Pharmaceuticals in Food and Water: Monitoring, Analytical Methods of Detection and Quantification, and Removal Strategies

Abstract

Pharmaceuticals, classified as emerging pollutants, are extensively applied in both human and veterinary medicine to treat various diseases. Their widespread application has led to their occurrence in water, soil, sediments, and living organisms. Even at trace levels (ng·L⁻¹–μg·L⁻¹), pharmaceuticals can significantly impact ecosystems and present threats to the environment and public health. Reliable analytical methods, such as liquid chromatography–tandem mass spectrometry (LC-MS/MS) and high-resolution mass spectrometry (LC-HRMS), are crucial for detecting and monitoring these compounds, including new or unknown substances. Removing pharmaceuticals from water remains challenging, as no single technique can completely eliminate all compounds and their toxic transformation products. Therefore, combining different treatment approaches, including membrane technologies, advanced oxidation processes (AOPs), and adsorption, into hybrid systems is necessary to improve removal efficiency and mitigate impacts on ecosystems and public health. In this review, a comprehensive overview of the occurrence of pharmaceuticals, their monitoring in food and water, and wastewater treatment is provided, highlighting current challenges and the need for further research.

1. Introduction

Until the late 1990s, the pharmaceutical industry was not considered to have a significant environmental impact. However, since the discovery of clofibric acid residues in German rivers in 1994, this perception has changed [1]. Pharmaceuticals are molecules with complex structures, diverse functionalities, and specific physicochemical and biological properties [2]. They are classified into human and veterinary medicinal products. Used to treat diseases, veterinary medicines are important to protect animal health. Several classes are commonly used, including antimicrobial and anti-inflammatory drugs, antiparasitics, tranquilizers, growth promoters, and insecticides [3]. Following administration, these compounds and their metabolites can accumulate in animal-derived products [4]. In human medicine, the most commonly used pharmaceuticals include analgesics and anti-inflammatory drugs such as acetaminophen, diclofenac, acetylsalicylic acid, and ibuprofen, as well as multiple antibiotic classes such as macrolides, penicillins, quinolones, and tetracyclines, and antiepileptics such as carbamazepine. Commonly used β-blockers include atenolol and propranolol, while hormones include progesterone, 17α-ethinylestradiol, and testosterone. Lipid regulators, including lovastatin and clofibrate, antidepressants including fluoxetine and paroxetine, and illicit substances such as cocaine, cannabinoids, amphetamines, opioids are also used [3]. These substances are administered orally or intravenously [2]. In the European Union (EU), approximately 3000 distinct pharmaceuticals are currently in use. In both human and veterinary medicine, antibiotics are the most widely employed, with annual consumption reaching 12,500 tons over the previous decade [5]. Globally, antibiotic consumption increased by 65% between 2000 and 2015. It is predicted to increase by 200% by 2030 [6].

Pharmaceuticals may reach the environment through three main pathways: discharge of wastewater from production facilities, disposal of unused or expired pharmaceuticals, and excretion following administration. Elevated concentrations of these compounds have often been detected near industrial facilities and hospitals [1]. Figure 1 illustrates additional pathways through which pharmaceuticals may enter the environment.

Approximately 70% of pharmaceutical compounds in wastewater originate from households, while about 20% can be attributed to livestock farming. The contribution from hospitals is only 5%, with the remaining 5% originating from non-point sources. Veterinary pharmaceuticals represent an additional source of micropollutants, as they are frequently used in the treatment of farm animals and are therefore present in various aquatic ecosystems. Studies have confirmed the presence of these compounds in livestock production systems, including pig, sheep, and poultry farming, as well as in dairy production and aquaculture [8].

For the last thirty years, pharmaceuticals have been detected worldwide in almost all types of environmental matrices such as drinking water, groundwater, surface water, and municipal wastewater, at levels from nanograms to micrograms per liter. Consequently, they are considered a major class of environmental pollutants of particular concern [5]. Their increasing use and release have become a global challenge due to their potentially adverse effects on humans, animals, and the environment. Pharmaceuticals are persistent in the environment and their degradation is influenced by multiple factors. Even at low or moderate concentrations, they can be toxic, promote bacterial resistance, disrupt the endocrine and immune systems, and adversely affect the function of various organs [9].

Antimicrobial resistance (AMR) is a major global public health issue driven by the overuse or inappropriate use of antibiotics, leading to microbial resistance to antimicrobial drugs. AMR has increased since the discovery of penicillin in 1928, with cases such as penicillin-resistant Staphylococcus aureus, tetracycline resistance, methicillin-resistant Staphylococcus aureus (MRSA), resistance to multiple antibiotic classes, multidrug-resistant (MDR) tuberculosis, and extended-spectrum β-lactamase (ESBL) resistance [10]. Residual antibiotics in the environment can lead to the selection and spread of antibiotic-resistant bacteria (ARB) and antibiotic resistance genes (ARGs), posing a significant risk to public health globally. Antimicrobial resistance is responsible for over 700,000 deaths each year, and it is projected to reach 10 million by 2050 without the implementation of effective measures [6].

Wastewater treatment plants have been reported to eliminate pharmaceuticals only partially. Furthermore, seasonal variations in the concentrations of these compounds have been observed in summer and winter, mainly due to enhanced attenuation and reduced pharmaceutical consumption during the summer months [5]. Continuous monitoring of these compounds in the environment using advanced analytical techniques is essential. However, to reduce their concentrations and harmful effects on ecosystems, more efficient removal methods are necessary.

This review focuses on recent advances in modern analytical approaches for detecting pharmaceuticals in food and water. This includes high-resolution mass spectrometry for analyzing complex matrices within a single multi-method. It also presents occurrence data in various matrices, highlighting their presence and potential risks. Finally, it discusses techniques for their elimination from the environment, mainly based on the literature published in the past five years.

2. Residues of Veterinary Drugs in Food and Water

2.1. The Importance of Residue Monitoring

Veterinary drug residues represent a considerable concern for the safety of animal-derived food products, including milk, eggs, meat, cheese, and honey [11]. Although veterinary medicines are essential for preventing and treating diseases in animals, their unauthorized or improper use can negatively impact human health and contribute to environmental pollution [11]. The withdrawal period is defined as the time required for drug residues in animals to fall below the maximum residue limit (MRL) [12]. Not following the recommended withdrawal period can leave veterinary drug residues above the MRLs in the final product, compromising food safety and posing risks to human health [12,13]. In addition to the consumption of animal products (meat, milk, and eggs), humans can also be exposed to veterinary residues via air, water, and dust. The use of veterinary pharmaceuticals is increasing, particularly in livestock and poultry production worldwide. Global consumption reached approximately 63,151 tons in 2010 and is projected to rise to 105,596 tons by 2030. Exposure to veterinary drugs residues has been associated with several negative effects, including the development of antibiotic resistance, allergic reactions, and hormonal disorders [12]. The most commonly used veterinary drugs include antibiotics (fluoroquinolones, macrolides, β-lactams, sulfonamides, and tetracyclines), antiparasitics (avermectins and benzimidazoles), and non-steroidal anti-inflammatory drugs (NSAIDs) [14]. For these reasons, regular monitoring in animal-derived foods is essential to ensure food safety, protect consumer health, and preserve the environment [11].

In the EU, residue monitoring of food of animal origin is conducted under Commission Regulation (EU) 2017/625 [15]. Member States conduct analyses as part of the National Residue Monitoring Program (NRMP), in accordance with Commission Regulation (EC) No. 37/2010, which defines the MRLs for pharmacologically active substances in food of animal origin [16]. Water quality control for human consumption in the EU is conducted under Directive (EU) 2020/2184, which specifies microbiological, chemical, indicator, and risk assessment parameters, but does not establish maximum limit (ML) values for pharmaceutical residues in water [17]. In the Republic of Croatia, this directive was transposed into national law through the Act on Water for Human consumption, published in the Official Gazette, No. 30/2023. Under this Act, the Regulation on Compliance Parameters, Methods of Analysis, and Monitoring of Water Intended for Human Consumption was adopted and published in the Official Gazette, No. 64/2023, 88/2023 and entering into force in June 2023 [18].

Although no MRL values are established for water in the EU, a monitoring system has been implemented through the Watch List. The list is updated under Article 8b of Directive 2008/105/EC on environmental quality standards to include substances posing a risk to the environment, including pharmaceuticals such as veterinary drugs (e.g., antibiotics and antiparasitics). Monitoring these substances provides data on their occurrence in surface waters. The 2025 edition of the Watch List includes norfloxacin, tetracycline, oxytetracycline, and tylosin, as well as other pharmaceuticals [19].

2.2. Analytical Approaches for Detecting and Quantifying Residues in Food

Analytical method selection depends on the sample type and the purpose of the analysis. Key criteria include speed, precision, accuracy, robustness, specificity, and sensitivity, along with a thorough understanding of the various techniques. Method validation for a specific matrix is also essential to ensure its applicability [20].

Sample preparation is a key step in the analysis of veterinary drug residues and typically includes purification, extraction, concentration, or derivatization. The choice of an appropriate preparation technique is essential for reliable detection. Commonly applied approaches include liquid–liquid extraction (LLE), solid-phase extraction (SPE), QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) [21], dispersive solid-phase extraction (DSPE), magnetic solid-phase extraction (MSPE), and dispersive liquid–liquid microextraction (DLLME) [22]. SPE is widely applied as a sample clean-up technique in the analysis of veterinary drugs [22,23], applied in both single-class and multi-class methods.

However, conventional SPE includes several steps: conditioning, sample loading, washing, and elution that are time-intensive and require considerable solvent volumes. Consequently, the QuEChERS method was introduced as an alternative clean-up approach. It reduces solvent consumption, improves efficiency, offers simple handling, and prevents clogging since SPE cartridges are not required [22].

The most commonly used analytical methods for determining veterinary drug residues in food are liquid chromatography (LC) often coupled with mass spectrometry (MS) [11]. These techniques enable detection at μg·kg⁻¹ or ng·kg⁻¹ levels [24]. For example, one-step SPE method combined with ultra-high-performance liquid chromatography–tandem mass spectrometry (UHPLC-MS/MS) was used to detect multi-class veterinary drugs, including antibiotics, antiparasitics, NSAIDs, prohibited drugs, and other in muscle tissue. The limit of quantification (LOQ) was 0.2–3.0 μg·kg⁻¹ with satisfactory recoveries of 70–120% [25].

Similarly, a total of 115 veterinary drugs and their metabolites (e.g., β-lactams, macrolides, amphenicols, tetracyclines, sulfonamides, and others) were prepared using the QuEChERS method with DSPE and analyzed by LC-MS/MS in beef. The limit of detection (LOD) and LOQ ranged from 0.24 to 245.90 ng·g⁻¹ and 0.73 to 745.15 ng·g⁻¹ [26].

High-resolution mass spectrometry (HRMS) is a modern technique that offers higher sensitivity and full-scan acquisition, enabling better characterization of sample composition than LC-MS/MS [27]. In addition, LC-HRMS allows targeted, suspect, and non-targeted screening of more than 200 compounds including antibiotics, NSAIDs, hormones, β-agonists and corticosteroids in food products [27,28,29]. Its high resolution and accuracy, selectivity, measurement of exact masses, and separation of peaks with similar m/z ratio at levels of 2–5 ppm makes it effective for multi-component analysis of complex food and environmental matrices. However, matrix effects can significantly influence analytical performance, and to minimize these effects, additional purification steps, isotopically labeled standards, or isotopic dilution approaches are implemented [29].

For example, an SPE approach coupled with LC-Orbitrap-HRMS was used for the analysis of 57 veterinary drugs, including lincosamides, quinolones, sulfonamides, tetracyclines, β-lactams, macrolides, and pleuromutilins in milk (cow, goat, and sheep). The screening target concentration (STC) ranged from 4 to 75 μg·kg⁻¹ [30].

A screening and confirmatory method was used to analyze 91 antibiotics, including quinolones, pleuromutilins, tetracyclines, sulfonamides, β-lactams, phenicols, and other classes in meat. The QuEChERS method was used for sample preparation, and LC-HRMS for detection. The detection capability (CCβ) ranged from 0.63 to 207.8 μg·kg⁻¹ while the decision limit (CCα) ranged from 0.38 to 1492.6 μg·kg⁻¹ depending on whether the substances are authorized or not [31]. In recent years, multi-methods for simultaneous analysis of veterinary drugs have been increasingly developed as shown in

Table 1. Summary of multi-residue analytical approaches applied to veterinary drug residues and other compounds in various food matrices.

Matrix Type	Number of Substances Analyzed	Extraction, Analytical Technique	Limits	References
Butter, milk powder, egg, and fish tissue	115 veterinary drugs and pharmaceuticals from >20 classes, including antibiotics (β-lactams, sulfonamides, macrolides, tetracyclines, quinolones), coccidiostats, anthelmintics, and NSAIDs	Solid–liquid extraction (SLE), LC-ESI-MS/MS	LOD and LOQ ranged 0.008–3.15 μg·kg−1	[32]
Meat, eggs, fish, dairy, and other animal-derived by-products, processed ingredients, and commercial items	353 veterinary drugs (parent compounds and markers, e.g., β-lactams, aminoglycosides, tetracyclines)	QuEChERS, LC-HRMS (screening method); LC-MS/MS (confirmatory method)	-	[33]
Milk and chicken feed	>140 veterinary drug residues (15 classes, e.g., aminoglycosides, β-lactams, macrolides, cephalosporins, penicilins, quinolones, tetracyclines)	SLE, UHPLC-QTrap-MS/MS	LOD (milk) = 2.2–603.5 μg·kg−1; LOD (feed) = 5.3–1814.7 μg·kg−1	[34]
Milk	132 veterinary drugs (≈15 classes; e.g., sulfonamides, β-lactams, tetracyclines, quinolones, macrolides, nitrofurans, benzimidazoles, anthelmintics, coccidiostats)	MSPE, HPLC-MS/MS	LOQ = 0.05–1 μg·kg−1	[35]
Meat (chicken, beef, pork), fishery products (shrimp, flatfish, eel), milk, and eggs	96 veterinary drugs (e.g., β-lactams, quinolones, macrolides, lincosamides, tetracyclines, anthelmintics)	SLE + DSPE, LC-MS/MS	LOD = 0.3–19.7 μg·kg−1; LOQ = 1–65 μg·kg−1	[36]
Pig muscle	65 veterinary drug residues (e.g., antibiotics, NSAIDs, anthelmintics, coccidiostats, and tranquilizers) and 97 pesticides	SLE + DSPE, LC-HRMS (QTOF)	-	[37]
Beef and chicken	146 veterinary drug residues (multi-class, including 15 isomer pairs and 55 hormones, e.g., sulfonamides, quinolones, β-agonists, glucocorticoids, β-blockers)	QuEChERS, HPLC-Q-Orbitrap HRMS	LOD = 0.15–3.03 μg·kg−1; LOQ = 0.5–10 μg·kg−1	[38]
Aquaculture products	192 veterinary drug residues (15 classes, e.g., β-agonists, antiviral drugs, macrolides, avermectins, nitrofurans, steroid hormones, fluoroquinolones, tetracyclines)	QuEChERS, HPLC-HRMS	LOD = 0.5–10 μg·kg−1	[39]
Pork	210 drugs (21 chemical classes, e.g., macrolides, aminoglycosides, antiviral drugs, glycosides, NSAIDs, corticosteroids, β-lactams)	SLE+DSPE, UPLC-MS/MS (Q-Trap)	LOQ: <10 μg·kg−1 for >90% analytes; CCα = 2–502 μg·kg−1; CCβ = 4–505 μg·kg−1	[40]
Beef muscle	87 pesticides, mycotoxin, and veterinary drugs residues, including antibiotics (e.g., quinolones, cephalosporins, macrolides, tetracyclines), sedatives, NSAIDs, anthelmintics, anticoccidials	Ionic liquid-based dispersive liquid–liquid microextraction (IL–DLLME), LC–MS/MS	LOD = 0.93–23.78 μg·kg−1; LOQ = 1.98–38.27 μg·kg−1	[41]
Buffalo and cow milk	20 pesticides and veterinary drug residues, e.g., β2-agonists, quinolones, hormones, triazine herbicides	QuEChERS, UPLC-MS/MS	LOD = 0.7–1.7 μg·L−1; LOQ = 2.0–5.0 μg·L−1	[42]

LOD = limit of detection; LOQ = limit of quantification, CCα = decision limit; CCβ = detection capability.

.

Besides LC-MS, LC-MS/MS, and LC-HRMS, several other analytical techniques have been applied. Liquid chromatography with ultraviolet detection (LC-UV) is suitable for the determination of veterinary drugs containing chromophoric groups, such as tetracyclines, which are capable of absorbing UV light, thereby enabling their detection. Similarly, fluorescence detection (FLD) can be applied for the analysis of ciprofloxacin and enrofloxacin due to their natural fluorescence. However, both UV and FLD have limitations for the simultaneous analysis of multiple residues, as they do not provide structural information for non-target compounds. Gas chromatography (GC) is used for the analysis of volatile, nonpolar, and thermally stable compounds; otherwise, an additional derivatization step is required prior to GC analysis [24]. GC-MS allows rapid, sensitive, and cost-effective detection, but it is generally limited to small compounds [11]. For example, GC-MS and GC-MS/MS have been applied for the analysis of synthetic and natural hormones, antibiotics (e.g., tilmicosin, lincomycin, and spectinomycin), and β-blockers [12,24]. Capillary electrophoresis (CE) offers low buffer and sample consumption, high separation efficiency, and low operational costs; however, its sensitivity is limited by the injection volumes. CE coupled with UV detection can be applied for the analysis of ofloxacin, ciprofloxacin, and certain sulfonamides, while CE with a diode array detector (DAD) is suitable for the determination of some sulfonamides [24]. Additionally, CE-MS offers effective detection and separation of various groups including anthelmintics, quinolones, and sulfonamides [12].

2.3. Analytical Approaches for Detecting and Quantifying Residues in Water

Detecting and quantifying trace-level pharmaceuticals in environmental matrices is challenging. Recent improvements in analytical instrumentation allow reliable detection at ng·L⁻¹ to μg·L⁻¹ levels [43] in various environmental samples, including drinking, groundwater, and surface water [44]. Since pharmaceuticals often occur at very low concentrations, a pre-concentration step is necessary to achieve trace levels and reduce matrix effects. SPE remains the most commonly used sample preparation method, as it requires small solvent volumes, allows pre-concentration and clean-up of samples, provides good reproducibility, has short preparation time, and can be used for different matrices [45].

For decades, LC-MS and LC-MS/MS have been widely applied analytical techniques, offering high sensitivity, rapid analysis, robustness, and selectivity even in challenging matrices, including wastewater [45,46]. Next-generation HRMS instruments have also been used [46].

For example, SPE combined with LC-MS/MS was applied for analysis of 44 pharmaceuticals from various groups including antibiotics, hormones, NSAIDs, anxiolytics, cardiovascular agents in estuarine and wastewater samples. Instrumental detection limits (IDL) and method quantification limits (MQL) ranged 0.001–25 pg and 0.01–30.3 ng·L⁻¹, respectively [47].

Also, an advanced SPE-LC-MS/MS method detects 34 pharmaceuticals and personal care products in various environmental samples, with IDL between 0.01 and 1 pg and MDL between 0.002 and 3.323 ng·L⁻¹ [48].

An automated online SPE-LC-MS/MS system was implemented for the analysis of 10 pharmaceuticals (e.g., antidepressants, antineoplastics, and rennin inhibitors) from wastewater. LODs vary between 1.30 and 10.6 ng·L⁻¹ [49].

Additional examples, including the number of analyzed compounds, extraction, analytical techniques and detection limits are provided in

Table 2. Summary of analytical approaches for pharmaceutical analysis in water matrices.

Matrix Type	Number of Substances Analyzed	Extraction, Analytical Technique	Limits	References
Wastewater effluents	76 pharmaceuticals (e.g., antibiotics, cytostatic, NSAIDs, hormones, corticosteroids, antiepileptics)	SPE, LC-MS/MS	MDL = 0.4–22 ng·L−1; LOQ = 1–73 ng·L−1	[50]
River water, drinking water, running water, effluent and influent wastewater	12 pharmaceuticals (e.g., NSAIDs, antibiotics, antiprotozoals)	Ultrasound assisted DLLME, UHPLC-MS/MS	LOD = 0.006–0.091 ng·mL−1 LOQ = 0.018–0.281 ng·mL−1	[51]
Surface water	31 pesticides and 31 pharmaceuticals by target (e.g., NSAIDs, β-blockers, antifungals, opioid analgesics, antihistamines, psychotropics, anticonvulsants) and 137 for suspect screening (e.g., NSAIDs, antibiotics, pesticides, hormones, antiepileptics)	QuEChERS + DSPE, LC-HRMS (Q-Orbitrap, HESI)	LOQ = 0.002–1.64 ng·L−1	[52]
Drinking water	52 pharmaceuticals (e.g., psychotropics, antiepileptics, opioids, cytostatics, antibiotics, NSAIDs)	Direct filtration, UHPLC-MS/MS	LOD = 0.70–96.93 ng·L−1 LOQ = 2.09–290.78 ng·L−1	[53]
Seawater and river water	25 pharmaceuticals (e.g., psychotropics, NSAIDs, hypolipidemics, analgesics, and other drugs)	SPE, LC-HRMS	MDL = 0.2–8.0 ng·L−1; MQL = 0.8–25 ng·L−1	[54]
Fresh surface waters and wastewater streams	7 pharmaceuticals (e.g., antiretroviral, antibacterial/antimicrobials, anthelmintics, and analgesics)	SPE, LC-MS	LOD = 0.0439–0.1219 μg·L−1; LOQ = 0.1462–0.4065 μg·L−1	[55]
Seawater	7 pharmaceuticals and 2 metabolites (e.g., analgesics and NSAIDs)	SPE, UHPLC-MS/MS	MDL = 0.02–8.18 ng·L−1 MQL = 0.06–24.8 ng·L−1	[56]
Drinking water, surface water, and wastewater	33 pharmaceuticals (e.g., psychiatric drugs as well as their metabolites, NSAIDs/analgesics, and antibiotics)	SPE, UHPLC-MS/MS	MDL = 0.02–185 ng·L−1; MQL = 0.04–562 ng·L−1	[57]
Surface water and hospital wastewater	7 pharmaceuticals (e.g., antiepileptics, antibiotics, and NSAIDs)	SPE, UPLC-MS/MS	MDL = 0.005–0.015 µg·L−1 (surface water) MDL = 0.014–0.123 µg·L−1 (hospital wastewater)	[58]
River water	6 pharmaceuticals (e.g., antibiotics, antiepileptics, and NSAIDs)	SPE, UPLC-MS/MS	LOD < 0.1–1 ng·L−1 LOQ < 0.1–3.4 ng·L−1	[45]

LOD = limit of detection; LOQ = limit of quantification, MDL = method detection limits, MQL = method quantification limits.

.

GC-MS and GC-MS/MS are applicable to certain compounds, including opioids (codeine), hemorheologic agents (pentoxifylline), and antineoplastics (cyclophosphamide), without the need for a derivatization step. In contrast, NSAIDs (ketoprofen, flurbiprofen, tolfenamic acid), β-blockers (nadolol), and lipid-lowering agents (etofyllinclofibrate, etofibrate) require derivatization prior to analysis, while the NSAID aspirin can be analyzed with or without derivatization [44]. CE coupled with different detectors such as UV, UV-DAD, and MS can also be applied; however, compared with HPLC, CE has lower sensitivity [7].

2.4. Occurrence of Pharmaceuticals in Food and Water

Recent studies indicate that pharmaceuticals are present in both water and food matrices. In this section, the focus will be on examples from the literature illustrating the actual occurrence.

Analyses conducted between 2008 and 2022 found that 151 out of 210 pharmaceuticals were detected in water from the Middle East and North Africa. The highest detection frequencies were observed for antibiotics in the concentration range 0.03–66,400 ng·L⁻¹ for compounds such as thiamphenicol and spiramycin, respectively [59].

A targeted analysis of 97 pharmaceuticals in wastewater and receiving waters detected concentrations up to 5623 ng·L⁻¹ for 2-hydroxyibuprofen in surface water and 12,664 ng·L⁻¹ for caffeine in wastewater in Portugal. Twelve compounds from various groups (e.g., NSAIDs, antibiotics, psychoactive drugs) were detected at 100% frequency in both matrices [60].

In seawater from the Romanian Black Sea, the detected concentrations of pharmaceuticals followed this order: caffeine (13,575 ng·L⁻¹) > ibuprofen > naproxen > diclofenac > ketoprofen (13.4 ng·L⁻¹). Detection frequencies were 42.9% (ibuprofen), 31.0% (ketoprofen), 23.8% (diclofenac), and 21.4% (naproxen) [61].

A total of 253 pharmaceuticals were analyzed in surface water of the Mrežnica River (Croatia). Surface water was taken from three different regions (rural, semirural, and urban), and the highest concentration was 291.4 ng·L⁻¹ (urban area), followed by 186.5 ng·L⁻¹ (semirural area) and 141.6 ng·L⁻¹ (rural area). In May 2020, the most represented group was stimulants (caffeine, cotinine), while in September 2021, analgesics (ibuprofen) [62].

From 2019 to 2023, a national monitoring program in the Republic of Korea analyzed 1135 livestock products for the presence of veterinary drugs. Residues were detected in 28.2% of the samples, mainly in chicken, pork, milk, beef, and eggs. The most frequently detected compounds were diclazuril, followed by flumequine, clopidol, and enrofloxacin [63].

Between 2001 and 2023, the EU Rapid Alert System for Food and Feed (RASFF) recorded 2,381 notifications related to veterinary drugs and 164 related to feed additives. The highest number of veterinary drug residue notifications was observed for crustaceans, followed by fish, meat, honey and poultry meat. The detected compounds in food were predominantly prohibited substances including nitrofurans, chloramphenicol, and dyes (leucomalachite green), as well as anthelmintics (ivermectin) and aminoglycosides (streptomycin), while feed additive notifications mainly included coccidiostats (clopidol and nicarbazin). The highest proportions of alert notifications were reported for eggs (31.4%), milk (29.4%), and meat products (28.5%) [64].

The presence of antibiotics and antiparasitics in animal products, including meat, meat products, and dairy products from Argentina and Uruguay markets, was investigated. Veterinary drugs were detected in 26.45% of the samples, with 14.81% containing antibiotics and 11.64% containing antiparasitics. Importantly, 10.58% of the samples had concentrations above MRLs. The detected analytes included ivermectin, doramectin, doxycycline, chlortetracycline, oxytetracycline, chloramphenicol, monensin, thiamphenicol, and florfenicol [65].

These studies highlight the presence of pharmaceuticals in diverse matrices, and the importance of continuous monitoring.

3. Removal of Pharmaceuticals from Water

Pharmaceuticals primarily enter the aquatic environment via wastewater from hospitals, aquaculture, industrial facilities, and households. Numerous studies in countries such as Spain, Australia, the United States, and the United Kingdom have reported the occurrence of 16 to 54 different pharmaceutical compounds in wastewater. Their occurrence in groundwater and drinking water is largely caused by insufficient elimination in wastewater treatment processes. As pharmaceuticals are recognized as significant environmental pollutants, additional research is required to establish more effective removal methods from wastewater and the environment [66]. Studies conducted in recent years have focused on removing pharmaceuticals from wastewater, showing that conventional treatment techniques, including chlorination, filtration, flocculation, and activated sludge treatment, are not sufficiently effective [67].

The overall removal efficiency of pharmaceuticals depends on both their diverse chemical and physical properties, including hydrophobicity, water temperature, reactivity to treatment processes, hydraulic conditions, and concentration, the applied technology. Methods for pharmaceutical removal are generally classified into three categories: physical, chemical, and biological [68]. The following sections provide a detailed description of membrane technologies, adsorption, advanced oxidation processes (AOPs), and hybrid systems, as these approaches are the most commonly applied in wastewater treatment.

3.1. Membrane Technologies

Membrane processes efficiently remove macro- and micropollutants from drinking water and wastewater, making them a widely applied treatment method [66]. A membrane is a thin physical or physico-chemical barrier that can be permeable or semi-permeable for a certain substance, whereby the feed stream is separated into two streams: retentate (concentrate) and permeate (most often pure water). Synthetic membranes are made from various polymeric materials (polyvinylidene fluoride (PVDF), polyethersulfone (PES), polysulfone (PSF)), ceramic materials (silica or alumina clay), natural materials (cellulose, chitin, starch, alginate), and other inorganic ceramic materials. Composite membranes with improved permeability and separation properties can be achieved by incorporating nanomaterials into conventional membranes [69].

Based on pore sizes, membrane processes are categorized into microfiltration (MF, 0.01–1 μm), ultrafiltration (UF, 10–100 nm), nanofiltration (NF, 1–10 nm), reverse osmosis (RO, <1 nm), and forward osmosis (FO) [70,71]. These processes are driven by the pressure difference on both sides of the membranes, so with regard to the driving force, they are known as pressure membrane processes, and are mostly used in industrial practice [72]. The choice of suitable membrane processes depends on the characteristics of the contaminants, including particle size, charge, hydrophobicity, and hydrophilicity. Effective removal of pharmaceuticals from water and wastewater is accomplished using NF, RO, and FO membranes. In NF and RO membranes, the removal mechanisms rely on size exclusion as well as hydrophobic and electrostatic interactions. Neutral and positively charged hydrophilic compounds are removed by size exclusion. On the other hand, hydrophobic compounds can interact with the surface of a hydrophobic membrane, adsorb on the surface or within the porous structure of the membrane, and penetrate through it, so such a membrane system does not have sufficient separation efficiency. Conversely, negatively charged solutes are efficiently rejected through electrostatic interactions due to the negatively charged membrane surface [70]. RO can achieve removal efficiency of up to 99% for pharmaceuticals [73,74]. However, the RO process is more energy intensive than other membrane operations since water molecules must pass through dense membranes, which requires high pressures, often more than 20 bar [69,75]. RO is particularly effective in removing antibiotics, as the membrane acts as a complete barrier to large molecules. Consequently, the permeate stream is free of antibiotics, while concentrated residues accumulate in the retentate unless further treatment is applied [76]. NF consumes less energy as it operates at lower pressures (5–20 bar), but achieves slightly lower removal efficiency. Nevertheless, it is highly effective in eliminating higher molecular weight compounds, such as pesticides and certain pharmaceuticals [74,77]. Chemical cleaning of NF membranes enhances pharmaceutical removal efficiency and prolongs the membrane’s durability [74]. The reliability of membrane technologies in water treatment, along with the development of new materials for membrane preparation, has encouraged competition in the market, so the cost of purchasing membranes has been decreasing in recent decades. RO membranes cost between 100 and 500 USD/m², while NF membranes range from 50 to 200 USD/m². The choice of suitable membrane material is critical for achieving optimal process efficiency. Although the initial cost of RO membranes is relative higher, their high removal efficiency for emerging pollutants makes them a worthwhile investment [77]. Combining different treatment technologies, such as advanced oxidation processes with NF or RO, represents an effective approach to enhance the removal of pharmaceutical compounds [74]. Regardless of the negative phenomenon of membrane fouling, which is inevitable in every membrane process, the application of membrane processes in water treatment is widespread, that is, unlimited. Costs can be reduced by using recycled RO membranes, while fouling can be mitigated through modification with nanomaterials such as titanium dioxide (TiO₂) and graphene oxide (GO). Membranes modified with a combination of dopamine, TiO₂, and GO demonstrated the best performance, achieving contaminant removal (dyes and pharmaceuticals) of up to 95.7%, greater stability, and improved permeability. Moreover, they enhanced hydrophilicity and reduced fouling due to the hydrated surface layer. Additional removal mechanisms include adsorption (~10%) and photocatalysis (~20%), which further contribute to the efficiency of the modified membranes. In addition to efficiently removing pharmaceuticals, these membranes simultaneously degrade pollutants, thereby avoiding the generation of concentrated waste that would require further treatment [78].

3.2. Adsorption

Pharmaceutical compounds present in various types of water and wastewater can be effectively removed using adsorption, either with natural adsorbents, such as coal, clay, zeolites, and ores, which are inexpensive, or with synthetic adsorbents, often derived from agricultural, industrial, and domestic wastes [5]. Adsorption is a surface phenomenon based on interactions between the adsorbent (solid phase) and the adsorbate (gas or liquid phase). Equilibrium is reached through the gradual adsorption of pollutants onto the adsorbent surface. There are two main types of adsorptions: chemical adsorption (chemisorption), which involves chemical reactions between the adsorbent and adsorbate (an irreversible process), and physical adsorption, which is driven by various forces such as van der Waals forces and hydrogen bonding (a reversible process). The adsorption process depends on multiple parameters, including temperature, contact time, solution pH, coexisting impurities, concentration, and other factors [67]. The efficiency of pharmaceutical removal depends on their physicochemical properties. This includes molecular size, functional groups, adsorption–desorption distribution coefficient, octanol/water partition coefficient, pK_a, polarity, as well as environmental and operational factors. For ionizable compounds, adsorption especially depends on the pH, since many pharmaceuticals can undergo protonation or deprotonation under neutral conditions based on their pK_a [76]. The advantages of adsorption include high removal efficiency, rapid process kinetics, low cost, and the ability to remove multiple pollutants simultaneously [67]. The process is also characterized by a simple design, low initial investment, and a small footprint. It is effective not only at low adsorbate concentrations but also allows batch or continuous operation with the possibility of adsorbent regeneration and reuse. Additional advantages include low energy consumption, operation under mild conditions, and high removal efficiency, which can reach up to 90% [5].

Adsorption is limited at the commercial scale due to the lack of high-capacity adsorbents and the absence of commercially available columns. The development of an efficient adsorbent is critical to process success. Advances in nanotechnology have enabled the design of new, rapid, and efficient nanoadsorbents for contaminant removal [79], and their application is becoming increasingly widespread [80]. Nanoadsorbents are particles ranging from 1 to 100 nm, composed of organic or inorganic materials. Due to their high adsorption affinity, they are often referred to as next-generation adsorbents. Their characteristics, including small dimensions, large active surface area, a highly porous structure, and adaptability, make them suitable for removing pollutants of varying hydrophobicity, speciation behavior, and molecular weight. The presence of highly adsorptive and chemically active atoms located on the nanoparticle surface maximizes the adsorption potential. Furthermore, nanoadsorbents can be regenerated and recycled after use [81].

Nanoparticles are categorized by their adsorption characteristics into carbon-based, metal-based, and metal oxide-based, as well as nanocomposites, while other relevant types include aerogels, nanoclays, nanofibers, and xerogels [81].

○

Carbon-based nanoparticles include carbon nanoparticles, nanotubes, and nanoplates.

○

Metal-based nanoparticles are composed of metals such as gold, silver, platinum, zinc, titanium, iron, cerium, or thallium.

○

Metal oxide-based nanomaterials cover a variety of metal oxides, including aluminum, iron, manganese, and titanium oxides.

○

Nanozeolites represent an important group with high porosity, high cation exchange capacity, and large specific surface area. Their structure consists of a framework of tetrahedral metal oxide units connected via oxygen atoms, which determines their adsorption characteristics.

○

Polymeric nanoadsorbents or nanocomposites are categorized into nanocomposites based on carbon nanotubes/polymers, metals and metal oxides/polymers, graphene/polymers, and dendrimers. These nanocomposites are considered promising alternatives to conventional adsorbents because of their versatile surface chemistry, mechanical strength, extensive surface area, and pore size distribution [81].

3.3. Advanced Oxidation Processes

Advanced oxidation processes (AOPs) are considered modern and environmentally safe solutions for enhancing wastewater treatment [82]. Highly reactive oxygen species (ROS), such as hydroxyl radicals, hydrogen peroxide (H₂O₂), ozone (O₃), and superoxide anion radicals, enable the effective removal of a wide range of emerging pollutants. Due to their low selectivity, AOPs can achieve complete mineralization to carbon dioxide (CO₂), water (H₂O), and inorganic ions or acids. Typical AOPs include ozonation, Fenton and photo-Fenton reactions, sonolysis, radiation, photocatalysis, and electrochemical oxidation [67]. These processes effectively degrade organic pollutants into less harmful compounds [83]. Enhanced removal can be achieved using two-component systems (O₃/UV, O₃/H₂O₂, H₂O₂/UV) or three-component systems (O₃/H₂O₂/UV). The main advantages of these methods include high efficiency, operational safety, non-toxicity, cost-effectiveness, and good photochemical stability [84].

Industrial-scale application of AOPs remains limited due to their higher costs compared to conventional treatments. AOPs should be used selectively as an additional step and not as a stand-alone method. The synergistic effects with other processes require further investigation. Energy costs are significant, emphasizing the need to develop more affordable photocatalysts that utilize a broader spectrum of light (not limited to UV) and to incorporate renewable energy sources. Fenton processes produce sludge, while photocatalytic processes may produce depleted or poisoned catalysts, presenting both environmental and financial challenges [85].

3.4. Hybrid Systems

Multiple conventional or advanced treatment methods are integrated in hybrid technologies, resulting in more efficient removal of micropollutants or persistent compounds. Individual treatment technologies are often insufficient to eliminate all compounds and their degradation products. Combining different processes can enhance the degradation and mineralization of persistent pollutants through the synergistic effects and advantages of each method. In recent years, numerous advanced and hybrid treatment systems have been investigated [76].

3.5. Effectiveness of Pharmaceuticals Removal in Wastewater Treatment

The efficiency of different methods for removing pharmaceuticals from water has been widely studied, taking into account treatment technique, compound type, and other factors. A summary of the relevant literature is provided in the following section.

Wastewater often contains elevated concentrations of pharmaceuticals, such as naproxen (1.37 mg·L⁻¹) and norfloxacin (0.561 mg·L⁻¹). RO/NF, ozonation, and activated sludge treatment were generally the most effective, achieving removal efficiencies of up to 99%. In municipal wastewater, RO removed carbamazepine, diclofenac, ofloxacin, and sulfamethoxazole with efficiencies of 96.0–99.9%, whereas activated sludge treatment removed antibiotics and analgesics from hospital wastewater with efficiencies of 41–99% [86].

Activated sludge treatment in conventional wastewater treatment plants removes compounds such as ibuprofen, naproxen, ketoprofen, diclofenac, sulfamethoxazole, and trimethoprim, with efficiencies ranging from 40 to 100%, depending on the compound and operational conditions such as pH and retention time [87].

Integrating adsorption with MF or UF provides a simple and cost-effective purification strategy. Activated carbon (AC) is a biodegradable adsorbent commonly applied as a pre-treatment, although it can also be used post-filtration. Using a negatively charged NF membrane, over 90% of diclofenac, gemfibrozil, ibuprofen, and naproxen were removed. The molecular weight had no significant impact on removal efficiency [87].

Comparing RO and NF membranes shows clear differences in performance. RO achieves excellent removal efficiencies (≥99%) for compounds such as amoxicillin, caffeine, carbamazepine, and estrogens (estradiol and ethinylestradiol). NF shows slightly lower efficiencies, ranging from ~50% for enrofloxacin to 99% for sulfamethoxazole. Overall, NF is generally less efficient than RO. NF membranes are more effective at removing compounds with lower molecular weights and weaker ionic charges, but their capacity to remove larger or more concentrated substances may be limited. For antibiotics, RO effectively removes ciprofloxacin and azithromycin, while NF achieves 70–78% for amoxicillin, which could pose a risk of bacterial resistance. Hormones and endocrine compounds are removed nearly 99% by RO, compared to ~80% by NF. Psychotropic drugs such as fluoxetine and diazepam are also removed more effectively by RO (~99%) than by NF (≤85%) [77].

Table 3. Removal efficiency of pharmaceuticals using modern water treatment techniques.

Method	Compounds	Removal Efficiency	References
Hybrid constructed wetlands (CWs) approach, incorporating tidal flow (TF) operation and utilizing local Jordanian zeolite as a wetland substrate	Ciprofloxacin, ofloxacin, erythromycin, enrofloxacin, flumequine, lincomycin, carbamazepin, diclofenac	>98% ciprofloxacin, ofloxacin, erythromycin, enrofloxacin; 43–81% flumequine, lincomycin; <8% carbamazepin, diclofenac	[88]
Adsorption on synthetic zeolite (NaP1_FA) and zeolite-carbon composite (NaP1_C)	Colistin, fluoxetine, amoxicillin, 17-α-ethinylestradiol	>90% removal within 2 min contact time	[89]
Biochar based electrochemical degradation	Acetaminophen, sulindac, carbamazepine	>99%	[90]
Photoelectrocatalytic (PEC) system with immobilized g-C3N4@PAN	Diclofenac	92% (5 min)	[91]
Pump-less forward osmosis low-pressure membrane (FO-LPM) hybrid system with 1 M NaCl draw solution and NF membrane	Propranolol, naproxen, antipyrine	98.8% (propranolol), 97.7% (naproxen), 95.5% (antipyrine), 99.8% in presence of natural organic matter and divalent ions	[92]
Ozone/hydrogen peroxide process (O3/H2O2)	Oxytetracycline	>99% degradation within 15 min	[93]
photo-Fenton reaction (Fe/H2O2/UV)
Fenton reaction (Fe/H2O2)
Ozonation (O3)
Ozone (O3) nanobubbles AOPs	Tetracycline	100% (20 min, 100 mg/L tetracycline, 8 mg/L ozone)	[94]
Hybrid plasma-microbubble system	Diclofenac	90.9% (after 45 min)	[95]
Adsorption on Fe3O4/SiO2 nanocomposite	Diclofenac	95.28% (influent), 97.44% (effluent); 94.83% (raw sewage), 88.61% (final sewage)	[96]
Adsorption on geopolymers (metakaolin-based (GMK) and organic–inorganic hybrid (GMK-S) geopolymer)	Ibuprofen	~29% (batch), ~90% (continuous)	[97]
Adsorption on bentonite (BN) and acid-treated bentonite (BA1)	Tetracycline hydrochloride	Up to 99% (30 min, optimal pH 5)	[98]
Chitosan-based coagulant (CTS-DMDAAC) combined with powdered activated carbon (PAC)	Ibuprofen, acetaminophen	without PAC: <15%; with PAC: 71.44% (ibuprofen), 79.9% (acetaminophen)	[99]
Nanofiltration (NF), Reverse osmosis (RO)	Acetaminophen, caffeine, carbamazepine, diclofenac, ibuprofen, iopromide, lincomycin, naproxen, propranolol, ranitidine, sulfamethoxazole, sulfamethazine, trimethoprim	NF: ~84.17%, RO: ~99.21%	[74]
Electrochemical oxidation (EO)—adsorption	Acetaminophen (ACM), ciprofloxacin (CIP), atenolol (ATN), amoxicillin (AMX)	Single pharmaceuticals EO: 94.6% (ACM) + 92% (CIP), Adsorption: 94.07% (ACM) + 91.15% (CIP), EO + adsorption >99.8% (ACM + CIP) Multiple pharmaceuticals EO + adsorption: >97.56% (ACM + CIP + ATN + AMX) EO: ACM (83.35%) + CIP (73.1%) + ATN (68.52%) + AMX (63.05%) Adsorption: ACM (80.37%) + CIP (66.5%) + ATN (73.07%) + AMX (60.5%)	[100]
Atmospheric cold plasma	Diclofenac, sulfamethoxazole, trimethoprim, carbamazepine, caffeine	Up to 98%	[101]

summarizes pharmaceutical removal systems and their efficiencies. Although individual chemical or membrane processes can be effective, hybrid systems often achieve higher removal of different pharmaceutical groups, making them a more suitable solution.

Antibiotics and their transformation products (TPs) are often found in the environment, but their effects are still not well understood. The study showed that about 58% of the analyzed compounds pose a medium to high risk for both ecological toxicity and antimicrobial resistance. This highlights the need for regular monitoring of these compounds [102]. The effectiveness of AOPs in removing pharmaceuticals from spiked distilled water was investigated. The TPs showed similar structure, stability, persistence, and toxicity as their parent compounds, with some exhibiting even higher toxicity. This indicates that additional treatment is needed to fully degrade both the parent compounds and their by-products, ensuring safe wastewater discharge into the environment [103].

4. Conclusions

The application of pharmaceuticals in human and veterinary medicine is essential for preventing and treating diseases; however, it also presents considerable risks to ecosystems and the environment. Pharmaceutical residues occur in water, food, soil, and sediments, and can be detected and quantified using highly sensitive analytical methods, such as LC-MS/MS and LC-HRMS. Methods for the removal of pharmaceuticals include physical, chemical, and biological approaches, each with advantages and limitations, including efficiency, cost, energy consumption, membrane fouling, and by-product formation. Advanced technologies, including NF/RO membrane processes, adsorption, and AOP, as well as hybrid systems combining multiple methods, achieve high removal efficiencies. Nevertheless, continuous monitoring of pharmaceuticals in food and environmental matrices, as well as the development of more efficient removal methods capable of eliminating both parent compounds and their toxic transformation products, is essential for the protection of ecosystems and human health.