection experiments. A Faraday Ozone L 40 G (Farady Ozone, Coimbatore, India) device, which is capable of producing ozone with a capacity of 40.000 mg h<sup>−</sup>1, was used as the ozone generator. The flow of ozone gas was controlled with the mass flow controller (Brooks GF040). An OxTube water treatment tube (OxTubeDN20, Sansox Oy, Lahti, Finland) was used for mixing and dissolving ozone hermetically in the test water. The OxTube hermetic dissolution method (Figure 1) treats the water in flowing condition in its hermetic tube. The air gases are sucked by the vacuum effect in the nozzle zone and led directly into the middle of the main flow. Other gases like pure oxygen, ozone, CO2 as well as chemicals can be fed and dispensed through the same channel. The water and gases are mixed evenly and the meeting probability of the molecules is high. Chemical reactions follow immediately in the hermetic condition. There are four main functions following each other seamlessly in one tube or in separate modules by function. The water is clarified and dissolved with desirable ingredients, e.g., air gases in the tube within a second or less.

**Figure 1.** OxTube hermetic dissolution method (Sansox Oy, Lahti, Finland).

Chemical concentrations were measured using a Chemetrics Inc. V-2000 spectrometer (Chemetrics Inc., Midland, VA, USA) and suitable measuring ampoules including a Chemetrics K7913 for peracetic acid, K-5543 for hydrogen peroxide and K-7423 for ozone.

#### **3. Results and Discussion**

The anthropogenic substances with detected concentrations over 1 μg L−<sup>1</sup> in the wastewater are shown in Table 1, as well as the removal efficiencies for the chemicals with the tested disinfection methods. The measurement uncertainty is between 45–51% in the analyses presented here. Each of the substances is discussed later in this manuscript.

Anthropogenic substances detected concentrations below concentrations of 1 μg L−<sup>1</sup> in the wastewater are presented in the Supplemental Materials (Table S1).

**Table 1.** Anthropogenic substances with detected concentrations over 1 μg L−<sup>1</sup> in wastewater effluent and their removal efficiencies with the depicted methods.


− = no removal detected; NR = not regulated in Directive 2013/39/EU.

#### *3.1. Cetirizine*

Cetirizine is an ingredient that is used in the treatment of symptoms of seasonal allergic rhinitis [15], perennial allergic rhinitis, and chronic idiopathic urticarial in adults [16]. Unfortunately, cetirizine has been shown to induce adverse biochemical effects in the mussel *Mytilus galloprovincialis* and is thus problematic from the ecotoxicological point of view [17]. In our study, the concentration of cetirizine detected in the Kuopio wastewater effluent (5.2 ± 1.3 <sup>μ</sup>g L−1) clearly exceeds the concentrations reported earlier in Finland. The appearance and level of cetirizine in municipal wastewaters has previously been studied in the city of Turku in 2007 [7]. In that study cetirizine was found to be the dominating antihistamine in nearly all samples. The sampling included 12 influent and 12 effluent samples, and it was conducted between March and September. The highest detected concentration of cetirizine in that study was 0.22 μg L−<sup>1</sup> (influent) and elimination rate of cetirizine in the sewage treatment process was 16% [7]. Concentrations ranging from 0.1 μg L−<sup>1</sup> to 0.7 μg L−<sup>1</sup> have been detected in the influent of WWTPs in Berlin. Cetirizine levels were significantly increased between the hay season [18]. The concentration of this chemical is only slightly degraded during the wastewater treatment process [7]. For instance cetirizine removal from wastewater has been tested with granular activated carbon (GAC). Only 30.4% of cetirizine was removed even when the contact time was 15 min with a GAC column [19]. The purification process with ozone and the OxTube hermetic dissolution method removed 99.9% of the cetirizine. The method consisting of PAA with UV disinfection was clearly less efficient, as it removed only 5%. The third method (with a

combination of H202 and UV) did not remove any of the cetirizine. The result obtained indicates that wastewater effluent disinfection with ozone is a very efficient method to remove cetirizine.

#### *3.2. Benzotriazoles (BZTs)*

Benzotriazoles (BZTs) are heterocyclic aromatic compounds that are widely used in industrial applications due to their excellent properties as corrosion inhibitors [20], antifreeze agents, and UV radiation stabilizers [21]. Another cause for the occurrence of BZTs in municipal wastewaters is their use in dishwasher products; tablets and powders [22]. BZTs are highly water soluble and highly polar compounds. In addition, they are moderately resistant against biological and photochemical degradation processes in the aquatic environment [23]. Moreover, BZTs have been identified in river water, groundwater, drinking water, wastewater as well as in soil, and in human samples. This is due to the low volatility of these compounds, their strong resistance to oxidation, and limited degradation under environmental conditions [24]. In our tests, the ozone purification process with the OxTube hermetic dissolution method removed 67.9% of the found BZT. PAA or H202 together with UV disinfection did not achieve removal efficiency. Loos et al. (2013) found that median concentrations of BZTs in an EU-wide wastewater treatment plant study were 2.7 μg L−<sup>1</sup> for 1H-benzotriazole, and 2.1 μg/L for methylbenzotriazole (mixture of 4- and 5-isomers, also called tolyltriazoles), with maximum values up to 221 μg L−<sup>1</sup> and 24.3 μg L<sup>−</sup>1, respectively. In our study concentrations of 2.1 ± 0.98 <sup>μ</sup>g L−<sup>1</sup> of BZT in wastewater were detected (BZTs were not specified), which were median concentrations compared to concentrations measured in the EU [25]. Our study addresses the fact that when using ozone disinfecting for wastewater effluent, significant removal of BZT can be achieved.

#### *3.3. Hydrocholorothiazide*

Hydrochlorothiazide is a diuretic and an antihypertensive drug that is widely used by itself or in combination with other drugs for the treatment of edema and hypertension, as well as for other disorders such as diabetes insipidus, hypoparathyroidism, or hypercalciuria [26,27]. In Finland, hydrochlorothiazide concentrations of 1.8–6.7 μg L−<sup>1</sup> have been reported in effluent wastewaters [28], which were on average higher than concentrations found in this study (1.7 ± 0.2 <sup>μ</sup>g L−1). This compound has been frequently detected in the influents and effluents of WWTPs in Europe. In the Netherlands [29] concentrations of 1.27 ± 0.26 <sup>μ</sup>g L−<sup>1</sup> (effluent) of hydrochlorothiazide were detected in municipal wastewater samples. In Spain, detected concentrations ranged between 2.5 μg L−<sup>1</sup> and 14 μg L−<sup>1</sup> in raw wastewater [30].

The removal of hydrochlorothiazide from wastewater has been studied using biological membranes in the laboratory and reduction percentages between 56% and 85% have been achieved. Slightly better removal has been achieved by conventional wastewater treatment [31]. In the present study, a removal rate of 91.1% was achieved with ozone purification using an OxTube hermetic dissolution method. With PAA and UV disinfection treatment, the removal was only 5.9%. The combination of H202 and UV did not remove hydrochlorothiazide at all. Therefore, ozone disinfection was a superior method in terms of hydrochlorothiazide removal.

#### *3.4. Furosemide*

Furosemide, a diuretic that has been widely used since the 1960s, is poorly metabolized by humans [32]. In 2016, it was the most used diuretic in Finland [33]. The average concentration of furosemide detected in the Kuopio wastewater effluent (1.6 ± 0.2 <sup>μ</sup>g L<sup>−</sup>1) is slightly higher than concentrations detected before in Finland. A furosemide concentration of 1.4 μg L−<sup>1</sup> in wastewater effluent has previously been reported in another Finnish WWTP, at the Turku Kakolanmäki WWTP (Turku, Finland) [28]. It has previously been detected at concentrations of 0.615 and 0.2 μg L−<sup>1</sup> in the Viskan river at Jössabron Borås, in Sweden [34]. In Norwegian surface water sample concentrations of up to 0.05 μg L−<sup>1</sup> and up to 1.9 μg L−<sup>1</sup>

in treated wastewater [35] were detected. Deblonde et al. [1] presented in their review furosemide concentrations of 0.413 μg L−<sup>1</sup> and 0.166 μg L−<sup>1</sup> in wastewater influent and effluent, respectively. Among human pharmaceuticals divided into six categories (IA, IB, IIA, IIB, III, IV), furosemide belongs to the highest risk group (IA) as it has been shown to pose a risk to the aquatic environment already at concentrations of potential exposure (PEC) > 0.1 μg L−<sup>1</sup> [36]. In the study by Jelic et al. (2011) removal rates for furosemide were found between WWTPs to be 30%, 60% and 80% [37]. In our experiment, 99.7% of furosemide was removed with ozone purification with the OxTube hermetic dissolution method and 5.9% using PAA and UV disinfection. With the treatment of H2O2 and UV disinfection, no reduction was detected. Thus furosemide was successfully removed from the wastewater effluent with using ozone as the disinfection method.

#### *3.5. Lamotrigine*

Lamotrigine is an anticonvulsant medication used to treat epilepsy and bipolar disorder. Lamotrigine has recently been recognized as a persistent pharmaceutical in the water environment and in wastewater effluent. Bollman et al. [38], found N2-glucuronide conjugates of lamotrigine cleaved to form lamotrigine and that the concentration of lamotrigine increased from 1.1 to 1.6 μg L−<sup>1</sup> in WWTPs. In this study, the lamotrigine concentration in wastewater was within the range of 1.5 ± 0.06 <sup>μ</sup>g L−1. In a previous study [39], it was found to be present in 94% of the studied wastewater samples, with a mean concentration of 0.488 μg L−1. The same study found lamotrigine in two drinking water samples. As lamotrigine has also been detected in groundwater, it has been suggested that lamotrigine could be used as an indicator for the presence of treated wastewater in raw water used for drinking water production [38]. Lamotrigine is very persistent chemically and physically and can resist UV photolysis and ozone, but it reacts rapidly with hydroxyl radicals. Therefore, advanced oxidation processes might be effective for removing this compound during water treatment [40]. In this study, 46.4% of lamotrigine was removed by ozone purification with the OxTube hermetic dissolution method. With PAA and UV disinfection there was no reduction and with H2O2 and UV disinfection the reduction was 6.7%. The removal capacity of the ozone disinfection was less efficient for lamotrigine than for other anthropogenic substances studied. However, ozone disinfection was more efficient for removal of lamotrigine than any other tested disinfection method.

#### *3.6. Diclofenac*

Diclofenac (2-2-2,6-dichlorophenylaminophenylacetic acid; DCF) is a common nonsteroidal anti-inflammatory drug that is used as oral tablets or as a topical gel. It is especially known for its harmful effects on vultures [41,42]. DCF is commonly found in municipal wastewater in Finland [43]. In 2002, the average concentration of DCF in wastewater influents was 0.35 ± 0.1 <sup>μ</sup>g L−<sup>1</sup> [44]. In 2013, DCF was selected for inclusion on the watch list of the WFD in order to collect data on it for the determination of risk reduction measures. According to the proposed EQS document, the maximum allowable concentrations of DCF is 0.1 μg L−<sup>1</sup> in fresh waters and 0.01 μg L−<sup>1</sup> in marine waters [45].

In recent years, the highest detected concentration of DCF in wastewater effluents in Finland has been 0.62 μg L−<sup>1</sup> [46] and in surface waters 0.022 and 0.05 μg L−<sup>1</sup> [10]. Furthermore, Lindholm-Lehto et al. [43] found some high concentrations of DCF. In this study, 1.4 ± 0.2 <sup>μ</sup>g L−<sup>1</sup> DCF was detected in the Kuopio wastewater effluent. Even though DCF is removed by natural processes such as photodegradation, the residues still remain in the environment as potential toxic metabolites and as the original compound. In the environment DCF is detected in lower concentrations, such as ng L−<sup>1</sup> to mg L−1, than in wastewater. It has been stated that DCF has adverse effects on several environmental species already at concentrations of ≤<sup>1</sup> <sup>μ</sup>g L−<sup>1</sup> [47]. It has been suggested that DCF used as an NSAID (non-steroidal anti-inflammatory drug) and as a pain gel cannot be removed effectively in WWTPs. The removal efficiencies of diclofenac in WWTPs varied from 0% up to 80%, but were in mainly in the range of 21–40% in the study by Zhang et al.

(2008) [48]. In our current study, DCF removal from the tested wastewater was 99.7% using ozone purification with the OxTube hermetic dissolution method. PAA and UV disinfection removed 7.1% and with H2O2 and UV disinfection the reduction of DCF was 16.7%. Diclofenac was efficiently removed from the wastewater effluent by using the ozone disinfection. Also, the combined H2O2 and UV disinfection was able to remove diclofenac more efficiently compared to the other studied substances.

#### *3.7. Venlafaxine*

Venlafaxine is one of the most abundant antidepressants in municipal wastewaters where concentrations of the substance have been generally shown to range between 0.003 and 0.743 μg L−<sup>1</sup> wastewater effluent receiving waters [49]. In this study concentrations of 1.0 ± 0.13 <sup>μ</sup>g L−<sup>1</sup> were found. Venlafaxine has also been detected at very low (<0.005 μg L−1) concentrations in untreated drinking water [50]. More than 60% of venlafaxine has successfully been removed with anaerobic biological reactors [51]. Ozone purification with the OxTube hermetic dissolution method removed 91.3% of the detected venlafaxine. H2O2 and UV disinfection removed 1.1%, and with PAA and UV disinfection there was no reduction. In this study, venlafaxine was removed efficiently from the wastewater effluent by using ozone disinfection.

#### *3.8. Losartan*

Losartan, an antihypertensive, was one of the 10 most used medicines in Finland in 2018 [52]. Losartan can undergo structural modification resulting in formation of valsartan acid, which is a persistent pollutant ending up into activated sludge [53]. Losartan can also be found in various water matrices such as surface water and rivers [54]. It has been shown to be present in municipal wastewaters, e.g., in Colombia losartan has been detected in wastewater effluent at concentrations of 1.97 and 1.00 μg L−<sup>1</sup> [55]. When studying pharmaceutical residues, Kot-Wask et al. (2016) found signs of losartan in wastewater from the Pomerania area in Poland [56]. In this study, a mean concentration of 0.9 ± 0.2 <sup>μ</sup>g L−<sup>1</sup> was detected. The removal of losartan has been studied with a WWTP that was designed for biological nitrogen removal and chemical precipitation of phosphorus. The removal efficiency of losartan in the system varied between 50–80% [57]. In our current study 99.6% of losartan was removed using ozone purification with the OxTube hermetic dissolution method. With PAA and UV disinfection, and H2O2 and UV disinfection the reduction was 13.8% and zero, respectively. Thus, the disinfection method using ozone as a disinfectant worked well in removal of losartan. Partial losartan reduction was also achieved with combined PAA and UV disinfection.

#### *3.9. The Most Efficient Removal of Anthropogenic Substances Achieved by Using Ozone Purification with OxTube Hermetic Dissolution Method*

Dissolved ozone has been used for years to disinfect and purify water [58]. Ozone is produced by separating oxygen from the air with an oxygen generator or industrial bottled instrument oxygen gas O2. Pure oxygen is passed through a strong electric field with continuous corona discharge. When ozone decomposes in water, the hydrogen peroxy (HO2) and hydroxyl (OH) are formed and they have great oxidizing capacity [59,60]. The half-life of ozone in aqueous solution depends, among other things, on pH and temperature of the water. In our study, the usage of ozone with the OxTube hermetic dissolution method was relatively efficient in removing of the detected anthropogenic substances. The reason for the achieved reduction capacities could be due to free radicals that are formed.

The use of ozone-based cleaning and disinfecting agents has increased in recent years in industry and water treatment sectors. The advantage of ozone compared to chlorine or other disinfectants is that ozone is very reactive, degrades rapidly and leaves no toxic or unwanted end products. It is an exceptionally good disinfectant with faster disinfection kinetics and more potency to eliminate most microorganisms than other chemical disinfectants in use. Ozonation followed by chlorination is proved to be better in terms of producing less disinfection byproducts than the sole use of chlorination [61].

Wastewater is a complex mixture of water and various substances, its viscosity is usually higher than water, the movement between substances is slow and thus its handling differs greatly from e.g., domestic water. This may be one reason why using OxTube hermetic dissolution method produced such good results in our case although we did not test the efficiency of ozone disinfection without this device.

#### **4. Conclusions**

Many anthropogenic substances are harmful to the environment. Out of the 121 analysed substances 44 were detected (Table S1) in the treated wastewater samples collected from the Kuopio (Lehtoniemi) WWTP. Eight substances (cetirizine, BZT, hydrocholorothiazide, furosemide, lamotrigine, DFC, venlafaxine, and losartan) were detected at concentrations over 1 μg L<sup>−</sup>1. Among these eight substances, DCF is the only one that appears on the European Union's WFD monitoring list. In 2013, it was included on the first watch list to gather monitoring data for the purpose of facilitating the determination of appropriate measures to address the risk posed by the substance.

The results from this study showed that ozone disinfection using an OxTube hermetic dissolution method can efficiently reduce the concentration of pharmaceuticals in wastewater effluent. In future work, the OxTube hermetic dissolution method should be compared to other ozone mixing devices to prove the performance and capacity of this novel dissolution technique.

**Supplementary Materials:** The following are available online at https://www.mdpi.com/2073-444 1/13/3/360/s1, Figure S1: Equipment used in the experiments; Table S1: List of the concentrations of analysed anthropogenic substances

**Author Contributions:** J.I.; writing—original draft preparation, I.N.; project administration, writing review and editing, M.N. and A.-M.H. writing—review and editing, T.P. and I.T.M. supervision, writing—review and editing E.A. and I.T.M.; funding acquisition. All authors have read and agreed to the published version of the manuscript.

**Funding:** This study was funded by the European Regional Development (A72637).

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Acknowledgments:** This study was part of the project "Fostering market penetration and implementation of combined use of low energy Led-UV -technologies and PAA-chemicals in water disinfection". The authors thank the staff of the Savonia University of Applied Sciences, in Kuopio, Finland, and the staff of the Finnish Institute for Health and Welfare.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


### *Review* **Application of Natural Coagulants for Pharmaceutical Removal from Water and Wastewater: A Review**

**Motasem Y. D. Alazaiza 1,\*, Ahmed Albahnasawi 2, Gomaa A. M. Ali 3, Mohammed J. K. Bashir 4, Dia Eddin Nassani 5, Tahra Al Maskari 1, Salem S. Abu Amr <sup>6</sup> and Mohammed Shadi S. Abujazar 6,7**


**Abstract:** Pharmaceutical contamination threatens both humans and the environment, and several technologies have been adapted for the removal of pharmaceuticals. The coagulation-flocculation process demonstrates a feasible solution for pharmaceutical removal. However, the chemical coagulation process has its drawbacks, such as excessive and toxic sludge production and high production cost. To overcome these shortcomings, the feasibility of natural-based coagulants, due to their biodegradability, safety, and availability, has been investigated by several researchers. This review presented the recent advances of using natural coagulants for pharmaceutical compound removal from aqueous solutions. The main mechanisms of natural coagulants for pharmaceutical removal from water and wastewater are charge neutralization and polymer bridges. Natural coagulants extracted from plants are more commonly investigated than those extracted from animals due to their affordability. Natural coagulants are competitive in terms of their performance and environmental sustainability. Developing a reliable extraction method is required, and therefore further investigation is essential to obtain a complete insight regarding the performance and the effect of environmental factors during pharmaceutical removal by natural coagulants. Finally, the indirect application of natural coagulants is an essential step for implementing green water and wastewater treatment technologies.

**Keywords:** natural coagulation; chemical coagulation; pharmaceuticals; *Moringa oleifera*; green treatment technology

#### **1. Introduction**

The discharge of pharmaceutical waste into the environment poses a threat to both humans and environmental systems. The disposal of these contaminants without proper treatment has resulted in pharmaceuticals being widespread in ecosystems [1]. The presence and accumulation of these emerging compounds harm the ecosystem. Human drugs such as ibuprofen and acetaminophen are continuously accumulating in the environment, resulting in pollutants in water bodies and causing harmful effects [2]. In addition, the mineralization rate of pharmaceuticals such as diclofenac and ibuprofen through photocatalysis is low, resulting in the accumulation of these compounds in the environment [2].

**Citation:** Alazaiza, M.Y.D.; Albahnasawi, A.; Ali, G.A.M.; Bashir,

M.J.K.; Nassani, D.E.; Al Maskari, T.; Amr, S.S.A.; Abujazar, M.S.S. Application of Natural Coagulants for Pharmaceutical Removal from Water and Wastewater: A Review. *Water* **2022**, *14*, 140. https://doi.org/ 10.3390/w14020140

Academic Editor: Laura Bulgariu

Received: 5 December 2021 Accepted: 5 January 2022 Published: 6 January 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

The effluent of wastewater treatment plants is the typical source of pharmaceutical compounds, since the conventional wastewater treatment methods are not designed to remove these micropollutants [3]. Therefore, these harmful chemicals accumulate and contaminate soil, rivers, oceans, and groundwater [4].

Recently, several studies reported the efficiency of the coagulation-flocculation treatment method for pharmaceuticals' removal, especially in rich organic wastewater [1]. Coagulation-flocculation consists of two steps: (1) the tendency of colloidal particles to form large flocs by destabilization, and (2) settling these large flocs by precipitation. The removal of pharmaceuticals directly by means of the coagulation process is not reported in the literature. The mechanism of pharmaceuticals' removal by coagulation process is indirect by using colloidal particles as a vehicle for pharmaceuticals [3,5,6].

For many years, chemical-based coagulants such as aluminum sulfate (alum) and polyaluminum [7,8] have had different environmental effects by producing highly toxic sludge. In addition, the consumption of water contaminated by the residual chemical coagulants may cause neurodegenerative diseases [9]. Thus, the transition towards natural-based coagulants for water and wastewater treatments has gained increasing attention in recent years [10].

Natural coagulants can be produced from natural sources such as plants and animals. Many studies reported several natural sources for extracting natural-based coagulants [11,12]. Natural resources that possess a higher molecular weight may contain a more extended polymer that increases these natural coagulants' efficiency [13–15]. These sources have been extensively studied to treat different types of wastewater, such as textile wastewater, dairy wastewater, and domestic wastewater [16,17]. In addition, coagulants can also be obtained from animal waste such as banes and shells [18]. The main challenge of using natural coagulants in general, especially animal-based coagulants, is their continuous availability for large-scale treatment [18].

Natural coagulants perform better at a wide pH range [19–21]. In addition, using natural coagulants does not change the pH of water compared to chemical coagulants. In addition, natural coagulants positively affect the ecosystem and the environment [10,22,23]

The application of natural coagulants has been reported in many studies for domestic and industrial wastewater [24]. However, fewer studies investigated the performance of natural coagulants for emergency pollutant removal. In addition, fewer reviews discussed the use of natural coagulant for pharmaceuticals removal. In line with the aforementioned gaps. These reviews present and discuss the recent natural coagulation method for pharmaceutical removal from water and wastewater. A comprehensive comparison between natural coagulants and chemical coagulants is also presented. Finally, this review highlights the required future research to overcome the shortcomings of using natural coagulants.

#### **2. Fundamental of Coagulation Processes**

The coagulation process is used wildly in water and wastewater treatment, as it is effective for removing suspended solids, turbidity, organic matter, oil, chemical oxygen demand (COD), and color [25]. The coagulation process is mainly conducted by adding a coagulant that allows small agglomerate particles (unsettleable fine particles) to form larger flocs that can settle. Coagulation and flocculation are interlinked. Coagulation is the clustering process under high-speed mixing, whereas flocculation is the settling process under gentle mixing. Generally, colloidal particles are negatively charged particles. Thus, coagulation is a chemical process that involves neutralizing these particles in water and wastewater, whereas flocculation is a physical process involving the formation of flakes from neutralized particles during the coagulation process. Thus, large flocs form during coagulation, and they aggregate and settle during flocculation [26].

Generally, the coagulation process depends on operating conditions such as settling time, mixing rate, coagulant type, and dosage. These factors determine the quality of the produced water. In addition, the coagulant dosage must be suitable for a decent suspension of particles, and the mixing speed should be high. The other coagulant properties, such as life span and quality, determine the coagulant's stability during storage. Following the coagulation-flocculation, the large flocs sink through gravitational settling; this process depends on the settling rate of the particles [27].

The colloidal particles' sizes range from 0.001 to 1.0 μm due to them being negatively charged and the small size being suspended in water. Four mechanisms are used to destabilize these fine particles using a coagulant; charge neutralization, polymer bridging, sweep flocculation, and double-layer compression (Figure 1).

**Figure 1.** Coagulation mechanisms diagram showing charge naturalization, polymer bridging, sweep flocculation, and double-layer compression, copied with permission from Ref. [10], Copyright, 2021, Elsevier.

In the charge neutralization mechanism, the oppositely charged ions are used to attract colloidal particles, and coagulants added to the wastewater will further neutralize the electrical load until it reaches zero zeta potential; as a result, the colloidal particle charge neutralizes, and the electrostatic repulsion decreases or is almost eliminated [28]. Generally, when a chemical coagulant is added to water, a hydrolysis process occurs, producing cationic species which react colloidally. The polymer bridging mechanism takes place when a polymer or polyelectrolyte coagulant with a long chain destabilizes the colloidal particles by making a bridge that forms a connection between them. The polymer coagulant adsorbs multiple particles to the polymer molecule surface [29]. Thus, strong clusters of macro flocs are produced and tied together by bridges. The flocs formed by polymer bridging are flaky with irregular void spaces. The sweep flocculation coagulant traps the colloidal particles and forces them to sink to the bottom. A net-like structure is formed by the hydrolysis process that makes up precipitation of amorphous metal hydroxide. The double-layer compression includes a coagulant that helps the colloidal particles to reduce the repulsion force and assemble. This mechanism works by means of the presence of a high concentration of electrolyte ions around the colloidal; thus, an opposite charge enters the diffused double layer which surrounds the colloids; as a result, the density is increased [30].

The strongest flocs are those formed through polymer bridging, followed by those formed through charge neutralization and sweep flocculation. The flocs formed through charge neutralization are compacted but not strong, because they depend on the physical rather than chemical bonds. Analysis such as initial floc aggregation, the flocculation index, and the relative settling factor indicated that flocs produced by sweep flocculation have good settling behavior but have a slower formation rate. Flocs produced by double-layer

compression are bigger due to the high aggregation rate, but their settling behavior is affected by the unnecessary friction force formed between flocs. Moreover, the coagulant's ionic charge significantly affects the strength of flocs. Divalent ions produce flocs stronger than monovalent ions and require less time to settle. Generally, the dominant coagulation mechanism for natural coagents is charge neutralization [10].

#### **3. Factor Affecting Coagulation Process**

Determination of optimum operating conditions is crucial, as an added coagulant is utilized thoroughly to remove the contaminants. Deferent optimal conditions can be achieved for different coagulants. A deep understanding of the reaction between pollutant and coagulant is needed to achieve high performance in addition to decreasing the cost and sludge volume. Many parameters affect the efficiency of the coagulation process for water and wastewater treatments, and these parameters are varied to control the optimal conditions for the highest efficiency. Coagulant dosage, pH, turbidity, mixing speed and time, and temperature are the main operating factors affecting coagulation speed [31]. These factors significantly impact the coagulation process, affecting the effectiveness and efficiency of coagulants in water and wastewater purification processes.

#### *3.1. Coagulant Dosage*

The optimal coagulant dosage is an important parameter that entirely controls coagulation reactions. The influence of coagulant dosage can be discussed for three different levels. The optimal coagulant dosage effectively aggregates the colloidal particles in water and wastewater. An underdosage inhabits the proper assembly of colloidal particles, whereas an overdosage pollutes the wastewater and causes an increase in organic load, turbidity, and higher slurry volume, which leads to an increase in the treatment cost [10].

#### *3.2. pH*

pH is an acidity/alkalinity measurement that varies between 1 and 14. The pH of water and wastewater is an essential environmental factor, as it affects chemical reactions during the treatment process [32,33]. The amphoteric coagulant molecules' charge highly influences the pH during the treatment process. In addition, alkalinity, which is defined as the capacity to neutralize acidity, controls the efficiency of the coagulation process. Most chemical-based coagulants, especially ferric-based coagulants, absorb a high percentage of alkalinity. Thus, adding a coagulant to wastewater with low alkalinity produces poor flocs. Additional alkaline agents such as caustic soda, slime, or soda ash should be added to the wastewater to overcome this problem. A pH value differing from the optimum pH produces a mixture of negative and positive charges of amino acids, which decreases the coagulant's cationic efficiency [29]. Moreover, pH determines the optimum coagulant dosage as it affects the protein molecule ionic charge. Therefore, the optimum pH's determination and adjustment must be performed before implementing the coagulation process.

#### *3.3. Initial Turbidity*

Initial turbidity is an essential factor that affects the coagulation process. The presence of a colloidal particle in water causes turbidity that affects the clarity of the water. Soil, abundant microorganisms, organic matter, decaying matter, colored compounds (pigment and dye), algae, and plankton induce turbidity in water, making it look murky, cloudy, and undesirable. Colloidal particles and turbidity are a challenge in water and wastewater treatment, as the increased rate of turbidity means more pollutant molecules are available, which means a higher number of collisions between the coagulant and pollutants may be produced [34]. More collisions result in sturdier and larger flocs, which settle faster.

On the other hand, a low initial turbidity decreases the collision chance between coagulants and pollutants. As a result, small flocs are formed, which settle slowly. Moreover, a low initial turbidity forms a flake-like structure that needs more time to sink.

#### *3.4. Mixing Speed and Time*

The mixing speed and time is an essential operation condition that affects the efficiency of the coagulation process. Rapid mixing is used during the coagulant's addition to evenly enhance the distribution of coagulant through the wastewater and destabilize the suspended particle, whereas gentle mixing is required to increase the collision between particles to form macro flocs [29]. These two speeds control the entire coagulation process as the efficiency of the coagulation process depends on the speed and time of mixing. Inadequate speed and time may inhabit the homogeneous agglomeration of the particles and increase the floc shear and tear.

#### **4. Natural Coagulants**

Recently, natural or green coagulants and their application for water and wastewater treatment have received attention, as they do not conserve alkalinity and maintain pH. In addition, natural coagulants do not add metals to the effluent, as chemical coagulants do; a lower sludge volume is produced, and thus, the cost of disposal is lower [10]. Natural coagulants are classified into plant-based coagulants and non-plant-based coagulants. Plantbased coagulants can be prepared from leaves, seeds, fruit wastes, the bark of trees, and other sources. Plant-based coagulants have been more widely investigated than non-plantbased coagulants due to their greater affordability [22]. A wide range of natural coagulants, such as moringa seeds, banana peel, jatropha curcas, cassava peel starch, watermelon, pawpaw, beans, nirmali seeds, and okra have been studied previously [35].

Natural coagulants in powder forms are usually added directly to wastewater. The preparation methods of natural coagulants depend on their source [36–38]. Figure 2 shows the preparation stages for natural powder coagulants from seeds. Oil extraction is an essential step for high oil-content seeds such as *Moringa oleifera*, which contain 30–40% oil, as when a coagulant made from high oil-content-based seeds is used without oil extraction, the organic matter in the treated wastewater will increase. Table 1 illustrates the main application forms of natural coagulants.

**Figure 2.** Flow chart of natural coagulant preparation from seeds, copied with permission from Ref. [10], Copyright, 2021, Elsevier.

#### *4.1. Plant-Based Coagulant*

Natural coagulants are used for water treatment; however, they are not used for industrial wastewater due to their higher costs than chemical coagulants. Generally, natural coagulants effectively treat water or wastewater with low turbidity ranging from 50 to 500 NTU (Nephelometric Turbidity Units). The primary sources of plant-based coagulants are *Moringa oleifera*, Nirmali seeds, cactus, and tannin. The extracted natural polymers from these seeds are biodegradable and eco-friendly [36]. Anionic polyelectrolytes are extracted from Nirmali seeds; this extract has hydroxyl (-OH) and carboxylic (-COOH) groups, increasing coagulation efficiency. The combination of galactan and polysaccharides extracted from Strychnospotatorum seeds may increase the turbidity removal efficiency up to 80%. The availability of the hydroxyl group (-OH) in the galactan and galactomannan enhances the adsorption process between the surface of colloidal and these polymers; thus, the polymers' bridging action may increase. The polyelectrolytes neutralize the negative

colloidal particles and adsorb onto the surface particles. Natural coagulants possess several functional and charged groups such as -COOH, -NH2, and -OH. Generally, the action of natural polymeric coagulants combines polymer bridging and charge neutralization.


**Table 1.** The main application forms of natural coagulants.

#### *4.2. Animal Base*

The source of animal-based coagulants is usually obtained from the exoskeleton of shellfish extracts, animal bone shell extracts, and chitosan. Chitosan is a polymer (celluloselike biopolymer) with a high molecular weight produced from the deacetylation of chitin, extracted from the shells of crabs, lobsters, shrimps, diatoms, fungi, insects, freshwater and marine sponges, and mollusks. The applicability of using chitosan as a natural coagulant has been studied intensively for wastewater treatment in the agricultural industry, textile industry, food processing industry, paper mills, soap and detergent industry, and other industries [34]. The main advantages of using chitosan as a coagulant are that when added to acidic wastewater, it reacts and produces positive charges that destabilize colloidal particles' negative charge [37].

#### **5. Pharmaceutical in Water and Wastewater**

Pharmaceuticals are a set of developed chemicals used for human and veterinary medication. Recently, they have been classified as ecological contaminants that threaten both humans and environments [50]. Pharmaceuticals include antibiotics, analgesics, both legal and illicit, beta-blockers, steroids, etc., and they have been detected in wastewater treatment plants' effluents, sediments, sludge, natural waters, groundwater, and drinking water. The presence of pharmaceuticals in the soil may trigger the development of antibioticresistant genes [51].

Currently, pharmaceuticals and their biotransformative compounds are bioaccumulating and harmfully affecting the ecosystem. However, these chemicals have been discharged to the environment for a long time, their environmental effects have only been considered recently. Many pharmaceuticals (around 160) have been detected in water bodies in low concentrations. These chemicals are classified as pseudo-persistent pollutants which environmentally persistent and are continuously discharged into the environment at low concentrations. These pharmaceuticals' eco-toxicological impacts on aquatic and terrestrial life are unknown [52].

#### *5.1. Pharmaceuticals' Consumption and Fate*

The consumption of pharmaceutical compounds has increased dramatically due to many reasons, such as a decrease in production cost and chronic disease treatment demand. As a result, the presence of these compounds has increased. Currently, the environmental management of pharmaceuticals is challenging, as these substances are found in wastewater treatment plants' effluents in low concentrations (usually in ng/L). Sophisticated analytical apparatuses and complex methods are needed to quantify pharmaceuticals at this low concentration [53].

Pharmaceuticals are generally moved and transported by the demonstrated routes in Figure 3 [54]. After consumption, metabolism in the human body, and extraction, pharmaceuticals usually reach aquatic environments by being discharged in treated domestic wastewater effluents [55]. During this route, pharmaceuticals may go through chemical reactions and transformation, forming by-products, which are sometimes more harmful and persistent than their parent compounds. Most of these compounds are non-biodegradable in conventional treatment methods; as a result, they remain and are discharged through wastewater treatment plants' effluents into water bodies such as lakes, rivers, and estuaries [56]. In veterinary products, pharmaceuticals reach aquatic systems through subsequent outflow and manure and direct application in aquaculture [57]. Microorganisms may convert the metabolic compounds to their parental form in surface and groundwater [58]. The ecological concern related to pharmaceuticals in water resources is not directly related to their quantity but to their availability and persistence, which directly affects aquatic life through their toxicity and their potential effect on endocrine function [54,59].

**Figure 3.** Pharmaceuticals' fates and environmental pathways, copied with permission from Ref. [54], Copyright, 2019, Elsevier.

#### *5.2. Technologies for Pharmaceutical Wastewater Treatment*

Pharmaceutical removal from water and wastewater is challenging due to their low concentration and resistance to degradation. Many technologies have been investigated for pharmaceutical removal from water and wastewater [60]. In this section, the pharmaceutical removal methods are discussed.

Activated sludge systems have been used for domestic and industrial wastewater treatments for a long time. Recently, the efficiency of this conventional treatment method for pharmaceuticals removal was investigated. Ren et al. [61] studied the removal of 21 parimutuels by an activated sludge treatment system. The result show that 14 compounds were biodegradable, whereas seven were non-biodegradable. Thus, activated sludge treatment methods are not efficient in completely removing pharmaceuticals from wastewater, as it is not designed for this type of pollutant. Electrocoagulation is more efficient and effective than chemical coagulation. In electrocoagulation, anodes are used to

treat contaminants, and the formed coagulants are used for their degradation. Many studies investigated the use of electrocoagulation treatment methods to remove pharmaceuticals such as dexamethasone, doxycycline hyclate, hydrolyzed peptone, caffeine, sulfamethazine, and cephalexin from wastewater. The results show a high removal efficiency (generally above 90%), indicating that these systems efficiently remove pharmaceuticals [62]. The main advantages of using electrocoagulation treatment are its easy chemical maintenance and high efficiency for colloidal particle removal. However, electricity and sacrificial electrodes are the main drawbacks of using this method, as they need to be replaced [63].

Advanced oxidation processes are effective in removing pharmaceuticals that conventional biological methods cannot remove. Among these methods, the Fenton reaction represents hydroxyl radical formation by a reaction between hydrogen peroxide (H2O2) and Fe (II). The hydroxyl radical is considered among the strongest oxidants that can oxidize a wide range of organic matters with low selectivity [64]. Therefore, Fenton-based reactions are commonly used for degradation emergency contaminants such as pharmaceuticals. pH control is essential for the Fenton reaction; thus, this treatment technology is usually performed at an acidic pH (3–5). The Fenton reaction method is found to be an effective method for a wide range of pharmaceuticals removal such as hydroxylamine, cyclohexanone, pyridine, toluene [65]. Many reports revealed that membrane bioreactor technologies can remove more micropollutants than conventional activated sludge systems due to their high MLSS (Mixed Liquor Suspended Solids) concentration and high sludge retention time, which allow the growth of low growth bacteria [66]. These bacteria can degrade complex organic compounds. The removal of acetaminophen, carbamazepine, mefenamic acid, ibuprofen, diazepam, naproxen, and ketoprofen by a membrane bioreactor was studied. Overall, more than 85% removal efficiency was obtained [67]. The major drawback of membrane bioreactors is the fouling of membranes that need frequent cleaning and sometimes replacement [68].

Photocatalysis is a reaction in which the presence of a catalyst accelerates the photoreaction [69–71]. The main advantage of photocatalysis reactions is the need for temperature or pressure or chemical agents such as hydrogen peroxide. However, this method is costly. Titanium oxide is the most studied catalyst for photocatalysis reactions due to its biological and chemical stability, inertness, and low cost compared to highly photoactive semiconductor materials. Titanium oxide can be used many times without losing its photocatalyst activity [72,73]. Nevertheless, the separation of titanium oxide from the reaction matrix is complicated. In addition, the transformation of organic matter is incomplete, and byproducts, sometimes with a higher toxicity than parent compounds, are produced. Figure 4 shows the problems of using titanium oxides as a catalyst in photocatalysis reactions for pharmaceutical removal [74]. Ozonation has been used as an advanced treatment in many wastewater treatment plants worldwide to enhance contaminant removal. Ozone is a colorless, unstable gas used as a disinfectant for organic and inorganic pollutants. Two mechanisms are used to degrade organic matter by ozonation; (1) an indirect attack by hydroxyl radicals produced by ozone decomposition, and (2) a direct electrophilic attack by ozone [75]. The main drawbacks of using ozone are the high operational cost; the by-products may be toxic; and that ozone is less soluble in water [68].

**Figure 4.** TiO2-related problems, copied with permission from Ref. [62], Copyright, 2021, Elsevier.

#### **6. Application of Natural Coagulants for Pharmaceutical Removal**

Recently, green water and wastewater treatment technologies have gained more attention. Among these technologies, natural coagulants are a promising method for wastewater treatment [76]. In this section, the recent advancements made in using naturalbased coagulants are presented.

In a recent study, Nonfodji et al. [77] prepared a natural coagulant from *Moringa oleifera* seeds, and they studied its performance for hospital wastewater treatment. The results indicate that the removal efficacy of turbidity and COD was 64 and 38%, respectively. In a subsequent study, Thirugnanasambandham and Karri [78] compared the COD, turbidity, and color removal by two types of coagulants; a natural coagulant (Azadirachta indica A. Juss) and a chemical coagulant (aluminum sulfate). Remarkably, the results indicate that natural-based coagulants may not only be effective for COD, turbidity, and color removal, but may also be economically competitive, as the operating costs were USD 0.56/m<sup>3</sup> and USD 1.73/m3 for natural coagulants and the chemical ones.

In another study, Maharani et al. [79] investigated the removal of COD and BOD from pharmaceutical waste using moringa seed coagulant and tapioca starch coagulant. The results point to high BOD (Biochemical Oxygen Demand) and COD removal for both natural coagulants. For moringa, the BOD and COD removals were 90 and 71%, respectively, whereas for tapioca, they were 95 and 94% for BOD and COD, respectively. These results indicate that natural coagulants might be a promising treatment technology for pharmaceutical waste treatment. Oliva et al. [80] studied the use of rice husk ash functionalized by *Moringa oleifera* protein for amoxicillin removal from water solutions. They also investigated the effect of operating parameters such as coagulant dosage, initial amoxicillin concentration, and contact time. The results indicate that the used biomaterials are feasible for pharmaceutical removal from water. Olivera [81] examined the potential of using biomaterial extracted from *Moringa oleifera* for the extraction of diclofenac and oxytetracycline from wastewater. The results show the high potential for pharmaceutical removal from wastewater using biomaterial.

The removal percentages were 88% for diclofenac and 50% for oxytetracycline. Santos et al. [82] examined tetracycline removal from river water by using *Moringa oleifera* seeds. The results show 50% tetracycline removal efficiency at 0.5 g/L *Moringa oleifera* dosage. Iloamaeke and Chizaram [83] examined the removal of pharmaceuticals by Phoenix dactylifera seeds-based coagulants. The results show that a maximum removal efficiency of 99.86% was achieved at a 100 mg/L coagulant dosage, a 50 min settling time, and a pH of 2.

Sibartie and Ismail [84] studied the performance of H. Sabdariffa and J. Curcas as a neutral coagulant for pharmaceutical wastewater treatment. The results demonstrate that at a coagulant dosage of 190 mg/L and pH 4, the maximum removal efficiency was achieved for turbidity (5.8%) and COD (30%) by H. Sabdariffa, while J. Curcas works best at pH 3 and a coagulant dosage of 200 mg/L to remove 51% of turbidity and 32% of COD. Table 2 presents the application of natural coagulants to remove different types of pharmaceuticals.


**Table 2.** Application of natural coagulant for the removal of different types of pharmaceuticals.

#### **7. The Transition from Chemical to Natural Coagulant: Comparative Evaluation on Performance**

The transition from chemical coagulation to natural coagulation can be an important step towards increasing green water treatment technology, reducing health risks and environmental pollution [23]. Natural coagulants can be obtained from plant or animal sources. Natural coagulants were discovered years ago, before chemical coagulant; over the years, the application of natural coagulants decreased due to the development of chemical coagulants. Recently, the rise of green water treatment technology, besides the environmental problems related to chemical coagulants, has motivated the consideration of natural coagulants again. This section presents a comparative discussion of natural and chemical coagulants.

Many studies evaluated the performance of natural coagulants for removing pollutants from water and wastewater; they concluded that natural coagulants can be competitive in terms of removal efficiency [26]. Table 3 presents the comparison performance of natural and chemical coagulants. The combination of chemical and natural coagulants may increase the performance of the coagulation process. In a study, the combination of alum and banana peels removed 94% of turbidity, whereas the use of alum and banana peels alone resulted in turbidity removal efficiency of 73.1 and 65.6%, respectively [85].

The advantages of using natural-based coagulants over chemical ones are: (1) natural coagulants may produce less sludge than chemical coagulant; thus, the environmental sustainability increases, while the sludge handling cost decreases; (2) the natural coagulant dosage is less than that of chemical coagulants; thus, the cost and sludge production is lower; (3) the toxicity of natural coagulants is lower than that of chemical coagulants [86]; and (4) the use of natural coagulants does not require skilled workers, as they have a low health impact and do not represent such as potential environmental hazard [23].

However, natural coagulants have some disadvantages that hinder their widespread use: (1) rapid mixing during the coagulation process induces cell rupture; thus, the organic matter load may increase and react with disinfectants in the following treatment process, resulting in disinfectant by-products [87,88]; (2) the vast majority of natural coagulants are extracted from plants, so the supply of these coagulants may be affected by seasonal production [89]; (3) natural coagulants are bio-based materials; thus, this material can decompose during long-term storage [9]; and (4) some natural coagulants are used as medicines; the high consumption of these materials in water treatment could affect their supply to the medicine sector [10].

**Table 3.** Comparison performance of natural and chemical coagulants.


#### **8. Recommendation and Future Prospective**

All the mentioned disadvantages of implementing natural coagulants for water and wastewater create challenges for future research. The current extraction methods of coagulants from plants and animals are complex; thus, a new reliable and straightforward extraction method should be developed for the easily accessible use of natural coagulants. Some studies reported a higher removal efficiency of chemical coagulants than natural coagulants. However, optimizing the natural coagulant extraction methods can increase the performance of these green coagulants; thus, intensive research is needed in this domain. The utilization of sources for natural coagulant production is a great challenge, as the water and wastewater industries consume many of these coagulants. More research needs to search for new sources, such as inedible plants or/and new medicine plants for natural coagulant production. Further investigations are required to determine the optimum conditions for a green coagulation-flocculation process for various wastewater types. More studies should be conducted to investigate the efficiency of natural coagulants for micropollutants' removal from water and wastewater.

#### **9. Conclusions**

The removal of pharmaceuticals from water and wastewater is challenging due to their low concentration and their resistance to biodegradation. Several studies reported the feasibility of using natural-based coagulants for water and wastewater treatments. The main mechanisms that natural coagulants use for pharmaceutical removal from water and wastewater are charge neutralization and polymer bridging. Plant-based natural coagulants are more affordable than animal-based ones. Although the application of natural coagulants for emergency pollutants, especially pharmaceuticals, is limited in the literature, the available data demonstrate a promising future for these bio-coagulants in this domain. A natural coagulant has advantages over a chemical coagulant as a low dosage is required, less sludge is produced, and low/no toxicity is presented. For the complete transition from chemical coagulants to natural coagulants, further research is required in areas such as developing reliable extraction methods, searching for new natural sources, determining the optimal conditions for pharmaceutical removal, and evaluating the effect of environmental parameters on the process' performance.

**Author Contributions:** Conceptualization and Funding, M.Y.D.A.; Writing Original Draft Preparation, A.A. and M.Y.D.A.; Writing—Review & Editing, G.A.M.A., M.J.K.B., S.S.A.A., D.E.N., M.S.S.A. and T.A.M.; validation, M.J.K.B. All authors have read and agreed to the published version of the manuscript.

**Funding:** The research leading to these results received funding from the Ministry of Higher Education, Research, and Innovation (MoHERI) of the Sultanate of Oman under the Block Funding Program, MoHERI Block Funding Agreement No. MoHERI/BFP/ASU/01/2021. In addition, the authors would like to thank A'Sharqiyah University for partially funding this research through the ASU Seed Fund Project No: ASU-FSFR/COE/01/2020.

**Conflicts of Interest:** The authors declare no conflict of interest.

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