Accepted Manuscript Title: Selected analytical challenges in the determination of pharmaceuticals in drinking/marine waters and soil/sediment samples Author: Anna Białk-Bieli´nska Jolanta Kumirska Marta Borecka Magda Caban Monika Paszkiewicz Ksenia Pazdro Piotr Stepnowski PII: DOI: Reference:
S0731-7085(16)30016-4 http://dx.doi.org/doi:10.1016/j.jpba.2016.01.016 PBA 10442
To appear in:
Journal of Pharmaceutical and Biomedical Analysis
Received date: Revised date: Accepted date:
31-8-2015 5-1-2016 7-1-2016
Please cite this article as: Anna Bialk-Bieli´nska, Jolanta Kumirska, Marta Borecka, Magda Caban, Monika Paszkiewicz, Ksenia Pazdro, Piotr Stepnowski, Selected analytical challenges in the determination of pharmaceuticals in drinking/marine waters and soil/sediment samples, Journal of Pharmaceutical and Biomedical Analysis http://dx.doi.org/10.1016/j.jpba.2016.01.016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Selected analytical challenges in the determination of pharmaceuticals in drinking/marine waters and soil/sediment samples
Anna Białk-Bielińska1*, Jolanta Kumirska1, Marta Borecka1, Magda Caban1, Monika Paszkiewicz1, Ksenia Pazdro2, Piotr Stepnowski1
1
Department of Environmental Analysis, Faculty of Chemistry, University of Gdańsk, ul.
Wita Stwosza 63, 80-308 Gdańsk, Poland 2
Institute of Oceanology, Polish Academy of Sciences, ul. Powstańców Warszawy 55, 81-712
Sopot, Poland
*Corresponding author: [email protected], (+48) 58 523 52 08
1
Highlights Review of selected aspects of the analysis of pharmaceuticals in the environment Presentation
of
recent
improvements
in
the
determination
of
challenges
in
the
of
pharmaceuticals Discussion
of
methodological
analysis
pharmaceuticals Presentation of application of carbon nanotubes in the analysis of pharmaceuticals
2
Abstract Recent developments and improvements in advanced instruments and analytical methodologies have made the detection of pharmaceuticals at low concentration levels in different environmental matrices possible. As a result of these advances, over the last 15 years residues of these compounds and their metabolites have been detected in different environmental compartments and pharmaceuticals have now become recognized as so-called ‘emerging’ contaminants. To date, a lot of papers have been published presenting the development of analytical methodologies for the determination of pharmaceuticals in aqueous and solid environmental samples. Many papers have also been published on the application of the new methodologies, mainly to the assessment of the environmental fate of pharmaceuticals. Although impressive improvements have undoubtedly been made, in order to fully understand the behaviour of these chemicals in the environment, there are still numerous methodological challenges to be overcome. The aim of this paper therefore, is to present a review of selected recent improvements and challenges in the determination of pharmaceuticals in environmental samples. Special attention has been paid to the strategies used and the current challenges (also in terms of Green Analytical Chemistry) that exist in the analysis of these chemicals in soils, marine environments and drinking waters. There is a particular focus on the applicability of modern sorbents such as carbon nanotubes (CNTs) in sample preparation techniques, to overcome some of the problems that exist in the analysis of pharmaceuticals in different environmental samples.
Keywords: analysis; environmental samples; pharmaceuticals; carbon nanotubes
3
1. Introduction For more than 15 years, pharmaceuticals and their metabolites have been recognized as so called ‘emerging contaminants’. This is due to recent developments and improvements in advanced instruments and analytical methodologies, which have made the detection of these chemicals at low concentration levels possible in different environmental matrices [1-2]. Residues of pharmaceuticals and their metabolites have been detected in different environmental compartments. Their wide usage and biological activity as well as their relatively strong resistance to degradation processes are the reasons why many scientists all over the world are concerned about the risks they might pose to the ecosystem and to human health [1-2]. In recent years it has therefore become of the utmost importance to understand the environmental fate of these compounds. This would have not been possible without the availability of appropriate, accurate and highly sensitive analytical methodologies for their determination in aqueous and solid environmental samples. To date, there have been a lot of papers published on the development of new analytical methodologies - as well as their application in different fields - and impressive improvements have been made [1-3]. However, in order to assess the environmental fate of these chemicals, there are still numerous methodological challenges to be overcome. The aim of this paper therefore, is to present a review of selected recent improvements that have been made and the challenges that exist in the analysis of pharmaceuticals in environmental samples. Special attention has been paid to the current state of knowledge regarding the occurrence and fate of these chemicals, as well as the strategies and challenges that exist in their analysis in soils, marine environments and drinking waters (Section 2-5) also in terms of the implementation of Green Analytical Chemistry (GAC) (Section 6). In our opinion there are still some gaps in these particular aspects that need to be discussed when
4
compared with the analysis of pharmaceuticals in surface or waste waters which to date have been more widely studied. In addition, in order to overcome some of the existing problems in the analysis of pharmaceuticals in different environmental samples, we also present a review of the available literature and data concerning the applicability of modern and very promising sorbents such as carbon nanotubes (CNTs) in sample preparation techniques (Section 7). The high efficiency of these sorbents in the extraction of pharmaceuticals from different matrices has already been proven in not only environmental samples but also in food/biological samples. Therefore, this will also be discussed in detail.
2. Analytical challenges in the determination of pharmaceutical residues in soil samples
2.1. Occurrence and fate of pharmaceuticals in soil Pharmaceuticals may be released into the soil environment when contaminated sewage sludge, sewage effluent, or animal manure is applied to land [e.g. 1-8]. Veterinary pharmaceuticals may also be excreted directly to soils by pasture animals. It has been reported that the concentrations of selected drugs in animal manure could be very high. For example, concentrations of norfloxacin and enrofloxacin in chicken manure from China were up to 225 and 1420 mg kg-1, respectively [9]. Moreover, it has been established that about 3.6 x 109 m3 of treated wastewater
is
currently
reused
in
the
U.S.
for
different
purposes,
including for agricultural and landscape irrigation, and water reuse is growing by 15% a year [10]. Similarly, approximately 6 x 106 t of biosolids are produced each year in the U.S., of which about 60% is applied to land [11-12]. Consequently, a range of pharmaceuticals has been detected in
5
agricultural soils, with reported concentrations up to the low mg kg-1 level [e.g. [1-8, 13−20]). These compounds may persist in soil matrices for long periods and may be toxic to terrestrial organisms (e.g. [3, 6, 8, 21-28]). For example, according to data presented by Langdon et al. [24], estrogenic activity was detectable at all of the sampling times that biosolids were applied to land. Furthermore, a number of studies have demonstrated the uptake of pharmaceuticals used in human and veterinary medicine into plants [29-39]. Additionally, the presence of veterinary or human drugs in the environment (e.g. in soil matrices) can induce pathogen resistance to antibiotics [e.g. 40-41]. The environmental fate of pharmaceuticals in the soil ecosystem is conventionally estimated by taking into account their persistence and sorption in soil. The residence time of veterinary and human drugs in the terrestrial environment can range from less than one day to months depending primarily on the temperature and the chemical structure of the pharmaceutical [4243]. The mobility of the pharmaceuticals in soil, and their consequent potential for contaminating groundwater, depends on: (i) the basic chemistry of these compounds; (ii) the amount of drug applied; (iii) the intensity of “rain” events; and (iv) the soil type, and is also correlated with their sorption tendencies. There are no regulations on concentration limits of pharmaceuticals in the environment, even though growing concerns in the US and Europe have resulted in the prescription of environmental risk assessments of veterinary pharmaceuticals [44-49]. For example, detailed emission and distribution models as well as environmental risk assessments for veterinary medicinal products have been provided by Montforts [50]. As has been already mentioned, thanks to improvements in analytical chemistry, many pharmaceutical compounds are more easily detected in surface water and wastewater 6
environmental compartments at ppb concentrations. A different situation can be seen in the case of soil matrices. In 2004 for example, there was only limited information available on this topic [5-6, 51]. Although our knowledge about the presence of pharmaceuticals in soils is increasing (e.g. [1-8, 13−20]), the information in peer-reviewed literature regarding the fate and the ecotoxicological effects of most pharmaceuticals is still limited [3, 6, 8, 12, 21-28, 52-60]. A similar situation can also be observed in the case of the availability of analytical methods for determining drugs in soil matrices. In the past decade, many methods have been developed for the analysis of pharmaceuticals in aqueous matrices, however, only limited exist for the determination of drugs in soil matrices. Review articles presenting these methods have been published by Stolker and Brinkman [61], Pavloviċ et al. [62], Wilga et al. [43], Kemper [63], Buchberger [64], Tadeo et al. [65], Babić and Mutavdžić Pavlović [66], Snow et al. [53-54] and Havens et al. [67]. For example, Snow et al. [54] reviewed articles published in 2013 which ranged from detailed descriptions of analytical methods, to fate and occurrence studies and sampling techniques for a wide group of pharmaceuticals occurring in agricultural environments. Babić and Mutavdžić Pavlović [66] presented some conventional and novel sample preparation methods for the determination of pharmaceuticals in solid environmental samples, including soils, and compared them from the viewpoint of their applicability to environmental analysis. Havens et al. [67] compared accelerated solvent extraction, soxhlet and sonication techniques for the extraction of estrogens, androgens and progestogens from soils. The application of ultrasound-assisted extraction for the extraction of emerging contaminants from environmental samples (e.g. pharmaceuticals from soil matrices) was presented by Albero et al. [68]. The current methodologies published since 2014 that have been used in the determination of selected pharmaceutical residues in soil matrices are presented in the next section.
7
2.2. Current methodologies used in the determination of pharmaceutical residues in soil matrices published since 2014 The characteristics of analytical methods for the analysis of pharmaceuticals in soils and concentrations of pharmaceuticals detected in soil samples from different geographical areas that have been published since 2014 are presented in Table 1. These methodologies can be divided into four major groups: (i) new methods developed for determining drugs in soil matrices [72-74], (ii) new analytical methods developed not for the analysis of real environmental soil samples but for the assessment of the fate of pharmaceuticals in such matrices, but which however could be potentially applied for this purpose [71], (iii) previously published methods, used with or without modifications, for the determination of a variety of drugs in real environmental soils [69-70], (iv) analytical methods developed for determining drugs in environmental samples but now applied for the establishment of their fate in such matrices [12]. The first group is represented by three methods: two [72-73] based on gas chromatography with mass spectrometry in Selected Ion Monitoring Mode (GC-(SIM)MS) measurements (Table 1) and the last one on liquid chromatography coupled to tandem mass spectrometry (LC–MS/MS) [74]. Aznar et at. [72] developed a method for the detection and quantification of fifteen pharmaceuticals belonging to five therapeutic classes (anti-inflammatory/analgesics, lipid regulators, antiepileptics, β-blockers and antidepressants). The target drugs were extracted from soil by ultrasound-assisted extraction (UAE) and directly subjected to derivatization by N-(tertbutyldimethylsilyl)-N-methyl-trifluoroacetamide (MTBSTFA) with 1% tert-butyldimethylchlorosilane (TBDMCS) prior to GC-MS analysis. In the second paper, [73] microwave-assisted extraction (MAE) was applied for the separation of eight NSAIDs and five estrogenic hormones from solid (e.g. soil) matrices. The obtained extracts were
8
purified by SPE using Oasis HLB cartridges, and subjected to derivatization by N,Obis(trimethylsilyl)trifluoroacetamide (BSTFA) and 1% trimethylchlorosilane (TMCS) in pyridine. In comparison to the methods presented in the literature [76-79], this approach allows the determination of more estrogenic hormones and NSAIDs in one analytical run and/or the correct assessment of the concentrations of estrone and 17α-ethinylestradiol by GC-MS. Mijangos et al. [74] developed a method for the simultaneous determination of 11 endocrine disrupting compounds including 6 hormones: diethylstilbestrol, estrone, 17βestradiol, testosterone, 19-norethindrone and progesterone in amended soil. This method used focused ultrasonic solid–liquid extraction (FULSE) and dispersive solid-phase extraction (dSPE) as a simplified clean-up strategy. FUSLE requires a low amount of sample (0.01–1.0 g, here 0.5 g), solvent (5–15 mL, here 10 mL) and short extraction times (from seconds to a few minutes, here 5 mins), hence dSPE, in comparison with traditional SPE, saves time, effort, money and solvent consumption. The second group is represented by a method developed for the analysis and evaluation of decreasing patterns of 16 veterinary antianxiety medications in soils [71]. This method is based on ultrasonic-assisted extraction and liquid chromatography–high resolution mass spectrometry (HPLC–HRMS) measurements. The purification of the obtained soil extracts was performed by the addition of 0.5 mL of n-hexane and centrifugation at 5000 rpm for 5 mins. The bottom layer was injected into the Orbitrap MS. This approach resulted in good validation outcomes for the target drugs in soil samples. The simplicity and high sample throughput makes the method more attractive for the analysis of real environmental soil samples. The third group of methods includes previously published methods used with or without modifications for analysing the occurrence and distribution of drugs in real soil samples [6970, 75]. For example, the occurrence of veterinary antibiotics and progesterone in broiler
9
manure and agricultural soils in Malaysia [69] was investigated using a method described by Ho et al. [80] (Table 1). Briefly, it was based on the addition of 5 mL MeOH:ACN:0.1 M EDTA:McIlvaine buffer (pH 4); 30:20:25:25, v/v/v/v/) and internal standards, vortex-mixing for 30 seconds, triplicate extraction in an ultrasonic bath for 10 mins (UAE) and centrifugation at 4000 rpm for 10 mins (Table 1). The supernatant (20 mL) was diluted by H2O to 500 mL, adjusted to pH 2.3, filtered, subjected to SPE (Oasis HLB) and analyzed by HPLC–(ESI)MS/MS. The same procedure, but with small modifications to the sample extraction and clean up steps, (see Table 1) was also applied by Wu et al. [70] for the analysis of the distribution and risk assessment of quinolone antibiotics in the soils from the organic vegetable farms of a subtropical city in southern China. Hou et al. [75] proposed a feasible and rapid determination of 17 veterinary antibiotics belonging to five classes: sulfonamides, tetracyclines, fluoroquinolones, macrolides and nitrofurans in soils by means of ultraperformance liquid chromatography (UPLC)-tandem mass spectrometry (MS/MS) (the total run time was only 10 mins). However the extraction procedure was based on a previous description [81]. The authors applied this method in the analysis of the occurrence and distribution of these drugs in amended soils in the Liaoning and Tianjin areas of northern China (Table 1) [75]. A good example of the last group of methods is the approach presented by Dodgen et al. [12] Soil samples were extracted using the EPA Method 1694 and the soil extracts were prepared for the analysis of the parent and transformation compounds of diclofenac and naproxen in the soil by a method modified from Wu et al. [82]. The coupled use of
14
C labeling and
chromatographic analysis in this study allowed a comprehensive investigation to be made of the transformation and the removal pathways of these drugs in soil. By use of this method, it was established that mineralization was the predominant removal process for diclofenac and naproxen.
10
2.3. Outlook Over the past ten years, different methods have been proposed for the monitoring of pharmaceutical residues in soil samples. However, methods for the identification and quantification of many drugs in soil samples have not yet been developed. The interest is concentrated onto the predominant therapeutic classes as antibiotics, analgesics/antiinflammatory
drugs,
hormones,
lipo-regulators,
beta-blockers,
anti-epileptics
and
antidepressants [e.g. 1-8, 13−20, Table 1], but the number of chemical compounds used as human and/or veterinary drugs is estimated over 4000 molecules and 10 000 products. Moreover, although anthelmintics together with antibiotics belong to the most commonly used veterinary drugs only limited data are available concerning the determination of anthelmintics in the soils and only few papers have dealt with the environmental fate of these drugs in the soils [83-86]. For this reason, research into the occurrence and fate of pharmaceuticals in soil environments still requires further development of the analytical methods. Only analytical methods which are sensitive, accurate and easy to apply in routine analysis will mean reliable risk assessments of the presence of pharmaceuticals in soil matrices can be made. The development, therefore, of such methods is still crucial. Sample preparation techniques play a key role in these methods. That is why efforts in this field have been mainly focused on optimization of the preparation, extraction and clean-up steps and on the enhancement of the environmental safety of these procedures. However, efforts also need to be made to develop on-line coupling, automatic or semi-automatic protocols. Currently, the proposed analytical procedures for determining pharmaceuticals are mainly based on HPLC-MS/MS and less frequently on GC-MS. The main trend in HPLC-MS/MS is to combine powerful MS detectors (QqTOF and Orbitrap) with modern chromatographic approaches such as UHPLC, GC×GC or LC×LC. Such approaches allow the development of
11
multi-analyte techniques for the detection of a wide range of drugs in a single analytical run. The main disadvantage, however, of these methodologies is the need for complex equipment and the high costs. For this reason, it is also very important to develop low cost screening methods based on microbiological, immunoassays and biosensors.
3. Analytical challenges in the determination of pharmaceutical residues in marine waters and sediments
3.1. Occurrence and fate of pharmaceuticals in marine waters and sediments In contrast to the large number of studies demonstrating the presence of pharmaceutical residues in wastewaters, drinking waters and/or surface waters, there are only a few studies which have reported on the occurrence of these compounds in marine ecosystems [87-91] despite seawater being the final sink for many traditional chemicals (both organic and inorganic) [92-93]. Moreover, sediments - as complex matrices – also provide a wide variety of binding sites and therefore can also act as major sinks for the deposition of particle reactive pollutants [94-95]. It can therefore be assumed that there is a similar fate for pharmaceuticals (as organic compounds) in this environment. The most vulnerable marine environments are coastal areas, where the centers of human populations are often found. These environments are therefore exposed to discharges of municipal effluent, which can cause a constant supply and accumulation of hazardous compounds, including pharmaceuticals. This is particularly relevant in the case of coastal lagoons, due to the fact that they are almost entirely land-locked and due to their shallowness. Hence water exchanges, which allow for the dilution and/or dispersion of organic pollutants, are limited in such confined environments [87, 89, 96-97]. According to data presented by Gaw et. al [87], since the year 2000 there have been only forty-nine studies, which have reported on concentrations of pharmaceutical residues in
12
estuarine and coastal waters. In these studies, 113 pharmaceuticals and their metabolites were detected at concentration ranges from 0.01 to 6800 ng L-1. The examined areas mainly include Europe - the North Sea (the coasts of Germany [98] and Belgium [99]), the Baltic Sea (the coasts of Poland [100-101] and Germany [102-103]), the Adriatic Sea (the coast of Italy) [102], the Aegean Sea and the Dardanelles (the coasts of Greece and Turkey) [102], the Mediterranean Sea (the coast of Israel) [102], the Balearic Sea (the coast of Spain) [102], the Atlantic Ocean (the coasts of Portugal [104] and Ireland [105]) and Asia - the Yellow Sea [106-109] and the South China Sea [110-115]. There is much less data available on the presence of pharmaceuticals in marine sediment samples. There have been only twenty-two studies, which show that in total 62 pharmaceuticals have been detected at concentration ranges from 20 µg g-1 dry weight to 2 616 µg g-1 wet weight [87]. Their presence has been evaluated mainly in Asia (the Mianqian Sea [116], the South China Sea [110, 117], the East China Sea [118] and the Yellow Sea [109, 119]) and different areas of the Pacific Ocean (the coast of the USA – the Puget Sound [119], the coast of New Zealand [120], the coast of Korea [121] and the coast of Chile [122]). As shown above, there is a significant knowledge gap when it comes to research into the fate assessments of pharmaceuticals in marine environments. However, during recent years there has been a growing interest in research focused on this topic, as seventy per cent of the studies which demonstrate the presence of pharmaceutical residues in marine environments, have been published since 2010 [87]. Access to marine samples is much more restricted and more expensive than in the case of terrestrial and freshwater ecosystems. Moreover, the analysis of pharmaceuticals in marine samples is a very difficult and demanding task. This is due to the fact that the environmental concentrations of these compounds are mostly in the ng L-1 to µg L-1 ranges and due to the complexity of the analyzed matrices. There is also a great variety of pharmaceutical compounds, their metabolites and transformation products, characterized by
13
different chemical properties, which means no comprehensive method exists for the multiresidue analysis of these compounds. Consequently, there is a growing need to develop analytical methods which will enable a reliable, sensitive, selective and fast determination of pharmaceutical residues in marine samples. The current methodologies used in the determination
of
pharmaceutical
residues
in
marine
environments
are
presented in the next section.
3.2. Current methodologies used in the determination of pharmaceutical residues in marine waters and sediments There are many traditional sample-preparation methods in use for the analysis of pharmaceuticals in marine samples. However, solid phase extraction (SPE) is the most commonly used extraction technique for the analysis of these compounds in aqueous samples [98-115]. This technique allows for sample extraction and clean-up, both of which are necessary to improve the sensitivity of detection. In addition, these steps can be carried out at the same time, what makes the analysis less time-consuming [113]. Prior to extraction, or just after collection, water samples are filtered through glass-fiber filters. Then, depending on the chemical properties of the analyzed compound/compounds, they are acidified (usually to pH 3) or pretreated to pH 7.5 – 8.0 [106-115]. Of the different SPE-cartridges available, Oasis HLB is the most commonly used cartridge for the extraction of selected compounds from seawater [102-103, 106-115]. This is due to the fact that this cartridge generates the best absolute recoveries (in a range from 61 to 112 %) for most pharmaceuticals. The newest trend is for the use of SPE speed disks [100-101], which are useful for isolating analytes from high-volume samples. In this way, high concentration ratios can be obtained, hence limits of detection and quantification can be reduced. The extraction efficiency obtained with the use of an SPE speed disk is in the range from 51.4 to 99.8 %.
14
The extraction of pharmaceuticals from sediment samples (similar to extraction from soils) is much more difficult. It requires the application of advanced extraction techniques to isolate the analytes as some of them strongly bind to the matrix, such as fluoroquinolones and tetracyclines [6]). For this purpose, ultrasound assisted extraction (UAE) [116, 118, 120, 122] and accelerated solvent extraction (ASE) / pressurized liquid extraction (PLE) [120-121] techniques are chosen. However, simple vortex-mixing has also been employed [109-110, 119]. The most commonly used solvents are a mixture of acetonitrile and citric acid [110, 116], a mixture of acetonitrile and EDTA-McIlvaine buffer [109, 119] or a methanol/methanol-water mixture [120-122]. The complexity of the sediment samples however, means that the obtained extracts need to be purified. It is therefore necessary to include a clean-up step at the sample preparation stage. This is carried out mainly with the use of solid-phase extraction [109-110, 116-122]. For this purpose, Oasis HLB cartridges [109, 120] or anion-exchange cartridges (SAX) in tandem with hydrophilic–lipophilic balance (HLB) cartridges are used [110, 116]. The recoveries obtained using these methodologies for the determination of pharmaceuticals in sediment samples were in the range of 45 to 126 % for most pharmaceuticals [109-110, 116-122]. Advances in analytical technology have been a key factor affecting the detection of pharmaceuticals in environmental matrices. The technologies now available allow for the determination of compounds occurring at trace levels (just a few ng/L or less) [104]. The majority of the data on the occurrence of pharmaceutical residues in marine environments are for antibiotics, non-steroidal anti-inflammatory drugs, lipid regulators and β-blockers [98122], which are polar compounds. For analysis of these, methods basing on reversed-phase high performance liquid chromatography should be used. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) has therefore been the analytical technique of choice for the determination of pharmaceuticals in marine samples [99-116, 118, 120-121]. The main
15
advantage of this technique is its high selectivity and sensitivity [104, 113]. In many cases, quantitative analysis of the compounds was performed using the multiple reaction monitoring mode (MRM), employing at least two of the highest characteristic precursor ion/product ion transitions [99-101, 103, 106, 108, 110, 113-114, 116, 118, 121]. Together with retention times, the characteristic ions were used to ensure correct peak assignment, which enhances the reliability of the obtained results. Recently there has been a trend toward the use of ultra-high performance liquid chromatography (UHPLC), which allows for faster analysis, better resolution and narrower peaks, compared to conventional HPLC methodologies [123]. This technique has also been successfully applied in the analysis of NSAIDs in marine waters [104] and pharmaceuticals from different therapeutic classes in marine sediments [118].
3.3. Outlook A major problem, when trace levels of pharmaceuticals are analyzed using the SPE-LCMS/MS technique, is matrix effects [123-128]. These effects can result in poor analytical accuracy and reproducibility. In the case of marine samples, analysis of the main factors responsible for these effects are: -
the analysis of seawater – the high salinity of these samples and high concentrations of dissolved organic matter (such as humic substances);
-
the analysis of sediments – the high organic matter content.
Operational strategies which can be undertaken to reduce/evaluate the matrix effect are the employment of isotope-labeled analogues and the use of the post-extraction addition technique. Both of these have been successfully applied in the analysis of marine samples [100-102, 106, 108-110, 112-116, 118, 121], although they raise the cost and/or the time of analysis. However, these strategies need to be undertaken in order to obtain reliable analytical
16
results and so there is a growing need to develop more selective and sensitive extraction methods in order to overcome the problem of matrix effects and reduce the time and cost of analysis.
4. Analytical challenges in the determination of pharmaceutical residues in drinking waters
4.1. Occurrence of pharmaceuticals in drinking waters The presence of pharmaceutical residues in drinking waters is a relatively new issue when it comes to environmental pollution from human activity and is closely related to the pollution of other water components (marine, rivers and lakes) as well as soils in natural environments. Drinking water can be produced from surface water, ground water or recycled wastewater, depending on water availability and the technology used, which in turn depends on the finances of the individual country as well as the required water quality. The reason for the occurrence of pharmaceuticals in all water matrices is that they are all closely related to each other and water is a good carrying medium for polar and semi-polar compounds. The main sources of pharmaceutical (and hormone), contamination of drinking water from both human and veterinary usage, are presented in Figure 1. The real situation is more complex because accidental contaminations can also occur. The fate of pharmaceuticals in the environment has already been the subject of advanced investigations [129-130]. It is already known that the elimination of pharmaceuticals in groundwater environments is limited because of an almost total lack of microorganisms, low levels of oxygen concentrations and the amount of energy needed for oxidation and other transformations [131]. In order to be able to state if the residues of these active compounds can pose a risk to human health, the levels of their concentrations need to be known. For this reason, there have been many investigations which have been ongoing from several years.
17
Some examples of pharmaceuticals which have been detected in drinking waters are presented in Table 2. Although concentrations of pharmaceuticals in drinking waters are low (ng L-1) and they do not pose a direct risk to human health [139-140] - their occurrence in drinking water still attracts attention because of overall concerns about the quality of drinking water [141]. Generally, the detection frequency of target pharmaceuticals is moderate and varies in range from 0 to 100% [142-143]. During some investigations, pharmaceuticals have been detected in surface waters but not found in drinking water (Netherlands, [144]). The most high-scale investigations into the presence of pharmaceutical residues in drinking water have been carried out in the USA, Canada, France, Germany, the UK, Italy and in Finland (review in [145-146]). Some countries already have long-term monitoring in place, which of course provides more valuable information. For example in Germany, the long-term analysis of ground water (as the main source of drinking water in the country) provides interesting information about the presence of pharmaceuticals together with other anthropogenic compounds, because the pathways of both are mostly the same [147]. This investigation has resulted in legislative consequences – for example phenazone-like residues (phenazone is an analgesic and antipyretic pharmaceutical) as well as other pharmaceuticals (e.g. carbamazepine, diclofenac, ibuprofen, primidon) have been recommended by the German Federal Protection Agency (Umwelt Bundesamt) to be added to the list of pharmaceuticals with maximal concentrations of 0.3 - 3 µg L-1 [148] to be monitored, although to date these compounds have not been included in regular water monitoring.
18
4.2. Current methodologies used in the determination of pharmaceutical residues in drinking waters The analytical methods used for the determination of pharmaceuticals in drinking waters are the same as for other water matrices. Generally, it is common practise that the methods developed for their analysis in surface or wastewater samples are also used in the analysis of drinking water samples [139, 149-151], which generally does not create any problems. The overall analytical procedures are the same, from sampling and preservation, extraction, the final determination by chromatography with mass spectrometry detection, to the final interpretation of the results. However, some differences and analytical challenges can occur and these will be discussed in this section.
4.2.1. Why, where and when to analyse Pharmaceuticals can pass into soil and occur in ground water, and thereby pollute water prepared for human consumption, despite the use of advanced technologies. Because of this, analytical methods are mainly used to: (i)
determine the level of pollution of drinking water by pharmaceutical residues [135, 151-154],
(ii)
determine the risk of the pharmaceutical presence [136, 155],
(iii)
evaluate the efficiency of the technology of water purification [133, 156-158] and the impact of climate on this process [159],
(iv)
investigate the life-time of pharmaceuticals in drinking water [160],
(v)
determine any by-products of pharmaceuticals produced during advance treatments [144, 161-163].
There is also the question of when and where to analyse drinking waters. Most of the available methods are based on the usage of shot analyses of grab samples in triplicate in
19
order to provide an overview of the problem. However, water samples can be also taken as 24-hour collected samples, which can be more appropriate for screening analysis. This strategy has already been used in the analysis of wastewater samples [164], but never for drinking water. The long-term analysis of polar compounds can be also carried out by the application of passive sampling techniques. Samples of drinking water can be collected directly in households, in water companies or in ground water intakes. The obtained results of pharmaceutical concentrations in all of these cases can be different, and making direct links between them is impossible, because of the problem of tracking water in complex municipal water systems. When the technology of purification is examined, water samples are taken before and after treatment. This can be done in-situ [133] or in a lab-scale investigation [157]. Particularly in the latter case, water samples can be taken at every step of the water treatment process. Similar experiments are used in investigations into the efficiency of new technologies used in the removal of pharmaceuticals during wastewater treatment [165]. Nevertheless, there is still a question mark over when drinking water samples should be taken. Screening investigations have the advantage that the obtained results are just as informative whether pollution is found to have occurred or not. This is because these samples can be taken at any time. Passive sampling also possesses the advantage that it is not impacted by the momentary and temporary variations in the concentrations of the pollutants [166]. For all of the above reasons, it is necessary that future regulations regarding the monitoring of pharmaceuticals in drinking waters specify when and where water samples should be collected.
4.2.2. Choice of analytes and indicators The number of active pharmaceutical compounds is high and is still growing. This makes the selection of analytes difficult and some notes should be considered:
20
(i) Analytes can be selected from a group of compounds that have already been detected in water matrices on the sampling side, which means the possibility of their presence in drinking water is also high. (ii) The method applied (and already validated for another water matrix) can dictate the group of analytes. (iii) Analytes can be taken from groups of pharmaceuticals which have already been proven to have a high negative impact on human health. Of the three presented ways to select analytes, the second is normally the most commonly applied as it is the simplest because the methods have already been validated. However, the selection of the target analytes depends on the aim of the research as well as the instruments available. It should also be noted that, although over the last five years there has been some information about the presence of pharmaceutical by-products produced after oxidation and during the chlorination process of drinking water treatment, [163] to date, there has been little information regarding the toxic effects of these by-products. This is due to their structural characteristics and problems concerning their pure synthesis for toxicological tests, even though it is possible to test extracts of degradation mixtures without the need to identify every product. Bearing in mind that the degradation might not be complete and some of the products can be even more toxic that the native compounds, non-target analysis of drinking waters (without any previous selection of analytes) can also be performed [163]. There have also been some studies which have focused on the selection of representative groups (indicators) of pharmaceuticals. For example, Kumar and Xagoraraki [167] presented a ranking system of endocrine-disturbing chemicals for the monitoring of surface and treated drinking waters in the USA. The proposed ranking system was based on four criteria: occurrence, treatment in drinking water treatment plants, ecological effects and health effects.
21
Of the seven attributes: prevalence, frequency of detection, removal, bioaccumulation, ecotoxicity, pregnancy and health effects, it was stated that health effects and the treatment in drinking water treatment plants were the most important. The total ranking for the selected pollutants was the sum of the importance of the factor weight. Out of a group of pharmaceuticals,
17α-ethinylestradiol,
19-norethisterone,
demeclocycline,
flumequine,
methylbenzyldene camphor were ranked as the top five. Of course in order to determine these indicators, the long term monitoring of pharmaceuticals in water matrices had been previously carried out, the USA being a country with a relatively high problem of pharmaceutical contamination in treated drinking water.
4.2.3. The main step – sample taking and preservation As sampling is a very crucial step in obtaining reliable results, representative samples must be collected which contain the average characteristics for the sampled matrices. Because drinking water is generally homogenous, grab samples can be taken [133, 152, 157, 159]. As has been previously highlighted, passive sampling is also a good technique for the long term monitoring and determination of average concentrations over time. However, although, it may seem to be the perfect choice for the analysis of pharmaceutical residues in drinking water, there are also some drawbacks. First of all, there is generally a lack of passive samplers for pharmaceuticals such as polar compounds (passive sampling is mostly used for non-polar compounds, such as pesticides). Secondly, there is a problem with the introduction of passive samplers into the water system (where and how) and their stability in water. Finally, their impact on the quality of the drinking water and the low reliability of the obtained results must be also considered. Drinking water samples are normally collected into plastic cans [159, 168], or into dark-glass bottles [96, 133-134]. Polar pharmaceuticals possess good solubility in water and should not
22
be adsorbed into the sides of the bottles. One exception that needs to be taken into account is the group of antibiotics. These samples should rather be collected into glass bottles and Na2EDTA will need to be added to the water as a stability agent and as an adsorption controller for these analytes [134, 169]. The collection and preservation of drinking water samples are generally the same as for other water matrices. There are only two important differences – a higher volume of the drinking water samples is needed (this will be discussed later) and there is a need to remove chlorine and other oxidation reagents. Free oxidation and chlorination reagents can decrease the concentrations of pharmaceuticals during transport and storage. An efficient way to eliminate chlorine is the addition of ascorbic acid [161] or Na2SO4 [135, 154, 158, 170]. The length of time of sampling storage is generally the same as for other water samples, but direct analysis is recommended, especially for antibiotics [169]. Some details about sampling and sample storage can be found in EPA report (2012 [171]).
4.2.4. The need for high volume extraction As concentrations of pharmaceuticals in drinking water are in the range of several ng L-1 (examples are presented in Table 2) and the average limit of detection of chromatography techniques coupled with mass spectrometry is close to 10 ng mL-1, the concentration factor (CF) during their analysis in these matrices should be high (around 1000). This means that if the extract volume is 1 mL, the sample volume should be 1000 mL. High volume extractions are typically coupled with a high matrix effect, because of the fact that some of the compounds can not be totally eliminated from the matrix and are concentrated together with the analytes. The drinking water matrix is not very complex and if appropriate extraction techniques are used (mostly solid-phase extraction, SPE), then limits of detection close to 1 ng L-1 can be achieved.
23
Water sample volumes of 1000 mL are recommended to determine pharmaceuticals in drinking water, groundwater and treated wastewater using the EPA Method 1694 (December 2007, EPA-821-R-08-002). This method has been used by several researchers [135, 143, 147, 172] and involves the extraction of 74 pharmaceuticals (in four groups) using Oasis HLB (60 mg of solid sorbent with a universal extraction properties) from various water samples with sufficient limits of detection. According to our experience – along with the manufacturers of SPE columns - the average volume of water samples which can be passed through the solid sorbent without any significant lost of extraction speed and efficiency, is in the range of 100 to 200 mL, which seems to be insufficient for the analysis of drinking water. Common SPE techniques can also be performed using speed extraction disks (speedisks), which are characterized by a fast extraction of high volume samples (80 – 90 mL min-1, up to 2 L, according to the manufacturer’s information). However, to date, speedisks have been used in the analysis of pharmaceuticals in drinking water only once [151], although they have been used in the analysis of estrogens in rivers [173-174], antibiotics in seawater [100-101] and a mixture of pharmaceuticals (19 analytes, e.g. trimethoprim, ampicillin, carbamazepine, ibuprofen) in surface and ground waters [168], reaching recoveries in the range of 49 – 110%. The observed matrix effects did not affect the results of the analysis. Nevertheless, it should be noted that the limits of detection presented in this paper were in the range of 0.15-12.46 ng L-1, which are similar to those presented in Table 2. Of course, the LOD values depend not only on the sample volume, but especially on the equipment used and the entire analytical protocol.
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4.2.5. The need for low limits of detection - GC-MS or LC-MS? The crucial need for very low limits of detection of pharmaceuticals in drinking water can be achieved only with the use of selective and sensitive equipment. This is why mass spectrometry (MS) is the preferred choice. Its advanced technology of ionization, mass analysis, detection and, essentially, data recording modes, combine to give researchers an excellent tool for the analysis of residues. Mass spectrometry is of course associated with matrix effects, but most of these effects can be removed by application of a correct sample preparation step [175]. Tandem mass spectrometry is always the preferred choice, because of the higher identification factor (more identification points [176]). The question remains of what choice of chromatographic technique will be coupled with the MS. Pharmaceuticals - being mostly polar and semi-polar - are non-volatile, therefore liquid chromatography is normally used as the most appropriate technique. The use of a derivatisation step for gas chromatography separation means this technique is both time and reagent consuming. However, recently it has been investigated and subsequently proven that appropriate derivatisation optimization can decrease the limits of detection for some pharmaceuticals [177]. This and other advantages of GC (the lower costs of equipment and analysis, the lack of liquid wastes) could mean future trends might see liquid chromatography become the preferred tool for the analysis of pharmaceuticals in water samples. This view is supported by an interlaboratory exercise which was undertaken in the case of the analysis of non-steroidal
anti-inflammatory pharmaceuticals
(examples
–
ibuprofen, naproxen,
ketoprofen) in environmental water [178]. Although it was concluded that generally both techniques could be applied successfully, the GC-MS provided better results in the case of analytes in complex matrices. The LODs of selected pharmaceuticals in water does not differ significantly between selected separation techniques. In support of this statement, a comparison of the detection limits for
25
several techniques used in the analysis of carbamazepine in drinking water is presented in Table 3. These pharmaceuticals were selected because of the fact they can be analysed using both LC and GC techniques [as trimethylsilyl derivatives [159]), and can be widely detected in drinking waters (Table 2 and [163]) as well as other water matrices [179-180]. As shown, there is no correlation between the used techniques, sample volumes and the obtained MDLs/MQLs. Therefore, the choice of technique for the analysis of residual pharmaceuticals in drinking water depends only on the laboratory staff and the possibilities. Nevertheless, in the end, all of the methods need to reach the ng L-1 limits of detections. It should also be noted that nowadays more and more methods are based on UHPLC separation (examples in Table 2 and 3) coupled with MS detection, which can achieve results for multiple analytes over very short periods of time.
4.3. Outlook Several authors have stated that the detected concentrations of pharmaceuticals in drinking waters are safe for humans [139-140, 144, 152, 183]. The same point of view has also been expressed both by the World Health Organization [184] and the U.S. Environmental Protection Agency (U.S. EPA) [185]. However, all have concluded there is a need for expanded research into the conditions of natural water and more advanced risk assessments to be made. Therefore, the long term monitoring of pharmaceuticals in drinking water is needed in order to assess how polluted this matrix is. Generally, adequate instruments and methods already exist, but if in the future the concentrations which could do harm to human health turn out to be lower than we now think, methods will need to be developed to reach lower limits of detection. In addition, the future monitoring of pharmaceuticals in drinking water samples will need to have clear definitions of reference methods as well as interlaboratory comparisons in order to certify the results that are obtained.
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5. Current approaches and challenges in the quality assurance and control in the analysis of the residues of pharmaceuticals in the environmental samples The quality and repeatability of monitoring tools used in environmental analytics cause that special care is taken in the areas of quality control and quality assurance (QC/QA). The results of the measurements must be meaningful (reliable), they must reflect accurately (simultaneously precise and true) the real content (amount) of the analytes present in the representative part of studied sample [186]. Quality control and quality assurance of the analytical results should include all stages of analytical process and what is more, be integral. A significant limitation of this action, in the case of the determination of the residues of pharmaceuticals in the environmental samples, is lack of availability of certified reference materials or reference methods. Due to that the validation of analytical methodologies apart from determining typical metrological parameters should include determination of: extraction effectiveness (EE), matrix effect (ME), absolute recovery (AR) [175] as well as estimation of expanded uncertainty. All these aspects are described in details below.
5.1. Validation procedures International Organization for Standardization defines the method validation as “confirmation through examination and provision of objective evidence that the requirements for a specified intended use or application are fulfilled” [187]. This procedure is required for new proposed analytical methods, the employment of different analysts or instrumentation, methods used in different laboratories, as well for established method revision and for demonstration of equivalence between two different methods [188-189]. The important information on the validation procedure could be found in the literature, as well as in the official guidelines, e.g. [188, 190-192]. One of them is the Commission Decision 2002/657/EC [193] implementing Council Directive 96/23/EC [194] which refers to the results of analytical methods and their
27
interpretation used for monitoring of some substances and their residues in life animals and animal products. High requirements for analytical methodologies became the reference not only for the quality control of food products but also all other analytical solutions that are being developed. According to this directive [193], to confirm the presence of a compound, 4 (group A) or 3 (group B) identification points (IP) are required depending on the group of analytes. Application of low-resolution mass spectrometers (QqQ, IT) and identification of pseudomolecular ion (precursor ion) allow to obtain 1 IP and 1.5 IP for every fragmentation ion (product ion). It means that working in MRM mode and choosing pseudomolecular ion as a precursor ion for every compound and two transitions pseudomolecular ion → fragmentation ion allows to obtain 4 IPs, what covers the requirement [193]. Very interesting information on drug confirmation by mass spectrometry coupled with chromatography, identification criteria and complicating factor, is presented by Yuan et al. [195]. Factors affecting the result quality and correct results interpretation are discussed and several emerging technologies and their potential applications are briefly explored. It should be also noticed that the official guidelines do not present a validation experiment sequence because the optimal sequence may depend on the method itself and the application [189]. Usually it involves the determination of the following validation parameters: i.
Selectivity
ii.
Linearity and range
iii.
Precision (repeatability and intermediate precision)
iv.
Accuracy
v.
Method Detection Limit
vi.
Method Quantitation Limit
vii.
Robustness/ruggedness
viii.
Stability [192].
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A practical approach in the planning of validation procedures in quantitative highperformance liquid chromatographic methods in pharmaceutical analysis has been presented by Bonfilio et al. in 2012 [196]. Relevant approaches of various parameters have been discussed and supported by the presentation of the several up-to-date examples. This information could be very useful as an introduction to analytical validation for practical applications [196]. It should be also noticed that determination of the validation parameters is mandatory while a transfer of analytical methodologies from one technique to another is planned, because the sample preparation stage can differently influence the quality of final determination. Additionally, the rules of System Suitability Test (SST) for developed and validated methodologies planned to use for routine analyses should be established in order to confirm their quality during their usage.
5.2. Quality assurance vs matrix effect and recovery All analytical approaches for the analysis of pharmaceutical residues in the environment use the mass spectrometry detection. Although the MS is a powerful tool for a residues analysis, because of its sensitivity and selectivity when the SIM or MRM mode of ions detection is used, it is fraught with a phenomenon called matrix effect (ME). The effect of matrix components on electrospray ionization in LC–MS has been described by Kebarle and Tang in 1993 for the first time [197]. The mechanism is still not fully understood [198], but one of the most probable reasons is competition between an analyte and a co-eluting matrix component during ionization [199], what cause a decrease in analyte ionization (ion suppression) or an increase in this ionization (ion enhancement). Both of these effects bring errors in final results. The ME depends on the type of ion source used during the analysis; and the electrospray (ESI) is the most sensitive not only to matrix components, but also to the eluent
29
composition, especially salts [200]. The atmospheric pressure ionization (APCI) is less sensitive to ME, because the ionization of molecules takes place in the gas phase, almost without the eluent components [198]. The possibility of co-elution of analytes and interferents in LC-MS is high, thereby ME need to be taken into account as one of the important factors for a protocol development. In the case of GC-MS, the nature of ME is different. Electron impact ionization (EI) is not affected from an injected sample composition, firstly because the ionization occur in a gas phase for separated molecules, secondly - the resolution of column is greater. This however does not mean that the GC-MS has no matrix effect. The detailed studies confirmed that the ME in the GC-MS techniques is related with a separation technique [187]. The accumulation of non-volatile matrix as well as products of its pyrolysis in the GC system may generate new active sites, what results in analytes adsorption, problem with peak shape and intensity, and finally lack of long-term repeatability [201]. The opposite effect, known as ‘matrix induced chromatographic response enhancement’ was also observed, mainly for pesticides [202]. Although the sample preparation step eliminates most of the matrix, the interferents can not be completly eliminated and ME is observed in both LC-MS and GC-MS analysis. One of the approaches during the optimization of extraction procedure is the evaluation of ME and finding the protocol with the lowest MEs. The measurement of matrix effect is relatively easy, but it increases the cost of whole procedure. Nevertheless, it is essential to measure the ME during the complex matrix analysis, like environmental samples, and what is even more important during trace analysis. The ME have an impact on the final result of pharmaceutical concentration, so the efficiency of the whole analytical procol. It should albo be pointed out that extraction process have a non-total efficiency. So the question is how to differentiate the effect of matrix and an extraction into whole analytical protocol. The matrix effect in LC–MS analysis was first assessed by Matuszewski et al. [203], who used very simple equations (1)–
30
(3) to determine the matrix effect (ME), recovery of extraction (RE) and overall process efficiency (PE): ME (%) = B/A × 100
(1)
RE (%) = C/B × 100
(2)
PE (%) = C/A × 100 = (ME × RE)/ 100
(3)
in which A is the peak area of the analyte(s) recorded for the standard solution, B is the peak area of the analyte(s) recorded for the sample spiked with the target compound(s) after extraction, and C is the peak area of the analyte(s) recorded for the sample spiked with the target compound(s) before extraction. This approach is very simple and diverse the ME and extraction efficiency, but also accumulate these two factors into one PE. Similar protocol for GC-MS technique was described in our previous paper [187]. where RE was described as extraction efficiency (EE), and PE as a absolute recovery (AR). Both approaches should be used not only for the analysis of pharmaceuticals in environmental samples but whenever complex sample is analyzed. Determination of ME in analytical methods based on the application of both LC–MS and GC– MS techniques yields information not only on the quality of sample preparation and purification, but what is more important it enables false-negative/false-positive results and incorrect analyte concentrations in sample to be avoided. Additionally, GC-MS seems to be less sensitive to the ME [187]. In the Table 4 examples of EE, ME and AR obtained for a selected analytes analyzed in different water samples are presented. Nevertheless, direct comparison of a ME, EE and AR values can not be performed, because the values were obtained for different methodologies (sample volume, extraction cartridges, range of concentration, etc.). One of the ways to eliminate the influence of matrix effect onto results (but not in a analytical process) is the usage of matrix-matched calibration, when the calibration curve is performed
31
by adding of analyte directly to the tested sample [168]. This approach need a matrix free form analytes (unfortunately lack of reference material in this case) and repetition of calibration every time when the sample matrix is changed, so it is labor-intensive and expensive, but gives the most reliable results. Other technique is the usage of isotopically labeled surrogate standards to compensate losses during extraction and impact matrix effects [205-206]. The best way of ME elimination is better sample preparation (both GC-MS and LC-MS), optimization of ion source parameters and mobile phase composition (LC-MS) and maintaining the analytical equipment in clear conditions (GC-MS). There is also other ways to avoid ME [187], but no universal protocol of its estimation. Nevertheless, the matrix effect is very important parameter of a quality assurance.
5.3. Assessment of expanded uncertainty Sample preparation procedures are multistep procedures, which involve many problems associated with the reliable quantification of the analyzed compounds. Moreover, as highlighted by Konieczka and Namieśnik [207], there is no such thing as an ‘errorless measurement’, which means that every analytical result is inseparably associated with the term ‘error of measurement’. In consequence, it means that the final results may be affected by a large error and do not reflect real concentrations of pharmaceutical residues in the environmental samples [100, 186]. Therefore, the uncertainty of the result of a determination must be calculated and accompany its presentation. Moreover it is a requirement of the ISO 17025:2005 standard [208]. Furthermore the expanded uncertainty budget allows to a detailed analysis of uncertainty sources and can highlight sensitive steps of the analytical method. Hence it is a powerful tool for optimizing sample preparation procedure [100, 158, 207]. Measurement is a process in which a set of steps is performed to determine the value of a quantity. Therefore for the correct estimation of uncertainty the sources and types of uncertainty for all these steps must be established. For this purpose, the most helpful tools are
32
a flow diagram, drawn on the basis of information presented in detail in a standard operating procedure, and an Ishikawa or fishbone diagram, which shows the influence of parameters (sources of uncertainty) on the total analytical procedure [186]. Moreover, the expanded uncertainty of the obtained data can be estimated according to the Guide to the Expression of Uncertainty in Measurement [209] or EURACHEM/CITAC guide [210]. Those Guides provide general rules for evaluating and expressing uncertainty in measurement that can be followed. Unfortunately, there are only a few original papers where the authors have estimated the expanded uncertainty of the analytical procedures [e. g 211-214]. Moreover, so far only seven papers have dealt with the estimation of expanded uncertainty of the methods for determining pharmaceuticals in environmental samples [158, 100-101, 215-218]. As it was mentioned before – the uncertainty estimation should be an essential component of the set of analytical results. It is essential to perform a meaningful assessment of environmental hazards. Therefore, the focus has to be intensified on this field, as the presentation of measurements together with their uncertainties is still a problem.
6. Implementation of Green Analytical Chemistry (GAC) in the analysis of pharmaceuticals in the environmental samples Growing ecological awareness led to the conclusion that taking care of the environment is becoming one of significant priorities of modern civilization development. Increase of demand for different products and goods necessary for living is connected with the necessity of development of low-waste technologies as well as ones with closed circulation of technological media and recirculation of wastes and side products. Because of this fact a lot of environmental actions has been undertaken for many years including introduction of 12 rules of Green Chemistry into chemistry and chemical technology in 1998 [219]. This term is inextricably connected with the spread of sustainable development rules and the trend of their
33
introduction into chemical factories, quality control points as well analytical laboratories. Actions such as prevention, resources saving, limit of the use of dangerous compounds, use of safe solvents and reagents, effective use of energy, limit of derivatization processes and others are included in the set of the mentioned rules [219]. In analytical practice a large number of analytical methods and techniques is applied and the number of measurements rises rapidly trying to ensure the possibility of trace and ultra-trace measurements. Thus, the development of green chemistry will be almost not possible without introduction those rules into analytical activity. Four parameters can decide about “green” character of analytical chemistry: (i) elimination (or at least limit of use) of chemical reagents especially organic solvents from analytical procedure; (ii) minimalize the labour and energy intensity of analytical procedure (per one analyte); (iii) minimize the use of high toxic and eco-toxic reagents from the analytical procedure; (iii) possibility of measurement of wide range of analytes in one analytical run [220-221]. It is worth to mention that presented environmental advantages are connected with economical advantages what causes their implementation attractiveness. The term of Green Analytical Chemistry (GAC) was introduced to chemical terminology in 2000 [221]. Available data suggests that the impact of different analytical methods and techniques on the environment is more often evaluated by the same ways as applied in the evaluation of impact of technological processes and manufacture techniques (e.g. Life Cycle Assessment, LCA). In such assessment not only amount of reagents and energy used during whole analytic process but also the cost and environmental damage connected with manufacture of reagents and solvents and utilization and hazardous waste management after analysis are taken into account. Basing on what has just been explained and on literature data it can be concluded
34
that the groups of analytical methods and techniques which utilize GAC rules develop extremely intensively [222]. The demand for more precise and stricter quality assessment of not only environmental, but also biomedical, clinical, agricultural or food measurements necessitates conducting research on two stages: (i) seeking for so called environmental friendly analytical methodologies which characterize the lack or low emission to the environment; (ii) determination of wide spectrum of analytes at getting lower concentrations in different matrices [220-222]. That is why an effort of many analysts concentrates on developing of new, more effective analytical procedures for determination of target compounds in either liquid or solid samples, or improvement of existing ones. It is possible thanks to introduction of new generation high sensitivity measuring instruments to analytical practice or by developing new procedures/ sample preparation technologies before final determination. This particular action is going to be of significant importance in chemical analysis for controlmeasurement needs. Nowadays, as it was already highlighted, methods based on high-performance liquid chromatography (HPLC) are the basic analytical tool in pharmaceutical analytics in environmental samples [223-225]. However, for several years ultra-high-performance liquid chromatographs have been introduced into analytical market. These devices are competitive to traditional high-performance liquid chromatographs. In modern UHPLC systems a lot of improvements were applied, starting from construction of pumps, injectors as well detectors where the volume of measurement cells was lowered and the sample throughput was increased. All modifications were designed to reduction of void volume of the system and preparing for work under several times higher pressures comparing to standard HPLC system. Introduction of such changes allowed to shorten analysis time and significantly increase of
35
sensitivity and resolution. It is worth noticing that the shorter time of analysis substantially reduces the cost of analysis, through more effective use of equipment and lower use of solvents. Shortened time of equilibration also supports mentioned advantages. It is so because void volume of the whole system was lowered from ca. 1-2 ml to ca. 120 μl. It is extremely important because shorter analysis time, less amount of solvents used and generation of smaller amount of wastes make this technique more environmentally friendly and economically efficient (reducing the cost of waste disposal) [226-228]. For example, when using a traditional column with 5 μm particle sizes, 4.6 mm of diameter and 150 mm of length at the flow of 1 mL/min, and time of analysis of 17 min, the usage of mobile phase equals 17 mL/analysis. After transfer of this method to UHPLC system the analysis time is reduced to 2.15 min, whereas the consumption of mobile phase is 1.18 mL/analysis, which gives almost 8 times saving of analysis time and 14 times lower usage of solvents. It also must be stressed that cost of UHPLC system is slightly higher comparing to classical HPLC system. Despite many advantages UHPLC technique slowly enter economical market, mainly remaining in the interest of scientific research area. It is due to the need of tedious and difficult transfer of analytical methods from conventional systems to ultra-high-performance ones. The fundamental relationship between the physical dimensions of a chromatographic column and the performance of separations performed using it are well known. Of these, perhaps the most critical to understanding the implications of transfer between HPLC and UHPLC are the relationship between column length, van Deemter equation considerations, pressure drop effect as well as extra column void volume effects. Taking above into account one could state that the theoretical relationships that govern the scaling of methods from HPLC to UHPLC conditions are from one side established but provide only a start up framework for the adjustment of chromatographic parameters. Any theoretical predictions are greatly imperfect. This is because of affecting the system by additional factors that are functions not only of the
36
above effects but also injection volumes, flow rates, gradient time and finally frictional heating, negligible in classical HPLC but having dramatic negative consequence for UHPLC performance, if not adequately addressed. For these reasons developed commercial calculators, algorithms and formulas for HPLC – UHPLC transfers shall always be adopted with an assistance of thorough experimental verification. Benefits of utilizing UHPLC methodologies are obvious. Application of thereof fit 4 rules of ‘green chemistry’ not only by limitation of solvent use and smaller wastes generation but also by decrease of time and energy consumption during analytical procedure. Additionally high resolution allows to develop of methods for measuring wide spectrum of compounds in one chromatographic run [i.e. 226-228]. The UHPLC technique is highly recommended for routine analyses of polar compounds, including biological activate substances such as: pharmaceuticals. However, as it was highlighted in the previous sections liquid chromatography in reverse phase coupled with mass spectrometry (LC-MS) or tandem mass spectrometry (LC-MS/MS) is still the most commonly used in analyses of these compounds. This technique ensures the high sensitivity and selectivity simultaneously allowing measurements of diverse structure compounds regardless of their polarity and thermolability. Gas chromatography coupled with mass spectrometry (GC-MS, GC-MS/MS) is also widely used for this purpose. Although ultra-high-performance liquid chromatography (UHPLC) has joined the routine HPLC in determination of pharmaceutical residues in environmental samples the number of its applications is still very low [104,118, 226, 229-232]. It proved to be useful i.e. 18 drugs from androgenes and progestagens groups in environmental samples [229], as well 74 pharmaceuticals and 84 pesticides and pharmaceuticals at times of < 10 min [230-231]. Furthermore Gros et al. presented the methodology for determining 54 antibiotics and their metabolites in environmental water samples at the analysis time shorter than 2.5 min [232].
37
However, the range of so far developed procedures is staggeringly modest both in terms of the diversity of analysed compounds and complexity of investigated matrices. Nowadays, a special attention is also paid to sample preparation procedures, which ensure not only the reduction of organic solvent consumption or their total elimination, but also decrease the number of steps and processes involved in the sample preparation stage. Because of these reasons in the last few years there was a rapid development of non-solvent sample preparation techniques, the use of agents which support extraction process (UV radiation, microwave radiation, ultrasonic, higher temperature) implementation of automated and miniaturized set designed for sample preparation, simultaneously ensuring high efficiency and economy [220222]. However, continuously the majority of work connected with sample preparation is done manually. That is why automation of analytical techniques allows to reduce the labour and energy intensity required in analytical procedures and further elimination of the human factor. Up till now, as it was presented in the previous sections, the most common technique of isolation and enriching of pharmaceuticals from different environmental matrices is solid phase extraction (SPE) [i.e.233-234]. This technique is very popular because of wide range of sorbents, high efficiency and small usage of solvents. Conducted research has confirmed that it allows selective isolation even small amounts of these compounds (ng level) from very complex matrices. It is also widely used in purification of solid sample extracts. Despite of many innovation that have been introduced mainly in the different shapes and dimensions of columns, forms of solid sorbent (i.e. fiber, extraction disc), the classical SPE columns are being the most frequently used in extraction of drug residues from liquid samples [235]. While extraction of residues of pharmaceuticals from solid matrices is more complicated as it was already highlighted, it is usually accomplished by the following techniques in solid-liquid system: i) shaking; ii) accelerated solvent extraction (ASE) or pressurized liquid extraction (PLE), ultrasonic solvent extraction (USE); or microwave assisted extraction (MAE) [i.e.
38
235]. The review papers presenting the application of these techniques as “green” techniques in sample preparation step for the analysis of different organic compounds (including pharmaceuticals) in environmental samples have been recently published [236-241].
7. Application of CNTs in sample preparation techniques to overcome selected problems in the determination of pharmaceuticals in environmental samples The efforts of many analysts have been focused on developing new, low-cost and effective analytical procedures or improving existing ones. Due to the low levels of pollutants in the environment, particular attention has been paid to investigating sample preparation, which can successfully isolate and concentrate a wide range of analytes. Efforts have also been focused on reducing the amount of liquid solvents or providing their complete elimination in the course of the analytical procedure, as well as minimizing the number of operations used in sample preparation, thereby reducing the time and cost of the whole procedure. One of the hot topics of research in recent years has been the use of carbon nanostructures as a sorbent in extraction techniques.
7.1. General characteristics of carbon nanotubes (CNTs) A wide range of carbon materials are available for use in analytical chemistry. Only a few studies describe the use of nanodiamonds, nano-onions, nanofibers, nanotubules, and nanorings, whereas recent applications have been primarily focused on the use of fullerenes and nanotubes (CNTs) [242-248]. In both cases, the basic structure is composed of a layer of sp2 bonded carbon atoms, wherein each atom is bonded to three other carbon atoms [249]. CNTs have a regular and symmetrical structure which resembles graphene, however, they have a cylindrical shape with a diameter of several tens of nanometers, and a length of micrometers [249]. Depending on the number of graphene layers, CNTs can be divided into
39
single-walled carbon nanotubes (SWCNTs) and multi-walled carbon nanotubes (MWCNTs). The design, synthesis, characteristics, and applications of nanomaterials are the most critical aspects in this emerging field of nanomaterials. Moreover, CNTs may be functionalized with various chemical groups to enhance their affinity for target compounds. This means the possibility of selective extraction of target analytes in both environmental and biological samples [250-252]. CNT can be functionalized in two ways: non-covalently and covalently. Non-covalent functionalization involves the physical adsorption of molecules onto the CNT side walls by Van der Waals interactions, π…π interactions, hydrogen bonding, electrostatic and hydrophobic interactions [251-252]. Covalent modification involves the formation of a bond between the functional groups and the skeleton of the carbon nanotubes. This type of functionalization can be carried out directly or indirectly. As a result of direct covalent functionalization, the hybridization of the carbon atom changes. In contrast, indirect functionalization takes place through the functional groups at the open ends of CNTs and the defects of the carbon sheet. The functional groups (for example: hydroxyl, carboxyl, or a carbonyl group) are introduced by heating the CNT under strong chemical conditions such as HNO3, H2SO4, and HCl, or other oxidants, such as H2O2, O3, KMnO4, and NaOCl. The carboxyl group is then converted to the acyl chloride and can undergo esterification or amidation [250].
7.2. Application of CNTs in sample preparation techniques The unique and tunable physicochemical properties of CNTs allows the development of new or improved analytical procedures compared to those that presently exist. Based on the results presented in recently published review papers, it can be concluded that the main advantages of using CNTs in sample preparation steps are as follows: (i) using CNTs in sample preparation, generally helps simplify this step;
40
(ii) their high surface-volume ratio and resulting high adsorption capability allows higher extraction efficiency and lower LODs values to be achieved than with using conventional sorbents; (iii) the physicochemical properties of CNTs can be controlled with functionalization which can ensure the flexibility needed for use in many analytical applications; (iv) their high adsorption capability enables the use of small amounts of a sorbent, which is a step towards miniaturization, and thus reduces the volume of solvents used; (v) they allow the extraction of small volume samples and samples > 1 L, without exceeding the breakthrough volume; (vi) CNTs can be very easily regenerated (chemically or thermally), and re-used without reducing extraction efficiency; (vii) many authors have reported that the consequences of all of these aspects will mean a reduction in the cost and time of sample preparation [242-248, 253-254]. All of these aspects are crucial in the improvement of existing sample preparation procedures used in the analysis of residues of pharmaceuticals in environmental samples. That is why for the last few years, CNTs have also been tested as potential adsorbents in sample preparation techniques used to extract these chemicals not only from environmental matrices but also others (such as food). This is additional proof of their wide applicability and will be discussed below. 7.2.1. Solid phase extraction At first, studies which compared the enrichment efficiency of CNTs with conventional sorbents such as C18, Oasis HLB, PS-DVB, XAD-2 or activated carbon were conducted. Cai et al. proposed the use of carbon nanotubes for enrichment endocrine disruptors [254]. A simple and quick method using MWCNTs (with a 30-60 nm outer diameter) has been developed for use in the isolation of three endocrine disruptors (bisphenol A, 4-n-nonylphenol
41
and 4-tert-octylphenol) from tap water, river, sea and wastewater. After evaluating the effects of various parameters on extraction efficiency, comparative studies with C18, XAD-2 and PS-DVB copolymers using the same parameters as MWCNTs were carried out. The results indicated that the MWCNTs were at least as effective as the C18 in the isolation of 4-nnonylphenol and 4-tert-octylphenol, but they were more effective than the C18 in the case of bisphenol A. The authors also demonstrated the better extraction ability of all three analytes with MWCNTs against the PS-DVB copolymer and XAD-2. It is also worth noting that the developed method allows the enrichment of up to 1 L of water, without exceeding the breakthrough volume. This fact, together with the small volume of eluent (2.5 ml methanol), allows the isolation of target compounds at concentrations as low as 0.018 ng mL-1. Research also worth mentioning is the work of Niu et al. [256], which presented a comparison of MWCNTs, SWCNTs, C18, and graphitized carbon black for the extraction of cephalosporins, sulfonamides, and phenolic compounds. Comparative studies have shown that the extraction yield is higher with the use of carbon nanotubes than for C18 in the extraction of highly polar analytes. For cephalosporins and sulfonamides, CNTs have shown an even higher sorption capability than graphitized carbon black. However, for some phenolic compounds, a higher extraction efficiency was achieved using graphitized carbon black, which suggests different mechanisms exist for the retention of these analytes. Finally, an extraction method was developed for sulfonamides as model compounds. Compounds containing amino or hydroxyl groups are more difficult to desorb, therefore the analytical procedures using these compounds needed to be optimized. Satisfactory recoveries (80-100%) of the analytes were obtained using a mixture of aqueous ammonium acetate(0.3 M): methanol (30:70, v/v). An SPE-GC-MS method, using MWCNTs for the determination of diazepam, estazolam, triazolam and alprazolam was described by Wang et al. [257] Under optimal conditions, recoveries were obtained of between 75 and 104% with LOD in the range of 2-5 µg kg-1. The
42
absorption capability of the MWCNTs against C18 under the same conditions was established using diazepam as a model compound. It was found that the MWCNTs are more effective in the extraction of diazepam than C18 and therefore less sorbent can be used. On the other hand, the extraction efficiency of MWCNTs and C18 in the enrichment of three barbiturates (e.g. barbital, amobarbital, and phenobarbital) was compared by Zhao et al. [258]. The results indicated that SPE cartridges packed with MWCNTs had a similar extraction capability as C18 in the cases of barbital and amobarbital, while the use of MWCNTs produced a higher extraction efficiency than C18 for phenobarbital. In addition to these results, an interesting investigation was reported by Polo-Luque et al. [259]. These authors describe the preparation of two hybrid materials MWCNTs/SWCNT-C18 with an ionic liquid HMIM PF6. These two hybrid materials were used for the extraction of sulfonamides from milk samples. The results indicated that extraction efficiency was higher using MWCNTs/C18 than for the SWCNTs/C18 or conventional C18. The limit of detection ranged from 0.069 to 0.030 mg L1
. The usefulness of MWCNTs as a sorbent in SPE for the isolation of some of the most
commonly consumed drugs, including four β-blockers and eight NSAIDs, from river and wastewater samples was examined by Dahane et al. [260]. Just 20 mg of carbon nanotubes was enough to pre-concentrate the analytes and 7 mL of methanol modified with 10% ammonium hydroxide allowed the complete elution of all of the pharmaceuticals from the MWCNTs sorbent. The authors compared the parameters of the developed method with the literature data. The recoveries obtained using MWCNTs for all of the analytes were the same as for conventional SPE sorbents such as Oasis HLB and Oasis MCX [261]. However, the MDLs values were lower than with the MWCNTs. In addition, one of the main benefits of the MWCNTs was the absence of a matrix effect for all the pharmaceuticals studied in river water and in wastewaters. The authors also emphasized that the price of the MWCNTs cartridge was 30% lower when compared to the Oasis HLB cartridge. Furthermore, a MWCNTs
43
cartridge can be re-used up to 10 times, after washing with 5 mL of methanol, whereas traditional cartridges are usually discarded. The MWCNTs SPE-HPLC-UV method was also applied in the isolation of nine antidepressants (e.g., imipramine, desipramine, amitriptyline, nortriptyline, clomipramine, trimipramine, trazodone, fluoxetine, and mianserin) from urine samples [262]. Studies have shown that 30 mg of MWCNTs was enough for the quantitative extraction of all of the analytes at therapeutic and toxic levels. The value of the recoveries ranged from 72 to 97%. The results of this study also showed the absence of matrix effects from the endogenous sample components and other drugs that may be present in the urine samples. This method is therefore suitable for the therapeutic monitoring of antidepressants in urine. 7.2.2. Dispersive solid phase extraction In standard mode, SPE sample loading is usually a time-consuming process (especially for large sample volumes), due to the limited speed and mass diffusion of the analytes in the sorbent mass packed in the cartridge. For example, at least 100 mins were required to load the sample 1 L of water in the SPE method [263]. In addition, solid particles commonly found in samples of food may cause clogging of the cartridge and can lead to failure of the extraction. Dispersive solid phase extraction can significantly reduce the amount of sample preparation time in comparison with conventional SPE, due to the fact that the sorbent is efficiently dispersed in the sample matrix instead of passing slowly via an extraction column. Therefore, the extraction time is better, because it avoids the time-consuming step of passing the solution through the column. Because of this, many researchers have applied this method of extraction using CNTs as a sorbent [264-276]. Oxidized multiwall carbon nanotubes (O-MWCNTs) were applied to the isolation method of eleven quinolone antibiotics (moxifloxacin, lomefloxacin, danofloxacin, ciprofloxacin, levofloxacin, marbofloxacin, enrofloxacin, difloxacin, pefloxacin, oxolinic acid and flumequine) from different water samples. The
44
recovery values for all of the analytes were in the range of 77.8-116% in Milli-Q, 73.5-108% in mineral water, 67.1-103% in tap water, 62.3-97.0% in wastewater, whereas the LODs were in the range of 28-75 ng L-1 in Milli-Q, 30-79 ng L-1 in mineral water 31- 87 ng L-1 in tap water and 31-94 ng L-1 in wastewater. These values are similar to those achieved with conventional SPE cartridges. However, this dSPE procedure is highly selective and can be easily applied to different matrices of water. [267]. The authors of this study also concluded that dispersion of the CNTs is very important due to the fact that the extraction yield directly depends on the area of contact between the sample and the extractant phase. In addition to the chemical modifications of the surface of the CNTs [266-268, 274], other methods for the disaggregation of CNTs, including non-covalent modification [275-276], or the addition of external energy (for example, ultrasound) have been described [277]. A method using MWCNTs as a sorbent in dSPE with ultrasound-assisted adsorption and desorption was developed for the isolation of estrogens from water samples [277]. By optimizing the extraction procedure, it has been shown that just 10 mg of CNTs is the optimum amount for an effective extraction of analytes. Of all the tested solvents, the best recovery values were obtained using 1.25 mL of acetone as the desorption solvent. Under optimized conditions, the recoveries for three analytes in spiked samples were over 82%. The detection limits were 0.076 ng mL-1 for estrone, 0.049 ng mL-1, for 17β-estradiol, and 0.057 ng mL-1 for estriol. The usefulness of CNTs as sorbents in dSPE for the isolation of pharmaceuticals has also been confirmed by other authors [264, 266, 278-281]. The recovery values were higher or comparable to those obtained using classical sorbents, however the amount of CNTs used was significantly lower. For example, a simple and inexpensive dSPE procedure for 10 β-2agonists (clenbuterol, ractopamine, salbutamol, bambuterol, penbuterol, tulobuterol, clorprenaline, mabuterol, cimaterol and terbutaline) in urine with MWCNTs as a sorbent was developed [266]. Recoveries of the target compounds from urine samples at pH 10.0 were
45
most efficient using 20 mg of MWCNTs, whilst a mixture of water:methanol (90:10, v/v) with 0.5% formic acid was shown to be the most suitable solvent for the desorption of the compounds from the MWCNTs. A simple and cost-effective pre-treatment procedure for the isolation of 18 sulfonamides from pork extracts using dSPE with MWCNTs was developed by Hou et al. [264]. The recoveries of the target compounds from the pork extracts were most effective when 150 mg of MWCNTs was used. Optimization of the extraction time was also done, whereby it was observed that increasing the time of extraction to over 2 minutes did not bring a significant improvement in the recovery values. Acetonitrile:50 mM ammonium acetate (95:5, v/v) was found to be the most suitable solvent mixture for the desorption of the compounds from the MWCNTs (recoveries > 90% for 14 sulfonamides). A new variant of dSPE, which has attracted a lot of attention in sample preparation, is magnetic solid phase extraction (mSPE) [278-281]. Typically, the adsorbent material is composed of a magnetic core (ie Fe3O4) and nanoparticles to extract various analytes. Adsorbents containing the retained analytes can easily be isolated from the solution by applying an external magnetic field after extraction. All of these advantages make mSPE a promising sample preparation technique in the extraction of many organic compounds including pharmaceuticals. Magnetic silica particles coated with MWCNTs-OH have been used for the convenient, rapid and efficient extraction of several estrogens (including diethylstilbestrol, estrone and estriol) from water [280] or milk samples [281]. In turn, molecularly imprinted magnetic carbon nanotube (MIPs/mCNTs) sorbent was used for the selective extraction of levofloxacin from serum samples [283]. Under optimal extraction conditions, recoveries ranged from 78.7 ± 4.8% to 83.4 ± 4.1%. The stability of the MIPs/mCNTs polymer was also evaluated, and the average recovery reduced by less than 7.6% after 5 cycles. Molecularly imprinted polymer-coated m-CNTs were also used as a selective sorbent in SPE for the isolation of naproxen from human urine samples [283]. All of
46
the aspects affecting the adsorption and desorption of the analyte at the MIPs/mCNTs were investigated. 7.2.3. Miniaturized devices for pharmaceuticals isolation It is worth noting that the introduction of CNTs during sample preparation helps to simplify this step and allows the miniaturization of devices. Fang et al. have developed a method for the simultaneous extraction and the determination of 10 sulfonamides in extracts of eggs and pork [284]. A MWCNTs column was used instead of a conventional sample loop in the sixport injector valve of the HPLC. This approach significantly reduced the sample pretreatment steps as well as the amount of chemical waste and analysis time (35 min.). In another example, as little as 6 mg of MWCNTs were packed in the mini-column and used in the isolation and determination of tetracyclines in water. Enrichment of the analytes was carried out using the online flow injection system connected to the CE-MS equipment. The MWCNTs showed greater extraction capabilities than the other two types of SWCNTs. Recoveries for all of the analytes ranged from 98.6 to 103.2%. The same approach was also used in the extraction and analysis of non-steroidal anti-inflammatory drugs (e.g., tolmetin, ketoprofen, and indomethacin) in urine. In this case, a high extraction efficiency was achieved using SWCNTs modified with COOH groups [285]. In order to extend the life of the COOHSWCNT - and to avoid problems associated with pressure due to the compactness of the minicolumn - the COOH-SWCNTs were chemically immobilized using a controlled porous glass. The coupling of the CNT on previously activated glass was achieved by leaving the glass for 5 hrs in contact with the COOH-SWCNTs and dimethylformamide containing 1,3dicyclohexylcarbodiimide. The high extraction capability was the result of the particular orientation of the immobilized COOH-SWCNTs. The developed method was used to analyze non-steroidal anti-inflammatory drugs in urine samples using CE-MS, which allowed the detection of compounds in concentrations of 1.6-2.6 µg L-1 for all of the analytes with only 5
47
ml of sample. The value of the recoveries ranged from 98.6% to 102.2%. A different approach to the miniaturization of conventional SPE was proposed by Bhadra et al. [286]. The proposed μ-SPE device consisted of a syringe with a replaceable needle containing the CNTs. The usefulness of functionalized or non-functionalized CNTs (0.3 mg) was tested in the isolation
of
five
different
pharmaceutical
compounds:
ibuprofen,
acetaminophen,
ciprofloxacin, fenofibrate, and sulfadiazine from water samples. It was demonstrated that the enrichment factor obtained using functionalized MWCNTs was significantly higher than that achieved using C18 under similar conditions. Another way to miniaturize the CNTs-SPE device was proposed by Springer et al. [287]. In this case, the classic SPE column was replaced by a 1000 µl pipette tip into which the CNTs were introduced. The prepared pipette was applied in th extraction of fluoroquinolones from milk samples.
A very simple analytical procedure was developed, involving protein
precipitation, followed by the SPE step with 5 mg of MWCNTs as a sorbent material and a mixture of methanol:formic acid (98:2, v:v) as the eluent. Under optimal SPE conditions recoveries for all of the analytes were between 84 and 106% whereas the LODs values were between 7.5 and 11.6 µg L-1.
7.2. Outlook In conclusion, the advantages of using CNTs as sorbents in extraction techniques are uncontested. Nevertheless, to date, commercial cartridges with CNTs are not available. The reason for this may be because there has been an insufficient work in this field, their full potential in analytical chemistry has still yet to be well-documented. Further studies to determine the usefulness of CNTs and their applicability are still being carried out, which could lead to the commercialization of CNTs as sorbents in techniques of extraction.
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However, before CNTs can enter into commercial use, any potential risks associated with their presence in the environment will need to be defined.
8. Conclusions Various differing analytical aspects and current challenges in the analysis of residues of pharmaceuticals in soil, marine ecosystems as well as in drinking waters have been presented. There are still many different outstanding problems in relation to this topic, and there is a need for future research, mainly focused on: The fact that knowledge about the determination of the occurrence and fate of residues of pharmaceuticals in soil and marine ecosystems is still limited. There is also an urgent need for the development of reliable, fast and simple methods for their determination in such matrices, which will enable the detection of pharmaceuticals at very low levels of concentration (especially crucial in the analysis of marine waters). Further investigations into more sensitive and selective extraction methods are also necessary to overcome the problem of the strong matrix effects associated with the extraction of high volumes of samples (in the case of marine waters) as well as the complexity of the investigated matrices (such as soils and sediments). The need for multi-analyte methods that will reach lower detection limits and will be easy to apply in routine analysis. The introduction of standard guidelines explaining how, when and where samples should be collected in order to determine concentrations of pharmaceuticals. The implementation of reference methods for the determination of these chemicals in different matrices. This aspect - as well as the one mentioned above - will enable the comparison of obtained results between different laboratories/countries, etc. and the
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establishment of maximal concentrations of these substances in different environmental compartments. The fact that QC/QA of analytical results should include all stages of analytical process and what is more be integral part of it. It should include not only standard validation of the analytical method but also the determination of matrix effects (ME) as well as expanded uncertainty. This is due to the fact that ME is very important parameter in QA as it enables false-negative/false-positive results and incorrect analyte concentration in sample to be avoided. Furthermore, sample preparation is a multistep procedure, which involves many problems associated with reliable quantification of the analyzed compounds. Hence final results may be affected by a large error and do not reflect real concentration of pharmaceutical residues in environmental samples. Therefore, uncertainty estimation should be an essential component of the set of analytical results. The focus has to be intensified on this field. The further implementation of GAC rules into the analysis of pharmaceuticals in the environmental samples mainly in terms of the application of on-line coupling, automatic and semi-automatic procedures, the development of multi-analyte techniques such as UHPLC, GC-GC or LC-LC as well as application of new and more selective sorbents for sample preparation techniques. The application of modern sorbents such as carbon nanotubes in different sample preparation techniques. The use of these very promising sorbents could overcome some of the discussed analytical problems in the determination of pharmaceuticals in different matrices and could assist in the growing need to develop new, low-cost and effective analytical procedures or improve existing ones. Due to the low concentration levels of these pollutants in environmental samples, particular attention should be paid to sample preparation steps to isolate and concentrate a wide range of analytes as well
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as to reduce the amount of liquid solvents or their complete elimination in the course of analytical procedures. The minimization of the number of operations used in sample preparation will thereby reduce the time and cost of the whole procedure. The unique properties of CNTs, such as for example their high surface-volume ratio and thus, their high adsorption capability allows higher extraction efficiencies to be achieved and lower LODs values than with using conventional sorbents. Their tunable physicochemical properties can also ensure the necessary flexibility necessary for their use in many analytical applications. Other unique properties of CNTs include their high adsorption capability which enables the use of small amounts of sorbent (necessary for the miniaturization and the reduction in the volume of solvent used), the possibility to extract small volume samples and samples > 1 L, without exceeding the breakthrough volume, their regenerability and reusability without reducing extraction efficiency [242-248, 253-254]. All of these properties prove their high applicability and the possibility to improve or develop new analytical protocols for the analysis of residues of pharmaceuticals in order to assess their environmental fate. However, for this reason further research is necessary.
Acknowledgments Financial support was provided by the Polish National Science Centre under grants DEC2011/03/B/NZ8/03009 and DEC-2011/03/B/NZ8/03010 and National Centre for Research and Development (NCBR) (Poland) under grant TANGO1/268806/NCBR/2015 as well as by the Polish Ministry of Research and Higher Education under grant DS 530-8616-D593-15.
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[277] Zhu H., Chen W., Li Z., He J., Tang X., Wang C., 2014. Extraction of natural estrogens in environmental waters by dispersive multiwalled carbon nanotubebased agitation-assisted adsorption and ultrasound-assisted desorption. Anal. Methods. 6, 1235–1241. [278] Zhang M., Wei F., Zhang Y.F., Nie J., Feng Y.Q., 2006. Novel polymer monolith microextraction using a poly(methacrylic acid-ethylene glycol dimethacrylate) monolith and its application to simultaneous analysis of several angiotensin II receptor antagonists in human urine by capillary zone electrophoresis. J. Chromatogr. A 1102, 294–301. [279] Gao Q., Luo D., Ding J., Feng Y.Q., 2010. Rapid magnetic solid-phase extraction based on magnetite/silica/poly(methacrylic acid-co-ethylene glycol dimethacrylate) composite microspheres for the determination of sulfonamide in milk samples. J. Chromatogr. A 1217, 5602–5609. [280] Guan Y., Jiang C., Hu C., Jia L., 2010. Preparation of multi-walled carbon nanotubes functionalized magnetic particles by sol–gel technology and its application in extraction of estrogens. Talanta. 83, 337–343. [281] Ding J., Gao Q., Li X.S., Huang W., Shi Z.G., Feng Y.Q., 2011. Magnetic solid-phase extraction based on magnetic carbon nanotube for the determination of estrogens in milk. J. Sep. Sci. 34, 2498–2504. [282] Xiao D., Wang C., Dai H., Peng J. He J., Zhang K., Kong S., Qiu P., He H., 2015. Applications of magnetic surface imprinted materials for solid phase extraction of levofloxacin in serum samples. J. Mol. Recognit. 28, 277–284. [283] Madrakian T., Ahmadi M., Afkhami A., Soleimani M., 2013. Selective solid-phase extraction of naproxen drug from human urine samples using molecularly imprinted polymer-coated magnetic multi-walled carbon nanotubes prior to its spectrofluorometric determination. Analyst 138, 4542–4549. [284] Fang G.Z., He J.X., Wang S., 2006. Multiwalled carbon nanotubes as sorbent for online coupling of solid-phase extraction to high-performance liquid chromatography for simultaneous determination of 10 sulfonamides in eggs and pork. J. Chromatogr. A 1127, 12–17. [285] Suárez B., Simonet B.M., Cárdenas S., Valcárcel M., 2007. Determination of nonsteroidal anti-inflammatory drugs in urine by combining an immobilized carboxylated carbon nanotubes minicolumn for solid-phase extraction with capillary electrophoresis-mass spectrometry J. Chromatogr. A 1159, 203–207. [286] Bhadra M., Sae-Khow O., Mitra S., 2012. Effect of carbon nanotube functionalization in micro-solid-phase extraction (μ-SPE) integrated into the needle of a syringe. Anal. Bioanal. Chem. 402, 1029–1039. [287] Springer V., Jacksén J., Ek P., Lista A.G., Emmer A., 2014. Determination of fluoroquinolones in bovine milk samples using a pipette-tip SPE step based on multiwalled carbon nanotubes prior to CE separation. J. Sep. Sci. 37, 158-164.
69
Figure 1. The main sources of pharmaceuticals in drinking water
70
Table 1. Characteristics of the analytical methods for the analysis of pharmaceuticals in soils and concentrations pharmaceuticals detected in soil samples from different geographical areas published since 2014 Recovery Detected [%] Therapeutic Sample Sample preparation Analytical MQLa/MDLb/LCLc level Geographical Compound (Apparent Ref. class pretreatment (extraction/clean-up) method [ng g–1] [ng g–1 area recovery d.w.] [%]) 5 mL MeOH:ACN:0.1 M EDTA:McIlvaine buffer (pH4); HPLCDoxycycline 30:20:25:25, v/v/v/v/), (ESI)MS/MS 4a/1b 98 728* Enrofloxacin IS addition, vortex(in the SRM 9a/3b 102 378* Three states: Erythromycin mixed 30 s; extraction mode) (Internal 10a/3b 102 < MQL Selangor, 13 a b standards: C3Flumequine triplicately in an 4 /1 92 1331* Veterinary Negeri Trimethoprim; a b Norfloxacin Homogenized ultrasonic bath for 10 8 /3 82 96* 13 C2 antibiotics Sembilan and [69] a b Sulfadiazine and sieved min (UAE), 7 /2 72 < MQL Erythromycin; and hormone Melaka located Tilmicosin centrifugation 4000 rpm, Ciprofloxacin-d8 10a/3b 93 < MQL in Peninsular Trimethoprim 10 min /Supernatant (20 hydrochloride; 2a/0.5b 102 60* 13 Malaysia C6 Tylosin mL) diluted by H2O to 9a/3b 103 679* Sulfamethazine; 13 Progesterone 500 mL, adjusted to pH 9a/3b 121 24* C6 2.3 and filtered was Thiabendazole) subjected to SPE (Oasis HLB) 5 mL 50% MgNO3 aqueous solution containing 4% aqueous ammonia, vortex-mix 10 min; extraction Guangdong triplicately in an province, a Enrofloxacin HPLC24.4* ultrasonic bath for 10 subtropical a Quinolone Ciprofloxacin Air-dried, (ESI)MS/MS 0.004 to 0.011 /0.001 42.0* min (UAE), 67 to 88 area located in [70] antibiotics Norfloxacin sieved (in the MRM to 0.003b 17.9* centrifugation 4500 rpm, Pearl River Lomefloxacin mode) 11.0* 5 min /Supernatant Delta region, concentrated to near Southern China dryness by rotary evaporated was subjected to SPE (Oasis HLB)
71
Veterinary antianxiety medications
4 Analytes including 2 NSAIDs
Acepromazine Azaperone Carazolol Chlorpromazine Fluphenazine Mesoridazine Metoprolol Perphenazine Prochlorperazine Promazine Propionylpromazine Propranolol Thioridazine Trifluoperazine Triflupromazine Xylazine
Diclofenac Naproxen
Air-dried, sieved
Air-dried, sieved
2 mL H2O, 2 mL 2 M aqueous NaOH, 10 mL EtOAc, vigorous shaking; extraction in an ultrasonic bath for 15 min (UAE), centrifugation 5000 rpm HPLC– 5 min/(LLE) HRMS Supernatant (5 mL) after (Accurate IS addition was dried mass under an N2 gas steam at 50 ◦C. The dried sample measurements of [M+H]+ dissolved in 1 mL ions) (Internal MeOH, vortex-mix with standard; 1 mL 1% aqueous FA acepromazine-d6(pH 3.5 adjusted with hydrochloride) NH4OH) was partitioned with 0.5 mL n-hexane and centrifuged at 5000 rpm for 5 min. The bottom layer was injected into the Orbitrap MS Sequentially extraction To using 35 mL freshly characterize prepared phosphate the extractable buffer (pH2):MOH (3:4, residue v/v) twice and 20 mL HPLC-UV MeOH once (each To identify extraction cycle 260 rpm transformatio for 1 h on a horizontal n products shaker and (UPLC -ESIcentrifugation at 2300 MS/MS rpm for 15 (in the MRM min)/Supernatant mixed mode) with 1200 mL of (Internal deionized water was standard: subjected to SPE (Oasis naproxen14labeled with C) HLB)
0.075c 0.25c 0.15c 0.075c 0.25c 0.15c 0.5c 0.25c 0.25c 0.5c 0.15c 0.15c 0.5c 0.5c 0.075c 0.25c
No data
89.6-94.7 92.3-102.6 85.2-93.5 88.7-102.9 94.8-99.9 78.6-88.8 83.0-90.8 91.1-102.4 96.7-98.2 78.3-94.6 89.1-93.6 94.3-101.3 58.9-81.5 93.6-94.5 86.3-94.3 93.9-100.3
61.7 74.5
No data. The method used for the establishme nt of extraction dissipation kinetics and adsorption– desorption isotherms
Dortmund and München, [71] Germany
No data. The method used for the study of California, CA, transformati Maricopa, AZ, [12] on and USA removal pathways of compounds in soil
72
15 Analytes NSAIDs Lipid regulators Antiepileptics β-blockers Antidepressan ts
Clofibric acid Ibuprofen Salicylic acid Allopurinol Paracetamol Gemfibrozil Fenoprofen Amitriptyline Metoprolol Naproxen Mefenamic acid Ketoprofen Carbamazepine Diclofenac Fenofibrate
Air-dried, sieved
Addition 3 g anhydrous sodium sulfate, left 60 min before extraction; addition 8 mL ACN containing 2% of NH4OH; 15 min in an ultrasonic water bath at room temperature (UAE). After extraction, the solvent evaporated and collected in graduated tubes, the samples washed with 1 mL of additional basic solvent (ACN containing 2% of NH4OH), and extracts evaporated to dryness. A second time extraction of the soil samples in the ultrasound bath (15 min) with 8 mL of ACN containing 2% of formic acid. Samples washed with 1 mL of acidic solvent. The extracts collected in the graduated tubes used in the first extraction step, evaporated to dryness, and reconstituted to 1 mL with ACN. An aliquot (100 μL) of the extract subjected to derivatization and GCMS analysis
GC-MS (in the SIM mode)
0.38a/0.14b 0.21a/0.07b 0.38a/0.14b 0.21a/0.07b 0.24a/0.07b 0.16a/0.04b 0.26a/0.09b 0.65a/0.24b 0.55a/0.18b 0.14a/0.04b 0.42a/0.16b 0.38a/0.14b 0.44a/0.16b 0.48a/0.16b 0.17a/0.53b
104.5-112.8 97.8-104.4 80.3-103.0 40.8-53.0 86.2-97.4 84.2-108.5 100.8-109.0 98.0-105.1 87.3-102.5 98.5-111.6 94.3-115.1 95.6-105.4 92.8-107.8 97.5-106.6 94.3-108.1
0.7 0.5±0.4 4.4±6.2 (37*) 1.3±16.2 (47*) 0.4±0.1 3.6±2.1 0.8±1.1 < MDL < MQL 0.7±2.2 1.5±0.8 < MDL 1.2±1.0 < MDL 7.0±1.0
Region Valencia and Murcia in Spain
[72]
73
NSAIDs Oestrogenic hormones
Salicylic acid Ibuprofen Paracetamol Flurbiprofen Naproxen Diflunisal Ketoprofen Diclofenac Diethylstilbestrol Estrone 17β-Estradiol 17α-Ethinylestradiol Estriol
11 Analytes including 6 hormones
Diethylstilbestrol Estrone 17β-Estradiol Testosterone 19-Norethindrone Progesterone
Freeze-dried, homogenised
Veterinary antibiotics: Tetracyclines (TCs)
Sulfadiazine SD Sulfamethoxazole (SMX) Sulfamonomethoxin
Freeze-dried, homogenized and sieved
Air-dried, sieved
10 mL H2O (adjusted to pH2) and 10 mL ACN, vortex-mix 1 min; addition 4 g of anhydrous magnesum sulphate and 1 g of sodium chloride, vortexmix 1 min; MAE extraction: 400 W, 8 GC-MS min to 115 °C, 15 min (in the SIM extraction at mode) 115 °C)/Organic layer evaporated to dryness in the nitrogen stream was dissolved in 100 mL distilled water, adjusted to pH2 using 1 M HCl and subjected to SPE (Oasis HLB) 10 mL Aceton:n-Hexane (70:30, v:v) solvent HPLCmixture using an ice (ESI)MS/MS bath, IS addition; (in the SRM sonication of 5 min at mode) 33% of power with (Internal pulse times on of 0.8 s standards: and pulse times off of [2H3]-17β0.2 s) Estradiol, (FUSLE)/Supernatant [2H9]filtered and evaporated Progesterone, to dryness was [2H4]reconstituted in ACN Nonylphenol, and subjected to dSPE [2H16](Envi-carb dSPE Bisphenol-A) protocol) Addition of surogates UPLCand 0.1 g NaF as the ion (ESI)MS/MS exchanger; 5 mL (in the MRM methanol:EDTA:citrate mode)
2.2a/0.7b 0.9a/0.3b 1.9a/0.6b 1.4a/0.5b 2.2a/0.7b 9.8a/3.3b 17.1a/5.7b 5.6a/1.9b 1.2a/0.4b 2.6a/0.9b 1.2a/0.4b 1.3a/0.4b 1.2a/0.4b
89.3 108.2 51.6 68.8 91.7 102.3 58.6 106.7 86.3 38.7 82.3 75.9 81.8
18.3* 8.0* < MDL 8.8 < MDL < MDL < MDL < MDL < MDL < MDL 9.0* < MDL < MDL
Northern Poland
[73]
1.0b 2.3b 3.2b 1.5b 2.8b 1.6b
5 (63) 9 (58) 7 (49) 13 (55) 30 (125) 13 (118)
All analytes < MDLs
Bilbao, Spain
[74]
65.6–90.0 for SAs 60.1–81.6 for TCs
1520.6±291 Liaoning and 4.8 TCs Tianjin areas of [75] 10 967.1* Northern China CTC
74
Sulfonamides e (SMN) (SAs) Sulfadimidine Fluoroquinolo (SM2) nes (FQs) sulfachlorpyridazine Macrolides (SCP) (MACs) Trimethoprim Nitrofurans (TMP) (NFs) Tetracycline (TC) Chlortetracycline (CTC) Oxytetracycline (OTC) Doxycycline (DOXY) Enrofloxacin (ENR Ciprofloxacin (CIP) Ofloxacin (OFL) Roxithromycin (ROX) Erythromycin (ERY) Tylosin (TYL) Furazolidone (FUR)
buffer (3:2:1, v/v/v), (Internal vortex-mix 30 s at 2500 standard: rpm; extraction Simeton; triplicately in an Surrogates: ultrasonic bath for 15 Meclocycline, min (UAE), Sulfadiazinecentrifugation 4000 rpm, phenyl-13C6, 5 min/Combined Lomefloxacin, Caffeine supernatant was trimethyldegreased by n-hexane, 13 C3) diluted to 250 mL with deionized sterile water, filtered, adjusted to pH4 and subjected to tandem SPE (SAX-HLB)
61.3–73.2 for FQs 47.3–73.4 for MACs, 58.2–67.4 for furazolidon e
12.3±16.5 SMX 20.9±13.2 SCP 43.0±48.4 SM2 32.9±28.0* CIP < 15 MACs < 15 FNs
* maximum concentration; ACN: acetonitrile; dSPE: dispersive solid-phase extraction; ESI: electrospray-ionisation; EtOAc: ethylacetate ;FA: formic acid; FUSLE: focused ultra-sonic solid–liquid extraction, HPLC: high-performance liquid chromatography; HRMS: high resolution mass spectrometry; LCL: lowest calibrated level; LLE: liquid-liquid extraction; MAE: microwave assisted extraction; MDL: method detection limit; MQL: method quantification limit; MRM: multiple reaction monitoring; MS: mass spectrometry; MS/MS: tandem mass spectrometry; NSAIDs: nonsteroidal anti-inflammatory drugs; SIM: selected ion monitoring; SPE: solid-phase extraction; SRM: selected reaction monitoring; UAE: ultrasound-assisted extraction; UPLC: ultra-performance liquid chromatography; UV: ultraviolet light.
75
Table 2. Maximal concentrations of selected pharmaceuticals detected in drinking waters around the world
Carbamazepine
Concentration (max) [ng L-1] 5.6
Atenolol Sotalol Hydrochlorthiaride Carbamaz epoxide Pherytoin
3 3 3 3 10
Spain (2011) [134]
Ibuprofen Indometacine Gemrozil Atorvastatin Carbamazepine Ranitidine Losartan
5 6 8 1 2 0.6 5
USA (2009) [135]
Sulfamethoxazole Carbamazepine Triclosan Ibuprofen
13.7 4.7 6.9 23.4
Portugal (2014) [136]
Carbamazepine Atenolol Propranolol Sulfonamides Erythromycin Ibuprofen Naproxen Gembrozil Indomethacin Diclofenac Paracetamol Amantadine Carbamazepine
14 2 6.7 1.9 5 21 6 18 37 11 47 9 25
Country (year) Ref. Canada (2009) [132] Spain (2008-2009) [133]
Japan (2015)
Pharmaceutical found
LOD [ng L-1] 3 5 0.1 1 0.01 0.02 UPLC-MS/MS 0.5 1.3 0.04 0.03 0.2 0.1 0.9 UPLC-MS/MS 0.3 0.2 1.2 1.6 LC-MS/MS No data UPLC-MS/MS
2.2 0.4
76
[137]
Diclofenak Epinastine Fenofibrate Ibuprofen Iopamidol
16 8 31 6 2400
China (2014) [138]
Atenolol Carbamazepine Clarithromycin Diclofenac Erythromycin Fluoxetine Ibuprofen Sulfametoxazole Trimetoprim
34.1 35.0 0.2 9.4 13.8 19.2 10.2 12.7 19.8
2.5 2.0 0.2 1.1 1.8 LC-MS, LC-MS/MS 0.5-10 LC-MS/MS
MCL - method confirmation limit
77
Table 3. Examples of methodology used for carbamazepine determination in raw and treated drinking water Technique SPE-GC-MS SPE-GC-MS SPE-LC-MS/MS SPE-LC-MS/MS SPE-UPLC-MS/MS On-line-SPE-LC-MS/MS
Sample type Treated drinking water (from wastewater) Raw and treated drinking water Treated drinking water Tap water Raw and treated drinking water Ground water
Sample volume [mL]
Detection limit [ng L-1]
Ref.
1000
5 (MQL)
[181]
100 1000 500 500 7.5
0.01 (MDL) 10 (MDL) 0.2 (MDL) 1.5 (MQL) 0.32 (MDL)
[159] [144] [135] [133] [182]
78
Table 4. Examples of ME, EE and AR obtained for pharmaceuticals determined in different environmental samples and techniques Analyte Sample type Matrix effect Extraction Absolute Ref. ME [%] efficiency EE, recovery ER [%] AR, PE [%] SPE-LC-MS/MS Ketoprofen sea water 59.4 92.9 37.8 [101] Trimetoprim sea water 54.2 92.6 45.8 [101] Flubendazole surface water 82.5 n.d. 90 [204] Tetracycline surface/ 89/56 n.d. 70/71 [158] drinking water Sulfamethoxazole surface/ 13/13 n.d. 90/96 [158] drinking water Diclofenac effluent 75 90 112 [205] wastewater SPE-GC-MS Propranolol wastewater 18.1 108.6 89.0 [187] Ketoprofen effluent 2 93 92 [177] wastewater
n.d. - no data
79
S0731-7085(16)30016-4 http://dx.doi.org/doi:10.1016/j.jpba.2016.01.016 PBA 10442
To appear in:
Journal of Pharmaceutical and Biomedical Analysis
Received date: Revised date: Accepted date:
31-8-2015 5-1-2016 7-1-2016
Please cite this article as: Anna Bialk-Bieli´nska, Jolanta Kumirska, Marta Borecka, Magda Caban, Monika Paszkiewicz, Ksenia Pazdro, Piotr Stepnowski, Selected analytical challenges in the determination of pharmaceuticals in drinking/marine waters and soil/sediment samples, Journal of Pharmaceutical and Biomedical Analysis http://dx.doi.org/10.1016/j.jpba.2016.01.016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Selected analytical challenges in the determination of pharmaceuticals in drinking/marine waters and soil/sediment samples
Anna Białk-Bielińska1*, Jolanta Kumirska1, Marta Borecka1, Magda Caban1, Monika Paszkiewicz1, Ksenia Pazdro2, Piotr Stepnowski1
1
Department of Environmental Analysis, Faculty of Chemistry, University of Gdańsk, ul.
Wita Stwosza 63, 80-308 Gdańsk, Poland 2
Institute of Oceanology, Polish Academy of Sciences, ul. Powstańców Warszawy 55, 81-712
Sopot, Poland
*Corresponding author: [email protected], (+48) 58 523 52 08
1
Highlights Review of selected aspects of the analysis of pharmaceuticals in the environment Presentation
of
recent
improvements
in
the
determination
of
challenges
in
the
of
pharmaceuticals Discussion
of
methodological
analysis
pharmaceuticals Presentation of application of carbon nanotubes in the analysis of pharmaceuticals
2
Abstract Recent developments and improvements in advanced instruments and analytical methodologies have made the detection of pharmaceuticals at low concentration levels in different environmental matrices possible. As a result of these advances, over the last 15 years residues of these compounds and their metabolites have been detected in different environmental compartments and pharmaceuticals have now become recognized as so-called ‘emerging’ contaminants. To date, a lot of papers have been published presenting the development of analytical methodologies for the determination of pharmaceuticals in aqueous and solid environmental samples. Many papers have also been published on the application of the new methodologies, mainly to the assessment of the environmental fate of pharmaceuticals. Although impressive improvements have undoubtedly been made, in order to fully understand the behaviour of these chemicals in the environment, there are still numerous methodological challenges to be overcome. The aim of this paper therefore, is to present a review of selected recent improvements and challenges in the determination of pharmaceuticals in environmental samples. Special attention has been paid to the strategies used and the current challenges (also in terms of Green Analytical Chemistry) that exist in the analysis of these chemicals in soils, marine environments and drinking waters. There is a particular focus on the applicability of modern sorbents such as carbon nanotubes (CNTs) in sample preparation techniques, to overcome some of the problems that exist in the analysis of pharmaceuticals in different environmental samples.
Keywords: analysis; environmental samples; pharmaceuticals; carbon nanotubes
3
1. Introduction For more than 15 years, pharmaceuticals and their metabolites have been recognized as so called ‘emerging contaminants’. This is due to recent developments and improvements in advanced instruments and analytical methodologies, which have made the detection of these chemicals at low concentration levels possible in different environmental matrices [1-2]. Residues of pharmaceuticals and their metabolites have been detected in different environmental compartments. Their wide usage and biological activity as well as their relatively strong resistance to degradation processes are the reasons why many scientists all over the world are concerned about the risks they might pose to the ecosystem and to human health [1-2]. In recent years it has therefore become of the utmost importance to understand the environmental fate of these compounds. This would have not been possible without the availability of appropriate, accurate and highly sensitive analytical methodologies for their determination in aqueous and solid environmental samples. To date, there have been a lot of papers published on the development of new analytical methodologies - as well as their application in different fields - and impressive improvements have been made [1-3]. However, in order to assess the environmental fate of these chemicals, there are still numerous methodological challenges to be overcome. The aim of this paper therefore, is to present a review of selected recent improvements that have been made and the challenges that exist in the analysis of pharmaceuticals in environmental samples. Special attention has been paid to the current state of knowledge regarding the occurrence and fate of these chemicals, as well as the strategies and challenges that exist in their analysis in soils, marine environments and drinking waters (Section 2-5) also in terms of the implementation of Green Analytical Chemistry (GAC) (Section 6). In our opinion there are still some gaps in these particular aspects that need to be discussed when
4
compared with the analysis of pharmaceuticals in surface or waste waters which to date have been more widely studied. In addition, in order to overcome some of the existing problems in the analysis of pharmaceuticals in different environmental samples, we also present a review of the available literature and data concerning the applicability of modern and very promising sorbents such as carbon nanotubes (CNTs) in sample preparation techniques (Section 7). The high efficiency of these sorbents in the extraction of pharmaceuticals from different matrices has already been proven in not only environmental samples but also in food/biological samples. Therefore, this will also be discussed in detail.
2. Analytical challenges in the determination of pharmaceutical residues in soil samples
2.1. Occurrence and fate of pharmaceuticals in soil Pharmaceuticals may be released into the soil environment when contaminated sewage sludge, sewage effluent, or animal manure is applied to land [e.g. 1-8]. Veterinary pharmaceuticals may also be excreted directly to soils by pasture animals. It has been reported that the concentrations of selected drugs in animal manure could be very high. For example, concentrations of norfloxacin and enrofloxacin in chicken manure from China were up to 225 and 1420 mg kg-1, respectively [9]. Moreover, it has been established that about 3.6 x 109 m3 of treated wastewater
is
currently
reused
in
the
U.S.
for
different
purposes,
including for agricultural and landscape irrigation, and water reuse is growing by 15% a year [10]. Similarly, approximately 6 x 106 t of biosolids are produced each year in the U.S., of which about 60% is applied to land [11-12]. Consequently, a range of pharmaceuticals has been detected in
5
agricultural soils, with reported concentrations up to the low mg kg-1 level [e.g. [1-8, 13−20]). These compounds may persist in soil matrices for long periods and may be toxic to terrestrial organisms (e.g. [3, 6, 8, 21-28]). For example, according to data presented by Langdon et al. [24], estrogenic activity was detectable at all of the sampling times that biosolids were applied to land. Furthermore, a number of studies have demonstrated the uptake of pharmaceuticals used in human and veterinary medicine into plants [29-39]. Additionally, the presence of veterinary or human drugs in the environment (e.g. in soil matrices) can induce pathogen resistance to antibiotics [e.g. 40-41]. The environmental fate of pharmaceuticals in the soil ecosystem is conventionally estimated by taking into account their persistence and sorption in soil. The residence time of veterinary and human drugs in the terrestrial environment can range from less than one day to months depending primarily on the temperature and the chemical structure of the pharmaceutical [4243]. The mobility of the pharmaceuticals in soil, and their consequent potential for contaminating groundwater, depends on: (i) the basic chemistry of these compounds; (ii) the amount of drug applied; (iii) the intensity of “rain” events; and (iv) the soil type, and is also correlated with their sorption tendencies. There are no regulations on concentration limits of pharmaceuticals in the environment, even though growing concerns in the US and Europe have resulted in the prescription of environmental risk assessments of veterinary pharmaceuticals [44-49]. For example, detailed emission and distribution models as well as environmental risk assessments for veterinary medicinal products have been provided by Montforts [50]. As has been already mentioned, thanks to improvements in analytical chemistry, many pharmaceutical compounds are more easily detected in surface water and wastewater 6
environmental compartments at ppb concentrations. A different situation can be seen in the case of soil matrices. In 2004 for example, there was only limited information available on this topic [5-6, 51]. Although our knowledge about the presence of pharmaceuticals in soils is increasing (e.g. [1-8, 13−20]), the information in peer-reviewed literature regarding the fate and the ecotoxicological effects of most pharmaceuticals is still limited [3, 6, 8, 12, 21-28, 52-60]. A similar situation can also be observed in the case of the availability of analytical methods for determining drugs in soil matrices. In the past decade, many methods have been developed for the analysis of pharmaceuticals in aqueous matrices, however, only limited exist for the determination of drugs in soil matrices. Review articles presenting these methods have been published by Stolker and Brinkman [61], Pavloviċ et al. [62], Wilga et al. [43], Kemper [63], Buchberger [64], Tadeo et al. [65], Babić and Mutavdžić Pavlović [66], Snow et al. [53-54] and Havens et al. [67]. For example, Snow et al. [54] reviewed articles published in 2013 which ranged from detailed descriptions of analytical methods, to fate and occurrence studies and sampling techniques for a wide group of pharmaceuticals occurring in agricultural environments. Babić and Mutavdžić Pavlović [66] presented some conventional and novel sample preparation methods for the determination of pharmaceuticals in solid environmental samples, including soils, and compared them from the viewpoint of their applicability to environmental analysis. Havens et al. [67] compared accelerated solvent extraction, soxhlet and sonication techniques for the extraction of estrogens, androgens and progestogens from soils. The application of ultrasound-assisted extraction for the extraction of emerging contaminants from environmental samples (e.g. pharmaceuticals from soil matrices) was presented by Albero et al. [68]. The current methodologies published since 2014 that have been used in the determination of selected pharmaceutical residues in soil matrices are presented in the next section.
7
2.2. Current methodologies used in the determination of pharmaceutical residues in soil matrices published since 2014 The characteristics of analytical methods for the analysis of pharmaceuticals in soils and concentrations of pharmaceuticals detected in soil samples from different geographical areas that have been published since 2014 are presented in Table 1. These methodologies can be divided into four major groups: (i) new methods developed for determining drugs in soil matrices [72-74], (ii) new analytical methods developed not for the analysis of real environmental soil samples but for the assessment of the fate of pharmaceuticals in such matrices, but which however could be potentially applied for this purpose [71], (iii) previously published methods, used with or without modifications, for the determination of a variety of drugs in real environmental soils [69-70], (iv) analytical methods developed for determining drugs in environmental samples but now applied for the establishment of their fate in such matrices [12]. The first group is represented by three methods: two [72-73] based on gas chromatography with mass spectrometry in Selected Ion Monitoring Mode (GC-(SIM)MS) measurements (Table 1) and the last one on liquid chromatography coupled to tandem mass spectrometry (LC–MS/MS) [74]. Aznar et at. [72] developed a method for the detection and quantification of fifteen pharmaceuticals belonging to five therapeutic classes (anti-inflammatory/analgesics, lipid regulators, antiepileptics, β-blockers and antidepressants). The target drugs were extracted from soil by ultrasound-assisted extraction (UAE) and directly subjected to derivatization by N-(tertbutyldimethylsilyl)-N-methyl-trifluoroacetamide (MTBSTFA) with 1% tert-butyldimethylchlorosilane (TBDMCS) prior to GC-MS analysis. In the second paper, [73] microwave-assisted extraction (MAE) was applied for the separation of eight NSAIDs and five estrogenic hormones from solid (e.g. soil) matrices. The obtained extracts were
8
purified by SPE using Oasis HLB cartridges, and subjected to derivatization by N,Obis(trimethylsilyl)trifluoroacetamide (BSTFA) and 1% trimethylchlorosilane (TMCS) in pyridine. In comparison to the methods presented in the literature [76-79], this approach allows the determination of more estrogenic hormones and NSAIDs in one analytical run and/or the correct assessment of the concentrations of estrone and 17α-ethinylestradiol by GC-MS. Mijangos et al. [74] developed a method for the simultaneous determination of 11 endocrine disrupting compounds including 6 hormones: diethylstilbestrol, estrone, 17βestradiol, testosterone, 19-norethindrone and progesterone in amended soil. This method used focused ultrasonic solid–liquid extraction (FULSE) and dispersive solid-phase extraction (dSPE) as a simplified clean-up strategy. FUSLE requires a low amount of sample (0.01–1.0 g, here 0.5 g), solvent (5–15 mL, here 10 mL) and short extraction times (from seconds to a few minutes, here 5 mins), hence dSPE, in comparison with traditional SPE, saves time, effort, money and solvent consumption. The second group is represented by a method developed for the analysis and evaluation of decreasing patterns of 16 veterinary antianxiety medications in soils [71]. This method is based on ultrasonic-assisted extraction and liquid chromatography–high resolution mass spectrometry (HPLC–HRMS) measurements. The purification of the obtained soil extracts was performed by the addition of 0.5 mL of n-hexane and centrifugation at 5000 rpm for 5 mins. The bottom layer was injected into the Orbitrap MS. This approach resulted in good validation outcomes for the target drugs in soil samples. The simplicity and high sample throughput makes the method more attractive for the analysis of real environmental soil samples. The third group of methods includes previously published methods used with or without modifications for analysing the occurrence and distribution of drugs in real soil samples [6970, 75]. For example, the occurrence of veterinary antibiotics and progesterone in broiler
9
manure and agricultural soils in Malaysia [69] was investigated using a method described by Ho et al. [80] (Table 1). Briefly, it was based on the addition of 5 mL MeOH:ACN:0.1 M EDTA:McIlvaine buffer (pH 4); 30:20:25:25, v/v/v/v/) and internal standards, vortex-mixing for 30 seconds, triplicate extraction in an ultrasonic bath for 10 mins (UAE) and centrifugation at 4000 rpm for 10 mins (Table 1). The supernatant (20 mL) was diluted by H2O to 500 mL, adjusted to pH 2.3, filtered, subjected to SPE (Oasis HLB) and analyzed by HPLC–(ESI)MS/MS. The same procedure, but with small modifications to the sample extraction and clean up steps, (see Table 1) was also applied by Wu et al. [70] for the analysis of the distribution and risk assessment of quinolone antibiotics in the soils from the organic vegetable farms of a subtropical city in southern China. Hou et al. [75] proposed a feasible and rapid determination of 17 veterinary antibiotics belonging to five classes: sulfonamides, tetracyclines, fluoroquinolones, macrolides and nitrofurans in soils by means of ultraperformance liquid chromatography (UPLC)-tandem mass spectrometry (MS/MS) (the total run time was only 10 mins). However the extraction procedure was based on a previous description [81]. The authors applied this method in the analysis of the occurrence and distribution of these drugs in amended soils in the Liaoning and Tianjin areas of northern China (Table 1) [75]. A good example of the last group of methods is the approach presented by Dodgen et al. [12] Soil samples were extracted using the EPA Method 1694 and the soil extracts were prepared for the analysis of the parent and transformation compounds of diclofenac and naproxen in the soil by a method modified from Wu et al. [82]. The coupled use of
14
C labeling and
chromatographic analysis in this study allowed a comprehensive investigation to be made of the transformation and the removal pathways of these drugs in soil. By use of this method, it was established that mineralization was the predominant removal process for diclofenac and naproxen.
10
2.3. Outlook Over the past ten years, different methods have been proposed for the monitoring of pharmaceutical residues in soil samples. However, methods for the identification and quantification of many drugs in soil samples have not yet been developed. The interest is concentrated onto the predominant therapeutic classes as antibiotics, analgesics/antiinflammatory
drugs,
hormones,
lipo-regulators,
beta-blockers,
anti-epileptics
and
antidepressants [e.g. 1-8, 13−20, Table 1], but the number of chemical compounds used as human and/or veterinary drugs is estimated over 4000 molecules and 10 000 products. Moreover, although anthelmintics together with antibiotics belong to the most commonly used veterinary drugs only limited data are available concerning the determination of anthelmintics in the soils and only few papers have dealt with the environmental fate of these drugs in the soils [83-86]. For this reason, research into the occurrence and fate of pharmaceuticals in soil environments still requires further development of the analytical methods. Only analytical methods which are sensitive, accurate and easy to apply in routine analysis will mean reliable risk assessments of the presence of pharmaceuticals in soil matrices can be made. The development, therefore, of such methods is still crucial. Sample preparation techniques play a key role in these methods. That is why efforts in this field have been mainly focused on optimization of the preparation, extraction and clean-up steps and on the enhancement of the environmental safety of these procedures. However, efforts also need to be made to develop on-line coupling, automatic or semi-automatic protocols. Currently, the proposed analytical procedures for determining pharmaceuticals are mainly based on HPLC-MS/MS and less frequently on GC-MS. The main trend in HPLC-MS/MS is to combine powerful MS detectors (QqTOF and Orbitrap) with modern chromatographic approaches such as UHPLC, GC×GC or LC×LC. Such approaches allow the development of
11
multi-analyte techniques for the detection of a wide range of drugs in a single analytical run. The main disadvantage, however, of these methodologies is the need for complex equipment and the high costs. For this reason, it is also very important to develop low cost screening methods based on microbiological, immunoassays and biosensors.
3. Analytical challenges in the determination of pharmaceutical residues in marine waters and sediments
3.1. Occurrence and fate of pharmaceuticals in marine waters and sediments In contrast to the large number of studies demonstrating the presence of pharmaceutical residues in wastewaters, drinking waters and/or surface waters, there are only a few studies which have reported on the occurrence of these compounds in marine ecosystems [87-91] despite seawater being the final sink for many traditional chemicals (both organic and inorganic) [92-93]. Moreover, sediments - as complex matrices – also provide a wide variety of binding sites and therefore can also act as major sinks for the deposition of particle reactive pollutants [94-95]. It can therefore be assumed that there is a similar fate for pharmaceuticals (as organic compounds) in this environment. The most vulnerable marine environments are coastal areas, where the centers of human populations are often found. These environments are therefore exposed to discharges of municipal effluent, which can cause a constant supply and accumulation of hazardous compounds, including pharmaceuticals. This is particularly relevant in the case of coastal lagoons, due to the fact that they are almost entirely land-locked and due to their shallowness. Hence water exchanges, which allow for the dilution and/or dispersion of organic pollutants, are limited in such confined environments [87, 89, 96-97]. According to data presented by Gaw et. al [87], since the year 2000 there have been only forty-nine studies, which have reported on concentrations of pharmaceutical residues in
12
estuarine and coastal waters. In these studies, 113 pharmaceuticals and their metabolites were detected at concentration ranges from 0.01 to 6800 ng L-1. The examined areas mainly include Europe - the North Sea (the coasts of Germany [98] and Belgium [99]), the Baltic Sea (the coasts of Poland [100-101] and Germany [102-103]), the Adriatic Sea (the coast of Italy) [102], the Aegean Sea and the Dardanelles (the coasts of Greece and Turkey) [102], the Mediterranean Sea (the coast of Israel) [102], the Balearic Sea (the coast of Spain) [102], the Atlantic Ocean (the coasts of Portugal [104] and Ireland [105]) and Asia - the Yellow Sea [106-109] and the South China Sea [110-115]. There is much less data available on the presence of pharmaceuticals in marine sediment samples. There have been only twenty-two studies, which show that in total 62 pharmaceuticals have been detected at concentration ranges from 20 µg g-1 dry weight to 2 616 µg g-1 wet weight [87]. Their presence has been evaluated mainly in Asia (the Mianqian Sea [116], the South China Sea [110, 117], the East China Sea [118] and the Yellow Sea [109, 119]) and different areas of the Pacific Ocean (the coast of the USA – the Puget Sound [119], the coast of New Zealand [120], the coast of Korea [121] and the coast of Chile [122]). As shown above, there is a significant knowledge gap when it comes to research into the fate assessments of pharmaceuticals in marine environments. However, during recent years there has been a growing interest in research focused on this topic, as seventy per cent of the studies which demonstrate the presence of pharmaceutical residues in marine environments, have been published since 2010 [87]. Access to marine samples is much more restricted and more expensive than in the case of terrestrial and freshwater ecosystems. Moreover, the analysis of pharmaceuticals in marine samples is a very difficult and demanding task. This is due to the fact that the environmental concentrations of these compounds are mostly in the ng L-1 to µg L-1 ranges and due to the complexity of the analyzed matrices. There is also a great variety of pharmaceutical compounds, their metabolites and transformation products, characterized by
13
different chemical properties, which means no comprehensive method exists for the multiresidue analysis of these compounds. Consequently, there is a growing need to develop analytical methods which will enable a reliable, sensitive, selective and fast determination of pharmaceutical residues in marine samples. The current methodologies used in the determination
of
pharmaceutical
residues
in
marine
environments
are
presented in the next section.
3.2. Current methodologies used in the determination of pharmaceutical residues in marine waters and sediments There are many traditional sample-preparation methods in use for the analysis of pharmaceuticals in marine samples. However, solid phase extraction (SPE) is the most commonly used extraction technique for the analysis of these compounds in aqueous samples [98-115]. This technique allows for sample extraction and clean-up, both of which are necessary to improve the sensitivity of detection. In addition, these steps can be carried out at the same time, what makes the analysis less time-consuming [113]. Prior to extraction, or just after collection, water samples are filtered through glass-fiber filters. Then, depending on the chemical properties of the analyzed compound/compounds, they are acidified (usually to pH 3) or pretreated to pH 7.5 – 8.0 [106-115]. Of the different SPE-cartridges available, Oasis HLB is the most commonly used cartridge for the extraction of selected compounds from seawater [102-103, 106-115]. This is due to the fact that this cartridge generates the best absolute recoveries (in a range from 61 to 112 %) for most pharmaceuticals. The newest trend is for the use of SPE speed disks [100-101], which are useful for isolating analytes from high-volume samples. In this way, high concentration ratios can be obtained, hence limits of detection and quantification can be reduced. The extraction efficiency obtained with the use of an SPE speed disk is in the range from 51.4 to 99.8 %.
14
The extraction of pharmaceuticals from sediment samples (similar to extraction from soils) is much more difficult. It requires the application of advanced extraction techniques to isolate the analytes as some of them strongly bind to the matrix, such as fluoroquinolones and tetracyclines [6]). For this purpose, ultrasound assisted extraction (UAE) [116, 118, 120, 122] and accelerated solvent extraction (ASE) / pressurized liquid extraction (PLE) [120-121] techniques are chosen. However, simple vortex-mixing has also been employed [109-110, 119]. The most commonly used solvents are a mixture of acetonitrile and citric acid [110, 116], a mixture of acetonitrile and EDTA-McIlvaine buffer [109, 119] or a methanol/methanol-water mixture [120-122]. The complexity of the sediment samples however, means that the obtained extracts need to be purified. It is therefore necessary to include a clean-up step at the sample preparation stage. This is carried out mainly with the use of solid-phase extraction [109-110, 116-122]. For this purpose, Oasis HLB cartridges [109, 120] or anion-exchange cartridges (SAX) in tandem with hydrophilic–lipophilic balance (HLB) cartridges are used [110, 116]. The recoveries obtained using these methodologies for the determination of pharmaceuticals in sediment samples were in the range of 45 to 126 % for most pharmaceuticals [109-110, 116-122]. Advances in analytical technology have been a key factor affecting the detection of pharmaceuticals in environmental matrices. The technologies now available allow for the determination of compounds occurring at trace levels (just a few ng/L or less) [104]. The majority of the data on the occurrence of pharmaceutical residues in marine environments are for antibiotics, non-steroidal anti-inflammatory drugs, lipid regulators and β-blockers [98122], which are polar compounds. For analysis of these, methods basing on reversed-phase high performance liquid chromatography should be used. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) has therefore been the analytical technique of choice for the determination of pharmaceuticals in marine samples [99-116, 118, 120-121]. The main
15
advantage of this technique is its high selectivity and sensitivity [104, 113]. In many cases, quantitative analysis of the compounds was performed using the multiple reaction monitoring mode (MRM), employing at least two of the highest characteristic precursor ion/product ion transitions [99-101, 103, 106, 108, 110, 113-114, 116, 118, 121]. Together with retention times, the characteristic ions were used to ensure correct peak assignment, which enhances the reliability of the obtained results. Recently there has been a trend toward the use of ultra-high performance liquid chromatography (UHPLC), which allows for faster analysis, better resolution and narrower peaks, compared to conventional HPLC methodologies [123]. This technique has also been successfully applied in the analysis of NSAIDs in marine waters [104] and pharmaceuticals from different therapeutic classes in marine sediments [118].
3.3. Outlook A major problem, when trace levels of pharmaceuticals are analyzed using the SPE-LCMS/MS technique, is matrix effects [123-128]. These effects can result in poor analytical accuracy and reproducibility. In the case of marine samples, analysis of the main factors responsible for these effects are: -
the analysis of seawater – the high salinity of these samples and high concentrations of dissolved organic matter (such as humic substances);
-
the analysis of sediments – the high organic matter content.
Operational strategies which can be undertaken to reduce/evaluate the matrix effect are the employment of isotope-labeled analogues and the use of the post-extraction addition technique. Both of these have been successfully applied in the analysis of marine samples [100-102, 106, 108-110, 112-116, 118, 121], although they raise the cost and/or the time of analysis. However, these strategies need to be undertaken in order to obtain reliable analytical
16
results and so there is a growing need to develop more selective and sensitive extraction methods in order to overcome the problem of matrix effects and reduce the time and cost of analysis.
4. Analytical challenges in the determination of pharmaceutical residues in drinking waters
4.1. Occurrence of pharmaceuticals in drinking waters The presence of pharmaceutical residues in drinking waters is a relatively new issue when it comes to environmental pollution from human activity and is closely related to the pollution of other water components (marine, rivers and lakes) as well as soils in natural environments. Drinking water can be produced from surface water, ground water or recycled wastewater, depending on water availability and the technology used, which in turn depends on the finances of the individual country as well as the required water quality. The reason for the occurrence of pharmaceuticals in all water matrices is that they are all closely related to each other and water is a good carrying medium for polar and semi-polar compounds. The main sources of pharmaceutical (and hormone), contamination of drinking water from both human and veterinary usage, are presented in Figure 1. The real situation is more complex because accidental contaminations can also occur. The fate of pharmaceuticals in the environment has already been the subject of advanced investigations [129-130]. It is already known that the elimination of pharmaceuticals in groundwater environments is limited because of an almost total lack of microorganisms, low levels of oxygen concentrations and the amount of energy needed for oxidation and other transformations [131]. In order to be able to state if the residues of these active compounds can pose a risk to human health, the levels of their concentrations need to be known. For this reason, there have been many investigations which have been ongoing from several years.
17
Some examples of pharmaceuticals which have been detected in drinking waters are presented in Table 2. Although concentrations of pharmaceuticals in drinking waters are low (ng L-1) and they do not pose a direct risk to human health [139-140] - their occurrence in drinking water still attracts attention because of overall concerns about the quality of drinking water [141]. Generally, the detection frequency of target pharmaceuticals is moderate and varies in range from 0 to 100% [142-143]. During some investigations, pharmaceuticals have been detected in surface waters but not found in drinking water (Netherlands, [144]). The most high-scale investigations into the presence of pharmaceutical residues in drinking water have been carried out in the USA, Canada, France, Germany, the UK, Italy and in Finland (review in [145-146]). Some countries already have long-term monitoring in place, which of course provides more valuable information. For example in Germany, the long-term analysis of ground water (as the main source of drinking water in the country) provides interesting information about the presence of pharmaceuticals together with other anthropogenic compounds, because the pathways of both are mostly the same [147]. This investigation has resulted in legislative consequences – for example phenazone-like residues (phenazone is an analgesic and antipyretic pharmaceutical) as well as other pharmaceuticals (e.g. carbamazepine, diclofenac, ibuprofen, primidon) have been recommended by the German Federal Protection Agency (Umwelt Bundesamt) to be added to the list of pharmaceuticals with maximal concentrations of 0.3 - 3 µg L-1 [148] to be monitored, although to date these compounds have not been included in regular water monitoring.
18
4.2. Current methodologies used in the determination of pharmaceutical residues in drinking waters The analytical methods used for the determination of pharmaceuticals in drinking waters are the same as for other water matrices. Generally, it is common practise that the methods developed for their analysis in surface or wastewater samples are also used in the analysis of drinking water samples [139, 149-151], which generally does not create any problems. The overall analytical procedures are the same, from sampling and preservation, extraction, the final determination by chromatography with mass spectrometry detection, to the final interpretation of the results. However, some differences and analytical challenges can occur and these will be discussed in this section.
4.2.1. Why, where and when to analyse Pharmaceuticals can pass into soil and occur in ground water, and thereby pollute water prepared for human consumption, despite the use of advanced technologies. Because of this, analytical methods are mainly used to: (i)
determine the level of pollution of drinking water by pharmaceutical residues [135, 151-154],
(ii)
determine the risk of the pharmaceutical presence [136, 155],
(iii)
evaluate the efficiency of the technology of water purification [133, 156-158] and the impact of climate on this process [159],
(iv)
investigate the life-time of pharmaceuticals in drinking water [160],
(v)
determine any by-products of pharmaceuticals produced during advance treatments [144, 161-163].
There is also the question of when and where to analyse drinking waters. Most of the available methods are based on the usage of shot analyses of grab samples in triplicate in
19
order to provide an overview of the problem. However, water samples can be also taken as 24-hour collected samples, which can be more appropriate for screening analysis. This strategy has already been used in the analysis of wastewater samples [164], but never for drinking water. The long-term analysis of polar compounds can be also carried out by the application of passive sampling techniques. Samples of drinking water can be collected directly in households, in water companies or in ground water intakes. The obtained results of pharmaceutical concentrations in all of these cases can be different, and making direct links between them is impossible, because of the problem of tracking water in complex municipal water systems. When the technology of purification is examined, water samples are taken before and after treatment. This can be done in-situ [133] or in a lab-scale investigation [157]. Particularly in the latter case, water samples can be taken at every step of the water treatment process. Similar experiments are used in investigations into the efficiency of new technologies used in the removal of pharmaceuticals during wastewater treatment [165]. Nevertheless, there is still a question mark over when drinking water samples should be taken. Screening investigations have the advantage that the obtained results are just as informative whether pollution is found to have occurred or not. This is because these samples can be taken at any time. Passive sampling also possesses the advantage that it is not impacted by the momentary and temporary variations in the concentrations of the pollutants [166]. For all of the above reasons, it is necessary that future regulations regarding the monitoring of pharmaceuticals in drinking waters specify when and where water samples should be collected.
4.2.2. Choice of analytes and indicators The number of active pharmaceutical compounds is high and is still growing. This makes the selection of analytes difficult and some notes should be considered:
20
(i) Analytes can be selected from a group of compounds that have already been detected in water matrices on the sampling side, which means the possibility of their presence in drinking water is also high. (ii) The method applied (and already validated for another water matrix) can dictate the group of analytes. (iii) Analytes can be taken from groups of pharmaceuticals which have already been proven to have a high negative impact on human health. Of the three presented ways to select analytes, the second is normally the most commonly applied as it is the simplest because the methods have already been validated. However, the selection of the target analytes depends on the aim of the research as well as the instruments available. It should also be noted that, although over the last five years there has been some information about the presence of pharmaceutical by-products produced after oxidation and during the chlorination process of drinking water treatment, [163] to date, there has been little information regarding the toxic effects of these by-products. This is due to their structural characteristics and problems concerning their pure synthesis for toxicological tests, even though it is possible to test extracts of degradation mixtures without the need to identify every product. Bearing in mind that the degradation might not be complete and some of the products can be even more toxic that the native compounds, non-target analysis of drinking waters (without any previous selection of analytes) can also be performed [163]. There have also been some studies which have focused on the selection of representative groups (indicators) of pharmaceuticals. For example, Kumar and Xagoraraki [167] presented a ranking system of endocrine-disturbing chemicals for the monitoring of surface and treated drinking waters in the USA. The proposed ranking system was based on four criteria: occurrence, treatment in drinking water treatment plants, ecological effects and health effects.
21
Of the seven attributes: prevalence, frequency of detection, removal, bioaccumulation, ecotoxicity, pregnancy and health effects, it was stated that health effects and the treatment in drinking water treatment plants were the most important. The total ranking for the selected pollutants was the sum of the importance of the factor weight. Out of a group of pharmaceuticals,
17α-ethinylestradiol,
19-norethisterone,
demeclocycline,
flumequine,
methylbenzyldene camphor were ranked as the top five. Of course in order to determine these indicators, the long term monitoring of pharmaceuticals in water matrices had been previously carried out, the USA being a country with a relatively high problem of pharmaceutical contamination in treated drinking water.
4.2.3. The main step – sample taking and preservation As sampling is a very crucial step in obtaining reliable results, representative samples must be collected which contain the average characteristics for the sampled matrices. Because drinking water is generally homogenous, grab samples can be taken [133, 152, 157, 159]. As has been previously highlighted, passive sampling is also a good technique for the long term monitoring and determination of average concentrations over time. However, although, it may seem to be the perfect choice for the analysis of pharmaceutical residues in drinking water, there are also some drawbacks. First of all, there is generally a lack of passive samplers for pharmaceuticals such as polar compounds (passive sampling is mostly used for non-polar compounds, such as pesticides). Secondly, there is a problem with the introduction of passive samplers into the water system (where and how) and their stability in water. Finally, their impact on the quality of the drinking water and the low reliability of the obtained results must be also considered. Drinking water samples are normally collected into plastic cans [159, 168], or into dark-glass bottles [96, 133-134]. Polar pharmaceuticals possess good solubility in water and should not
22
be adsorbed into the sides of the bottles. One exception that needs to be taken into account is the group of antibiotics. These samples should rather be collected into glass bottles and Na2EDTA will need to be added to the water as a stability agent and as an adsorption controller for these analytes [134, 169]. The collection and preservation of drinking water samples are generally the same as for other water matrices. There are only two important differences – a higher volume of the drinking water samples is needed (this will be discussed later) and there is a need to remove chlorine and other oxidation reagents. Free oxidation and chlorination reagents can decrease the concentrations of pharmaceuticals during transport and storage. An efficient way to eliminate chlorine is the addition of ascorbic acid [161] or Na2SO4 [135, 154, 158, 170]. The length of time of sampling storage is generally the same as for other water samples, but direct analysis is recommended, especially for antibiotics [169]. Some details about sampling and sample storage can be found in EPA report (2012 [171]).
4.2.4. The need for high volume extraction As concentrations of pharmaceuticals in drinking water are in the range of several ng L-1 (examples are presented in Table 2) and the average limit of detection of chromatography techniques coupled with mass spectrometry is close to 10 ng mL-1, the concentration factor (CF) during their analysis in these matrices should be high (around 1000). This means that if the extract volume is 1 mL, the sample volume should be 1000 mL. High volume extractions are typically coupled with a high matrix effect, because of the fact that some of the compounds can not be totally eliminated from the matrix and are concentrated together with the analytes. The drinking water matrix is not very complex and if appropriate extraction techniques are used (mostly solid-phase extraction, SPE), then limits of detection close to 1 ng L-1 can be achieved.
23
Water sample volumes of 1000 mL are recommended to determine pharmaceuticals in drinking water, groundwater and treated wastewater using the EPA Method 1694 (December 2007, EPA-821-R-08-002). This method has been used by several researchers [135, 143, 147, 172] and involves the extraction of 74 pharmaceuticals (in four groups) using Oasis HLB (60 mg of solid sorbent with a universal extraction properties) from various water samples with sufficient limits of detection. According to our experience – along with the manufacturers of SPE columns - the average volume of water samples which can be passed through the solid sorbent without any significant lost of extraction speed and efficiency, is in the range of 100 to 200 mL, which seems to be insufficient for the analysis of drinking water. Common SPE techniques can also be performed using speed extraction disks (speedisks), which are characterized by a fast extraction of high volume samples (80 – 90 mL min-1, up to 2 L, according to the manufacturer’s information). However, to date, speedisks have been used in the analysis of pharmaceuticals in drinking water only once [151], although they have been used in the analysis of estrogens in rivers [173-174], antibiotics in seawater [100-101] and a mixture of pharmaceuticals (19 analytes, e.g. trimethoprim, ampicillin, carbamazepine, ibuprofen) in surface and ground waters [168], reaching recoveries in the range of 49 – 110%. The observed matrix effects did not affect the results of the analysis. Nevertheless, it should be noted that the limits of detection presented in this paper were in the range of 0.15-12.46 ng L-1, which are similar to those presented in Table 2. Of course, the LOD values depend not only on the sample volume, but especially on the equipment used and the entire analytical protocol.
24
4.2.5. The need for low limits of detection - GC-MS or LC-MS? The crucial need for very low limits of detection of pharmaceuticals in drinking water can be achieved only with the use of selective and sensitive equipment. This is why mass spectrometry (MS) is the preferred choice. Its advanced technology of ionization, mass analysis, detection and, essentially, data recording modes, combine to give researchers an excellent tool for the analysis of residues. Mass spectrometry is of course associated with matrix effects, but most of these effects can be removed by application of a correct sample preparation step [175]. Tandem mass spectrometry is always the preferred choice, because of the higher identification factor (more identification points [176]). The question remains of what choice of chromatographic technique will be coupled with the MS. Pharmaceuticals - being mostly polar and semi-polar - are non-volatile, therefore liquid chromatography is normally used as the most appropriate technique. The use of a derivatisation step for gas chromatography separation means this technique is both time and reagent consuming. However, recently it has been investigated and subsequently proven that appropriate derivatisation optimization can decrease the limits of detection for some pharmaceuticals [177]. This and other advantages of GC (the lower costs of equipment and analysis, the lack of liquid wastes) could mean future trends might see liquid chromatography become the preferred tool for the analysis of pharmaceuticals in water samples. This view is supported by an interlaboratory exercise which was undertaken in the case of the analysis of non-steroidal
anti-inflammatory pharmaceuticals
(examples
–
ibuprofen, naproxen,
ketoprofen) in environmental water [178]. Although it was concluded that generally both techniques could be applied successfully, the GC-MS provided better results in the case of analytes in complex matrices. The LODs of selected pharmaceuticals in water does not differ significantly between selected separation techniques. In support of this statement, a comparison of the detection limits for
25
several techniques used in the analysis of carbamazepine in drinking water is presented in Table 3. These pharmaceuticals were selected because of the fact they can be analysed using both LC and GC techniques [as trimethylsilyl derivatives [159]), and can be widely detected in drinking waters (Table 2 and [163]) as well as other water matrices [179-180]. As shown, there is no correlation between the used techniques, sample volumes and the obtained MDLs/MQLs. Therefore, the choice of technique for the analysis of residual pharmaceuticals in drinking water depends only on the laboratory staff and the possibilities. Nevertheless, in the end, all of the methods need to reach the ng L-1 limits of detections. It should also be noted that nowadays more and more methods are based on UHPLC separation (examples in Table 2 and 3) coupled with MS detection, which can achieve results for multiple analytes over very short periods of time.
4.3. Outlook Several authors have stated that the detected concentrations of pharmaceuticals in drinking waters are safe for humans [139-140, 144, 152, 183]. The same point of view has also been expressed both by the World Health Organization [184] and the U.S. Environmental Protection Agency (U.S. EPA) [185]. However, all have concluded there is a need for expanded research into the conditions of natural water and more advanced risk assessments to be made. Therefore, the long term monitoring of pharmaceuticals in drinking water is needed in order to assess how polluted this matrix is. Generally, adequate instruments and methods already exist, but if in the future the concentrations which could do harm to human health turn out to be lower than we now think, methods will need to be developed to reach lower limits of detection. In addition, the future monitoring of pharmaceuticals in drinking water samples will need to have clear definitions of reference methods as well as interlaboratory comparisons in order to certify the results that are obtained.
26
5. Current approaches and challenges in the quality assurance and control in the analysis of the residues of pharmaceuticals in the environmental samples The quality and repeatability of monitoring tools used in environmental analytics cause that special care is taken in the areas of quality control and quality assurance (QC/QA). The results of the measurements must be meaningful (reliable), they must reflect accurately (simultaneously precise and true) the real content (amount) of the analytes present in the representative part of studied sample [186]. Quality control and quality assurance of the analytical results should include all stages of analytical process and what is more, be integral. A significant limitation of this action, in the case of the determination of the residues of pharmaceuticals in the environmental samples, is lack of availability of certified reference materials or reference methods. Due to that the validation of analytical methodologies apart from determining typical metrological parameters should include determination of: extraction effectiveness (EE), matrix effect (ME), absolute recovery (AR) [175] as well as estimation of expanded uncertainty. All these aspects are described in details below.
5.1. Validation procedures International Organization for Standardization defines the method validation as “confirmation through examination and provision of objective evidence that the requirements for a specified intended use or application are fulfilled” [187]. This procedure is required for new proposed analytical methods, the employment of different analysts or instrumentation, methods used in different laboratories, as well for established method revision and for demonstration of equivalence between two different methods [188-189]. The important information on the validation procedure could be found in the literature, as well as in the official guidelines, e.g. [188, 190-192]. One of them is the Commission Decision 2002/657/EC [193] implementing Council Directive 96/23/EC [194] which refers to the results of analytical methods and their
27
interpretation used for monitoring of some substances and their residues in life animals and animal products. High requirements for analytical methodologies became the reference not only for the quality control of food products but also all other analytical solutions that are being developed. According to this directive [193], to confirm the presence of a compound, 4 (group A) or 3 (group B) identification points (IP) are required depending on the group of analytes. Application of low-resolution mass spectrometers (QqQ, IT) and identification of pseudomolecular ion (precursor ion) allow to obtain 1 IP and 1.5 IP for every fragmentation ion (product ion). It means that working in MRM mode and choosing pseudomolecular ion as a precursor ion for every compound and two transitions pseudomolecular ion → fragmentation ion allows to obtain 4 IPs, what covers the requirement [193]. Very interesting information on drug confirmation by mass spectrometry coupled with chromatography, identification criteria and complicating factor, is presented by Yuan et al. [195]. Factors affecting the result quality and correct results interpretation are discussed and several emerging technologies and their potential applications are briefly explored. It should be also noticed that the official guidelines do not present a validation experiment sequence because the optimal sequence may depend on the method itself and the application [189]. Usually it involves the determination of the following validation parameters: i.
Selectivity
ii.
Linearity and range
iii.
Precision (repeatability and intermediate precision)
iv.
Accuracy
v.
Method Detection Limit
vi.
Method Quantitation Limit
vii.
Robustness/ruggedness
viii.
Stability [192].
28
A practical approach in the planning of validation procedures in quantitative highperformance liquid chromatographic methods in pharmaceutical analysis has been presented by Bonfilio et al. in 2012 [196]. Relevant approaches of various parameters have been discussed and supported by the presentation of the several up-to-date examples. This information could be very useful as an introduction to analytical validation for practical applications [196]. It should be also noticed that determination of the validation parameters is mandatory while a transfer of analytical methodologies from one technique to another is planned, because the sample preparation stage can differently influence the quality of final determination. Additionally, the rules of System Suitability Test (SST) for developed and validated methodologies planned to use for routine analyses should be established in order to confirm their quality during their usage.
5.2. Quality assurance vs matrix effect and recovery All analytical approaches for the analysis of pharmaceutical residues in the environment use the mass spectrometry detection. Although the MS is a powerful tool for a residues analysis, because of its sensitivity and selectivity when the SIM or MRM mode of ions detection is used, it is fraught with a phenomenon called matrix effect (ME). The effect of matrix components on electrospray ionization in LC–MS has been described by Kebarle and Tang in 1993 for the first time [197]. The mechanism is still not fully understood [198], but one of the most probable reasons is competition between an analyte and a co-eluting matrix component during ionization [199], what cause a decrease in analyte ionization (ion suppression) or an increase in this ionization (ion enhancement). Both of these effects bring errors in final results. The ME depends on the type of ion source used during the analysis; and the electrospray (ESI) is the most sensitive not only to matrix components, but also to the eluent
29
composition, especially salts [200]. The atmospheric pressure ionization (APCI) is less sensitive to ME, because the ionization of molecules takes place in the gas phase, almost without the eluent components [198]. The possibility of co-elution of analytes and interferents in LC-MS is high, thereby ME need to be taken into account as one of the important factors for a protocol development. In the case of GC-MS, the nature of ME is different. Electron impact ionization (EI) is not affected from an injected sample composition, firstly because the ionization occur in a gas phase for separated molecules, secondly - the resolution of column is greater. This however does not mean that the GC-MS has no matrix effect. The detailed studies confirmed that the ME in the GC-MS techniques is related with a separation technique [187]. The accumulation of non-volatile matrix as well as products of its pyrolysis in the GC system may generate new active sites, what results in analytes adsorption, problem with peak shape and intensity, and finally lack of long-term repeatability [201]. The opposite effect, known as ‘matrix induced chromatographic response enhancement’ was also observed, mainly for pesticides [202]. Although the sample preparation step eliminates most of the matrix, the interferents can not be completly eliminated and ME is observed in both LC-MS and GC-MS analysis. One of the approaches during the optimization of extraction procedure is the evaluation of ME and finding the protocol with the lowest MEs. The measurement of matrix effect is relatively easy, but it increases the cost of whole procedure. Nevertheless, it is essential to measure the ME during the complex matrix analysis, like environmental samples, and what is even more important during trace analysis. The ME have an impact on the final result of pharmaceutical concentration, so the efficiency of the whole analytical procol. It should albo be pointed out that extraction process have a non-total efficiency. So the question is how to differentiate the effect of matrix and an extraction into whole analytical protocol. The matrix effect in LC–MS analysis was first assessed by Matuszewski et al. [203], who used very simple equations (1)–
30
(3) to determine the matrix effect (ME), recovery of extraction (RE) and overall process efficiency (PE): ME (%) = B/A × 100
(1)
RE (%) = C/B × 100
(2)
PE (%) = C/A × 100 = (ME × RE)/ 100
(3)
in which A is the peak area of the analyte(s) recorded for the standard solution, B is the peak area of the analyte(s) recorded for the sample spiked with the target compound(s) after extraction, and C is the peak area of the analyte(s) recorded for the sample spiked with the target compound(s) before extraction. This approach is very simple and diverse the ME and extraction efficiency, but also accumulate these two factors into one PE. Similar protocol for GC-MS technique was described in our previous paper [187]. where RE was described as extraction efficiency (EE), and PE as a absolute recovery (AR). Both approaches should be used not only for the analysis of pharmaceuticals in environmental samples but whenever complex sample is analyzed. Determination of ME in analytical methods based on the application of both LC–MS and GC– MS techniques yields information not only on the quality of sample preparation and purification, but what is more important it enables false-negative/false-positive results and incorrect analyte concentrations in sample to be avoided. Additionally, GC-MS seems to be less sensitive to the ME [187]. In the Table 4 examples of EE, ME and AR obtained for a selected analytes analyzed in different water samples are presented. Nevertheless, direct comparison of a ME, EE and AR values can not be performed, because the values were obtained for different methodologies (sample volume, extraction cartridges, range of concentration, etc.). One of the ways to eliminate the influence of matrix effect onto results (but not in a analytical process) is the usage of matrix-matched calibration, when the calibration curve is performed
31
by adding of analyte directly to the tested sample [168]. This approach need a matrix free form analytes (unfortunately lack of reference material in this case) and repetition of calibration every time when the sample matrix is changed, so it is labor-intensive and expensive, but gives the most reliable results. Other technique is the usage of isotopically labeled surrogate standards to compensate losses during extraction and impact matrix effects [205-206]. The best way of ME elimination is better sample preparation (both GC-MS and LC-MS), optimization of ion source parameters and mobile phase composition (LC-MS) and maintaining the analytical equipment in clear conditions (GC-MS). There is also other ways to avoid ME [187], but no universal protocol of its estimation. Nevertheless, the matrix effect is very important parameter of a quality assurance.
5.3. Assessment of expanded uncertainty Sample preparation procedures are multistep procedures, which involve many problems associated with the reliable quantification of the analyzed compounds. Moreover, as highlighted by Konieczka and Namieśnik [207], there is no such thing as an ‘errorless measurement’, which means that every analytical result is inseparably associated with the term ‘error of measurement’. In consequence, it means that the final results may be affected by a large error and do not reflect real concentrations of pharmaceutical residues in the environmental samples [100, 186]. Therefore, the uncertainty of the result of a determination must be calculated and accompany its presentation. Moreover it is a requirement of the ISO 17025:2005 standard [208]. Furthermore the expanded uncertainty budget allows to a detailed analysis of uncertainty sources and can highlight sensitive steps of the analytical method. Hence it is a powerful tool for optimizing sample preparation procedure [100, 158, 207]. Measurement is a process in which a set of steps is performed to determine the value of a quantity. Therefore for the correct estimation of uncertainty the sources and types of uncertainty for all these steps must be established. For this purpose, the most helpful tools are
32
a flow diagram, drawn on the basis of information presented in detail in a standard operating procedure, and an Ishikawa or fishbone diagram, which shows the influence of parameters (sources of uncertainty) on the total analytical procedure [186]. Moreover, the expanded uncertainty of the obtained data can be estimated according to the Guide to the Expression of Uncertainty in Measurement [209] or EURACHEM/CITAC guide [210]. Those Guides provide general rules for evaluating and expressing uncertainty in measurement that can be followed. Unfortunately, there are only a few original papers where the authors have estimated the expanded uncertainty of the analytical procedures [e. g 211-214]. Moreover, so far only seven papers have dealt with the estimation of expanded uncertainty of the methods for determining pharmaceuticals in environmental samples [158, 100-101, 215-218]. As it was mentioned before – the uncertainty estimation should be an essential component of the set of analytical results. It is essential to perform a meaningful assessment of environmental hazards. Therefore, the focus has to be intensified on this field, as the presentation of measurements together with their uncertainties is still a problem.
6. Implementation of Green Analytical Chemistry (GAC) in the analysis of pharmaceuticals in the environmental samples Growing ecological awareness led to the conclusion that taking care of the environment is becoming one of significant priorities of modern civilization development. Increase of demand for different products and goods necessary for living is connected with the necessity of development of low-waste technologies as well as ones with closed circulation of technological media and recirculation of wastes and side products. Because of this fact a lot of environmental actions has been undertaken for many years including introduction of 12 rules of Green Chemistry into chemistry and chemical technology in 1998 [219]. This term is inextricably connected with the spread of sustainable development rules and the trend of their
33
introduction into chemical factories, quality control points as well analytical laboratories. Actions such as prevention, resources saving, limit of the use of dangerous compounds, use of safe solvents and reagents, effective use of energy, limit of derivatization processes and others are included in the set of the mentioned rules [219]. In analytical practice a large number of analytical methods and techniques is applied and the number of measurements rises rapidly trying to ensure the possibility of trace and ultra-trace measurements. Thus, the development of green chemistry will be almost not possible without introduction those rules into analytical activity. Four parameters can decide about “green” character of analytical chemistry: (i) elimination (or at least limit of use) of chemical reagents especially organic solvents from analytical procedure; (ii) minimalize the labour and energy intensity of analytical procedure (per one analyte); (iii) minimize the use of high toxic and eco-toxic reagents from the analytical procedure; (iii) possibility of measurement of wide range of analytes in one analytical run [220-221]. It is worth to mention that presented environmental advantages are connected with economical advantages what causes their implementation attractiveness. The term of Green Analytical Chemistry (GAC) was introduced to chemical terminology in 2000 [221]. Available data suggests that the impact of different analytical methods and techniques on the environment is more often evaluated by the same ways as applied in the evaluation of impact of technological processes and manufacture techniques (e.g. Life Cycle Assessment, LCA). In such assessment not only amount of reagents and energy used during whole analytic process but also the cost and environmental damage connected with manufacture of reagents and solvents and utilization and hazardous waste management after analysis are taken into account. Basing on what has just been explained and on literature data it can be concluded
34
that the groups of analytical methods and techniques which utilize GAC rules develop extremely intensively [222]. The demand for more precise and stricter quality assessment of not only environmental, but also biomedical, clinical, agricultural or food measurements necessitates conducting research on two stages: (i) seeking for so called environmental friendly analytical methodologies which characterize the lack or low emission to the environment; (ii) determination of wide spectrum of analytes at getting lower concentrations in different matrices [220-222]. That is why an effort of many analysts concentrates on developing of new, more effective analytical procedures for determination of target compounds in either liquid or solid samples, or improvement of existing ones. It is possible thanks to introduction of new generation high sensitivity measuring instruments to analytical practice or by developing new procedures/ sample preparation technologies before final determination. This particular action is going to be of significant importance in chemical analysis for controlmeasurement needs. Nowadays, as it was already highlighted, methods based on high-performance liquid chromatography (HPLC) are the basic analytical tool in pharmaceutical analytics in environmental samples [223-225]. However, for several years ultra-high-performance liquid chromatographs have been introduced into analytical market. These devices are competitive to traditional high-performance liquid chromatographs. In modern UHPLC systems a lot of improvements were applied, starting from construction of pumps, injectors as well detectors where the volume of measurement cells was lowered and the sample throughput was increased. All modifications were designed to reduction of void volume of the system and preparing for work under several times higher pressures comparing to standard HPLC system. Introduction of such changes allowed to shorten analysis time and significantly increase of
35
sensitivity and resolution. It is worth noticing that the shorter time of analysis substantially reduces the cost of analysis, through more effective use of equipment and lower use of solvents. Shortened time of equilibration also supports mentioned advantages. It is so because void volume of the whole system was lowered from ca. 1-2 ml to ca. 120 μl. It is extremely important because shorter analysis time, less amount of solvents used and generation of smaller amount of wastes make this technique more environmentally friendly and economically efficient (reducing the cost of waste disposal) [226-228]. For example, when using a traditional column with 5 μm particle sizes, 4.6 mm of diameter and 150 mm of length at the flow of 1 mL/min, and time of analysis of 17 min, the usage of mobile phase equals 17 mL/analysis. After transfer of this method to UHPLC system the analysis time is reduced to 2.15 min, whereas the consumption of mobile phase is 1.18 mL/analysis, which gives almost 8 times saving of analysis time and 14 times lower usage of solvents. It also must be stressed that cost of UHPLC system is slightly higher comparing to classical HPLC system. Despite many advantages UHPLC technique slowly enter economical market, mainly remaining in the interest of scientific research area. It is due to the need of tedious and difficult transfer of analytical methods from conventional systems to ultra-high-performance ones. The fundamental relationship between the physical dimensions of a chromatographic column and the performance of separations performed using it are well known. Of these, perhaps the most critical to understanding the implications of transfer between HPLC and UHPLC are the relationship between column length, van Deemter equation considerations, pressure drop effect as well as extra column void volume effects. Taking above into account one could state that the theoretical relationships that govern the scaling of methods from HPLC to UHPLC conditions are from one side established but provide only a start up framework for the adjustment of chromatographic parameters. Any theoretical predictions are greatly imperfect. This is because of affecting the system by additional factors that are functions not only of the
36
above effects but also injection volumes, flow rates, gradient time and finally frictional heating, negligible in classical HPLC but having dramatic negative consequence for UHPLC performance, if not adequately addressed. For these reasons developed commercial calculators, algorithms and formulas for HPLC – UHPLC transfers shall always be adopted with an assistance of thorough experimental verification. Benefits of utilizing UHPLC methodologies are obvious. Application of thereof fit 4 rules of ‘green chemistry’ not only by limitation of solvent use and smaller wastes generation but also by decrease of time and energy consumption during analytical procedure. Additionally high resolution allows to develop of methods for measuring wide spectrum of compounds in one chromatographic run [i.e. 226-228]. The UHPLC technique is highly recommended for routine analyses of polar compounds, including biological activate substances such as: pharmaceuticals. However, as it was highlighted in the previous sections liquid chromatography in reverse phase coupled with mass spectrometry (LC-MS) or tandem mass spectrometry (LC-MS/MS) is still the most commonly used in analyses of these compounds. This technique ensures the high sensitivity and selectivity simultaneously allowing measurements of diverse structure compounds regardless of their polarity and thermolability. Gas chromatography coupled with mass spectrometry (GC-MS, GC-MS/MS) is also widely used for this purpose. Although ultra-high-performance liquid chromatography (UHPLC) has joined the routine HPLC in determination of pharmaceutical residues in environmental samples the number of its applications is still very low [104,118, 226, 229-232]. It proved to be useful i.e. 18 drugs from androgenes and progestagens groups in environmental samples [229], as well 74 pharmaceuticals and 84 pesticides and pharmaceuticals at times of < 10 min [230-231]. Furthermore Gros et al. presented the methodology for determining 54 antibiotics and their metabolites in environmental water samples at the analysis time shorter than 2.5 min [232].
37
However, the range of so far developed procedures is staggeringly modest both in terms of the diversity of analysed compounds and complexity of investigated matrices. Nowadays, a special attention is also paid to sample preparation procedures, which ensure not only the reduction of organic solvent consumption or their total elimination, but also decrease the number of steps and processes involved in the sample preparation stage. Because of these reasons in the last few years there was a rapid development of non-solvent sample preparation techniques, the use of agents which support extraction process (UV radiation, microwave radiation, ultrasonic, higher temperature) implementation of automated and miniaturized set designed for sample preparation, simultaneously ensuring high efficiency and economy [220222]. However, continuously the majority of work connected with sample preparation is done manually. That is why automation of analytical techniques allows to reduce the labour and energy intensity required in analytical procedures and further elimination of the human factor. Up till now, as it was presented in the previous sections, the most common technique of isolation and enriching of pharmaceuticals from different environmental matrices is solid phase extraction (SPE) [i.e.233-234]. This technique is very popular because of wide range of sorbents, high efficiency and small usage of solvents. Conducted research has confirmed that it allows selective isolation even small amounts of these compounds (ng level) from very complex matrices. It is also widely used in purification of solid sample extracts. Despite of many innovation that have been introduced mainly in the different shapes and dimensions of columns, forms of solid sorbent (i.e. fiber, extraction disc), the classical SPE columns are being the most frequently used in extraction of drug residues from liquid samples [235]. While extraction of residues of pharmaceuticals from solid matrices is more complicated as it was already highlighted, it is usually accomplished by the following techniques in solid-liquid system: i) shaking; ii) accelerated solvent extraction (ASE) or pressurized liquid extraction (PLE), ultrasonic solvent extraction (USE); or microwave assisted extraction (MAE) [i.e.
38
235]. The review papers presenting the application of these techniques as “green” techniques in sample preparation step for the analysis of different organic compounds (including pharmaceuticals) in environmental samples have been recently published [236-241].
7. Application of CNTs in sample preparation techniques to overcome selected problems in the determination of pharmaceuticals in environmental samples The efforts of many analysts have been focused on developing new, low-cost and effective analytical procedures or improving existing ones. Due to the low levels of pollutants in the environment, particular attention has been paid to investigating sample preparation, which can successfully isolate and concentrate a wide range of analytes. Efforts have also been focused on reducing the amount of liquid solvents or providing their complete elimination in the course of the analytical procedure, as well as minimizing the number of operations used in sample preparation, thereby reducing the time and cost of the whole procedure. One of the hot topics of research in recent years has been the use of carbon nanostructures as a sorbent in extraction techniques.
7.1. General characteristics of carbon nanotubes (CNTs) A wide range of carbon materials are available for use in analytical chemistry. Only a few studies describe the use of nanodiamonds, nano-onions, nanofibers, nanotubules, and nanorings, whereas recent applications have been primarily focused on the use of fullerenes and nanotubes (CNTs) [242-248]. In both cases, the basic structure is composed of a layer of sp2 bonded carbon atoms, wherein each atom is bonded to three other carbon atoms [249]. CNTs have a regular and symmetrical structure which resembles graphene, however, they have a cylindrical shape with a diameter of several tens of nanometers, and a length of micrometers [249]. Depending on the number of graphene layers, CNTs can be divided into
39
single-walled carbon nanotubes (SWCNTs) and multi-walled carbon nanotubes (MWCNTs). The design, synthesis, characteristics, and applications of nanomaterials are the most critical aspects in this emerging field of nanomaterials. Moreover, CNTs may be functionalized with various chemical groups to enhance their affinity for target compounds. This means the possibility of selective extraction of target analytes in both environmental and biological samples [250-252]. CNT can be functionalized in two ways: non-covalently and covalently. Non-covalent functionalization involves the physical adsorption of molecules onto the CNT side walls by Van der Waals interactions, π…π interactions, hydrogen bonding, electrostatic and hydrophobic interactions [251-252]. Covalent modification involves the formation of a bond between the functional groups and the skeleton of the carbon nanotubes. This type of functionalization can be carried out directly or indirectly. As a result of direct covalent functionalization, the hybridization of the carbon atom changes. In contrast, indirect functionalization takes place through the functional groups at the open ends of CNTs and the defects of the carbon sheet. The functional groups (for example: hydroxyl, carboxyl, or a carbonyl group) are introduced by heating the CNT under strong chemical conditions such as HNO3, H2SO4, and HCl, or other oxidants, such as H2O2, O3, KMnO4, and NaOCl. The carboxyl group is then converted to the acyl chloride and can undergo esterification or amidation [250].
7.2. Application of CNTs in sample preparation techniques The unique and tunable physicochemical properties of CNTs allows the development of new or improved analytical procedures compared to those that presently exist. Based on the results presented in recently published review papers, it can be concluded that the main advantages of using CNTs in sample preparation steps are as follows: (i) using CNTs in sample preparation, generally helps simplify this step;
40
(ii) their high surface-volume ratio and resulting high adsorption capability allows higher extraction efficiency and lower LODs values to be achieved than with using conventional sorbents; (iii) the physicochemical properties of CNTs can be controlled with functionalization which can ensure the flexibility needed for use in many analytical applications; (iv) their high adsorption capability enables the use of small amounts of a sorbent, which is a step towards miniaturization, and thus reduces the volume of solvents used; (v) they allow the extraction of small volume samples and samples > 1 L, without exceeding the breakthrough volume; (vi) CNTs can be very easily regenerated (chemically or thermally), and re-used without reducing extraction efficiency; (vii) many authors have reported that the consequences of all of these aspects will mean a reduction in the cost and time of sample preparation [242-248, 253-254]. All of these aspects are crucial in the improvement of existing sample preparation procedures used in the analysis of residues of pharmaceuticals in environmental samples. That is why for the last few years, CNTs have also been tested as potential adsorbents in sample preparation techniques used to extract these chemicals not only from environmental matrices but also others (such as food). This is additional proof of their wide applicability and will be discussed below. 7.2.1. Solid phase extraction At first, studies which compared the enrichment efficiency of CNTs with conventional sorbents such as C18, Oasis HLB, PS-DVB, XAD-2 or activated carbon were conducted. Cai et al. proposed the use of carbon nanotubes for enrichment endocrine disruptors [254]. A simple and quick method using MWCNTs (with a 30-60 nm outer diameter) has been developed for use in the isolation of three endocrine disruptors (bisphenol A, 4-n-nonylphenol
41
and 4-tert-octylphenol) from tap water, river, sea and wastewater. After evaluating the effects of various parameters on extraction efficiency, comparative studies with C18, XAD-2 and PS-DVB copolymers using the same parameters as MWCNTs were carried out. The results indicated that the MWCNTs were at least as effective as the C18 in the isolation of 4-nnonylphenol and 4-tert-octylphenol, but they were more effective than the C18 in the case of bisphenol A. The authors also demonstrated the better extraction ability of all three analytes with MWCNTs against the PS-DVB copolymer and XAD-2. It is also worth noting that the developed method allows the enrichment of up to 1 L of water, without exceeding the breakthrough volume. This fact, together with the small volume of eluent (2.5 ml methanol), allows the isolation of target compounds at concentrations as low as 0.018 ng mL-1. Research also worth mentioning is the work of Niu et al. [256], which presented a comparison of MWCNTs, SWCNTs, C18, and graphitized carbon black for the extraction of cephalosporins, sulfonamides, and phenolic compounds. Comparative studies have shown that the extraction yield is higher with the use of carbon nanotubes than for C18 in the extraction of highly polar analytes. For cephalosporins and sulfonamides, CNTs have shown an even higher sorption capability than graphitized carbon black. However, for some phenolic compounds, a higher extraction efficiency was achieved using graphitized carbon black, which suggests different mechanisms exist for the retention of these analytes. Finally, an extraction method was developed for sulfonamides as model compounds. Compounds containing amino or hydroxyl groups are more difficult to desorb, therefore the analytical procedures using these compounds needed to be optimized. Satisfactory recoveries (80-100%) of the analytes were obtained using a mixture of aqueous ammonium acetate(0.3 M): methanol (30:70, v/v). An SPE-GC-MS method, using MWCNTs for the determination of diazepam, estazolam, triazolam and alprazolam was described by Wang et al. [257] Under optimal conditions, recoveries were obtained of between 75 and 104% with LOD in the range of 2-5 µg kg-1. The
42
absorption capability of the MWCNTs against C18 under the same conditions was established using diazepam as a model compound. It was found that the MWCNTs are more effective in the extraction of diazepam than C18 and therefore less sorbent can be used. On the other hand, the extraction efficiency of MWCNTs and C18 in the enrichment of three barbiturates (e.g. barbital, amobarbital, and phenobarbital) was compared by Zhao et al. [258]. The results indicated that SPE cartridges packed with MWCNTs had a similar extraction capability as C18 in the cases of barbital and amobarbital, while the use of MWCNTs produced a higher extraction efficiency than C18 for phenobarbital. In addition to these results, an interesting investigation was reported by Polo-Luque et al. [259]. These authors describe the preparation of two hybrid materials MWCNTs/SWCNT-C18 with an ionic liquid HMIM PF6. These two hybrid materials were used for the extraction of sulfonamides from milk samples. The results indicated that extraction efficiency was higher using MWCNTs/C18 than for the SWCNTs/C18 or conventional C18. The limit of detection ranged from 0.069 to 0.030 mg L1
. The usefulness of MWCNTs as a sorbent in SPE for the isolation of some of the most
commonly consumed drugs, including four β-blockers and eight NSAIDs, from river and wastewater samples was examined by Dahane et al. [260]. Just 20 mg of carbon nanotubes was enough to pre-concentrate the analytes and 7 mL of methanol modified with 10% ammonium hydroxide allowed the complete elution of all of the pharmaceuticals from the MWCNTs sorbent. The authors compared the parameters of the developed method with the literature data. The recoveries obtained using MWCNTs for all of the analytes were the same as for conventional SPE sorbents such as Oasis HLB and Oasis MCX [261]. However, the MDLs values were lower than with the MWCNTs. In addition, one of the main benefits of the MWCNTs was the absence of a matrix effect for all the pharmaceuticals studied in river water and in wastewaters. The authors also emphasized that the price of the MWCNTs cartridge was 30% lower when compared to the Oasis HLB cartridge. Furthermore, a MWCNTs
43
cartridge can be re-used up to 10 times, after washing with 5 mL of methanol, whereas traditional cartridges are usually discarded. The MWCNTs SPE-HPLC-UV method was also applied in the isolation of nine antidepressants (e.g., imipramine, desipramine, amitriptyline, nortriptyline, clomipramine, trimipramine, trazodone, fluoxetine, and mianserin) from urine samples [262]. Studies have shown that 30 mg of MWCNTs was enough for the quantitative extraction of all of the analytes at therapeutic and toxic levels. The value of the recoveries ranged from 72 to 97%. The results of this study also showed the absence of matrix effects from the endogenous sample components and other drugs that may be present in the urine samples. This method is therefore suitable for the therapeutic monitoring of antidepressants in urine. 7.2.2. Dispersive solid phase extraction In standard mode, SPE sample loading is usually a time-consuming process (especially for large sample volumes), due to the limited speed and mass diffusion of the analytes in the sorbent mass packed in the cartridge. For example, at least 100 mins were required to load the sample 1 L of water in the SPE method [263]. In addition, solid particles commonly found in samples of food may cause clogging of the cartridge and can lead to failure of the extraction. Dispersive solid phase extraction can significantly reduce the amount of sample preparation time in comparison with conventional SPE, due to the fact that the sorbent is efficiently dispersed in the sample matrix instead of passing slowly via an extraction column. Therefore, the extraction time is better, because it avoids the time-consuming step of passing the solution through the column. Because of this, many researchers have applied this method of extraction using CNTs as a sorbent [264-276]. Oxidized multiwall carbon nanotubes (O-MWCNTs) were applied to the isolation method of eleven quinolone antibiotics (moxifloxacin, lomefloxacin, danofloxacin, ciprofloxacin, levofloxacin, marbofloxacin, enrofloxacin, difloxacin, pefloxacin, oxolinic acid and flumequine) from different water samples. The
44
recovery values for all of the analytes were in the range of 77.8-116% in Milli-Q, 73.5-108% in mineral water, 67.1-103% in tap water, 62.3-97.0% in wastewater, whereas the LODs were in the range of 28-75 ng L-1 in Milli-Q, 30-79 ng L-1 in mineral water 31- 87 ng L-1 in tap water and 31-94 ng L-1 in wastewater. These values are similar to those achieved with conventional SPE cartridges. However, this dSPE procedure is highly selective and can be easily applied to different matrices of water. [267]. The authors of this study also concluded that dispersion of the CNTs is very important due to the fact that the extraction yield directly depends on the area of contact between the sample and the extractant phase. In addition to the chemical modifications of the surface of the CNTs [266-268, 274], other methods for the disaggregation of CNTs, including non-covalent modification [275-276], or the addition of external energy (for example, ultrasound) have been described [277]. A method using MWCNTs as a sorbent in dSPE with ultrasound-assisted adsorption and desorption was developed for the isolation of estrogens from water samples [277]. By optimizing the extraction procedure, it has been shown that just 10 mg of CNTs is the optimum amount for an effective extraction of analytes. Of all the tested solvents, the best recovery values were obtained using 1.25 mL of acetone as the desorption solvent. Under optimized conditions, the recoveries for three analytes in spiked samples were over 82%. The detection limits were 0.076 ng mL-1 for estrone, 0.049 ng mL-1, for 17β-estradiol, and 0.057 ng mL-1 for estriol. The usefulness of CNTs as sorbents in dSPE for the isolation of pharmaceuticals has also been confirmed by other authors [264, 266, 278-281]. The recovery values were higher or comparable to those obtained using classical sorbents, however the amount of CNTs used was significantly lower. For example, a simple and inexpensive dSPE procedure for 10 β-2agonists (clenbuterol, ractopamine, salbutamol, bambuterol, penbuterol, tulobuterol, clorprenaline, mabuterol, cimaterol and terbutaline) in urine with MWCNTs as a sorbent was developed [266]. Recoveries of the target compounds from urine samples at pH 10.0 were
45
most efficient using 20 mg of MWCNTs, whilst a mixture of water:methanol (90:10, v/v) with 0.5% formic acid was shown to be the most suitable solvent for the desorption of the compounds from the MWCNTs. A simple and cost-effective pre-treatment procedure for the isolation of 18 sulfonamides from pork extracts using dSPE with MWCNTs was developed by Hou et al. [264]. The recoveries of the target compounds from the pork extracts were most effective when 150 mg of MWCNTs was used. Optimization of the extraction time was also done, whereby it was observed that increasing the time of extraction to over 2 minutes did not bring a significant improvement in the recovery values. Acetonitrile:50 mM ammonium acetate (95:5, v/v) was found to be the most suitable solvent mixture for the desorption of the compounds from the MWCNTs (recoveries > 90% for 14 sulfonamides). A new variant of dSPE, which has attracted a lot of attention in sample preparation, is magnetic solid phase extraction (mSPE) [278-281]. Typically, the adsorbent material is composed of a magnetic core (ie Fe3O4) and nanoparticles to extract various analytes. Adsorbents containing the retained analytes can easily be isolated from the solution by applying an external magnetic field after extraction. All of these advantages make mSPE a promising sample preparation technique in the extraction of many organic compounds including pharmaceuticals. Magnetic silica particles coated with MWCNTs-OH have been used for the convenient, rapid and efficient extraction of several estrogens (including diethylstilbestrol, estrone and estriol) from water [280] or milk samples [281]. In turn, molecularly imprinted magnetic carbon nanotube (MIPs/mCNTs) sorbent was used for the selective extraction of levofloxacin from serum samples [283]. Under optimal extraction conditions, recoveries ranged from 78.7 ± 4.8% to 83.4 ± 4.1%. The stability of the MIPs/mCNTs polymer was also evaluated, and the average recovery reduced by less than 7.6% after 5 cycles. Molecularly imprinted polymer-coated m-CNTs were also used as a selective sorbent in SPE for the isolation of naproxen from human urine samples [283]. All of
46
the aspects affecting the adsorption and desorption of the analyte at the MIPs/mCNTs were investigated. 7.2.3. Miniaturized devices for pharmaceuticals isolation It is worth noting that the introduction of CNTs during sample preparation helps to simplify this step and allows the miniaturization of devices. Fang et al. have developed a method for the simultaneous extraction and the determination of 10 sulfonamides in extracts of eggs and pork [284]. A MWCNTs column was used instead of a conventional sample loop in the sixport injector valve of the HPLC. This approach significantly reduced the sample pretreatment steps as well as the amount of chemical waste and analysis time (35 min.). In another example, as little as 6 mg of MWCNTs were packed in the mini-column and used in the isolation and determination of tetracyclines in water. Enrichment of the analytes was carried out using the online flow injection system connected to the CE-MS equipment. The MWCNTs showed greater extraction capabilities than the other two types of SWCNTs. Recoveries for all of the analytes ranged from 98.6 to 103.2%. The same approach was also used in the extraction and analysis of non-steroidal anti-inflammatory drugs (e.g., tolmetin, ketoprofen, and indomethacin) in urine. In this case, a high extraction efficiency was achieved using SWCNTs modified with COOH groups [285]. In order to extend the life of the COOHSWCNT - and to avoid problems associated with pressure due to the compactness of the minicolumn - the COOH-SWCNTs were chemically immobilized using a controlled porous glass. The coupling of the CNT on previously activated glass was achieved by leaving the glass for 5 hrs in contact with the COOH-SWCNTs and dimethylformamide containing 1,3dicyclohexylcarbodiimide. The high extraction capability was the result of the particular orientation of the immobilized COOH-SWCNTs. The developed method was used to analyze non-steroidal anti-inflammatory drugs in urine samples using CE-MS, which allowed the detection of compounds in concentrations of 1.6-2.6 µg L-1 for all of the analytes with only 5
47
ml of sample. The value of the recoveries ranged from 98.6% to 102.2%. A different approach to the miniaturization of conventional SPE was proposed by Bhadra et al. [286]. The proposed μ-SPE device consisted of a syringe with a replaceable needle containing the CNTs. The usefulness of functionalized or non-functionalized CNTs (0.3 mg) was tested in the isolation
of
five
different
pharmaceutical
compounds:
ibuprofen,
acetaminophen,
ciprofloxacin, fenofibrate, and sulfadiazine from water samples. It was demonstrated that the enrichment factor obtained using functionalized MWCNTs was significantly higher than that achieved using C18 under similar conditions. Another way to miniaturize the CNTs-SPE device was proposed by Springer et al. [287]. In this case, the classic SPE column was replaced by a 1000 µl pipette tip into which the CNTs were introduced. The prepared pipette was applied in th extraction of fluoroquinolones from milk samples.
A very simple analytical procedure was developed, involving protein
precipitation, followed by the SPE step with 5 mg of MWCNTs as a sorbent material and a mixture of methanol:formic acid (98:2, v:v) as the eluent. Under optimal SPE conditions recoveries for all of the analytes were between 84 and 106% whereas the LODs values were between 7.5 and 11.6 µg L-1.
7.2. Outlook In conclusion, the advantages of using CNTs as sorbents in extraction techniques are uncontested. Nevertheless, to date, commercial cartridges with CNTs are not available. The reason for this may be because there has been an insufficient work in this field, their full potential in analytical chemistry has still yet to be well-documented. Further studies to determine the usefulness of CNTs and their applicability are still being carried out, which could lead to the commercialization of CNTs as sorbents in techniques of extraction.
48
However, before CNTs can enter into commercial use, any potential risks associated with their presence in the environment will need to be defined.
8. Conclusions Various differing analytical aspects and current challenges in the analysis of residues of pharmaceuticals in soil, marine ecosystems as well as in drinking waters have been presented. There are still many different outstanding problems in relation to this topic, and there is a need for future research, mainly focused on: The fact that knowledge about the determination of the occurrence and fate of residues of pharmaceuticals in soil and marine ecosystems is still limited. There is also an urgent need for the development of reliable, fast and simple methods for their determination in such matrices, which will enable the detection of pharmaceuticals at very low levels of concentration (especially crucial in the analysis of marine waters). Further investigations into more sensitive and selective extraction methods are also necessary to overcome the problem of the strong matrix effects associated with the extraction of high volumes of samples (in the case of marine waters) as well as the complexity of the investigated matrices (such as soils and sediments). The need for multi-analyte methods that will reach lower detection limits and will be easy to apply in routine analysis. The introduction of standard guidelines explaining how, when and where samples should be collected in order to determine concentrations of pharmaceuticals. The implementation of reference methods for the determination of these chemicals in different matrices. This aspect - as well as the one mentioned above - will enable the comparison of obtained results between different laboratories/countries, etc. and the
49
establishment of maximal concentrations of these substances in different environmental compartments. The fact that QC/QA of analytical results should include all stages of analytical process and what is more be integral part of it. It should include not only standard validation of the analytical method but also the determination of matrix effects (ME) as well as expanded uncertainty. This is due to the fact that ME is very important parameter in QA as it enables false-negative/false-positive results and incorrect analyte concentration in sample to be avoided. Furthermore, sample preparation is a multistep procedure, which involves many problems associated with reliable quantification of the analyzed compounds. Hence final results may be affected by a large error and do not reflect real concentration of pharmaceutical residues in environmental samples. Therefore, uncertainty estimation should be an essential component of the set of analytical results. The focus has to be intensified on this field. The further implementation of GAC rules into the analysis of pharmaceuticals in the environmental samples mainly in terms of the application of on-line coupling, automatic and semi-automatic procedures, the development of multi-analyte techniques such as UHPLC, GC-GC or LC-LC as well as application of new and more selective sorbents for sample preparation techniques. The application of modern sorbents such as carbon nanotubes in different sample preparation techniques. The use of these very promising sorbents could overcome some of the discussed analytical problems in the determination of pharmaceuticals in different matrices and could assist in the growing need to develop new, low-cost and effective analytical procedures or improve existing ones. Due to the low concentration levels of these pollutants in environmental samples, particular attention should be paid to sample preparation steps to isolate and concentrate a wide range of analytes as well
50
as to reduce the amount of liquid solvents or their complete elimination in the course of analytical procedures. The minimization of the number of operations used in sample preparation will thereby reduce the time and cost of the whole procedure. The unique properties of CNTs, such as for example their high surface-volume ratio and thus, their high adsorption capability allows higher extraction efficiencies to be achieved and lower LODs values than with using conventional sorbents. Their tunable physicochemical properties can also ensure the necessary flexibility necessary for their use in many analytical applications. Other unique properties of CNTs include their high adsorption capability which enables the use of small amounts of sorbent (necessary for the miniaturization and the reduction in the volume of solvent used), the possibility to extract small volume samples and samples > 1 L, without exceeding the breakthrough volume, their regenerability and reusability without reducing extraction efficiency [242-248, 253-254]. All of these properties prove their high applicability and the possibility to improve or develop new analytical protocols for the analysis of residues of pharmaceuticals in order to assess their environmental fate. However, for this reason further research is necessary.
Acknowledgments Financial support was provided by the Polish National Science Centre under grants DEC2011/03/B/NZ8/03009 and DEC-2011/03/B/NZ8/03010 and National Centre for Research and Development (NCBR) (Poland) under grant TANGO1/268806/NCBR/2015 as well as by the Polish Ministry of Research and Higher Education under grant DS 530-8616-D593-15.
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Figure 1. The main sources of pharmaceuticals in drinking water
70
Table 1. Characteristics of the analytical methods for the analysis of pharmaceuticals in soils and concentrations pharmaceuticals detected in soil samples from different geographical areas published since 2014 Recovery Detected [%] Therapeutic Sample Sample preparation Analytical MQLa/MDLb/LCLc level Geographical Compound (Apparent Ref. class pretreatment (extraction/clean-up) method [ng g–1] [ng g–1 area recovery d.w.] [%]) 5 mL MeOH:ACN:0.1 M EDTA:McIlvaine buffer (pH4); HPLCDoxycycline 30:20:25:25, v/v/v/v/), (ESI)MS/MS 4a/1b 98 728* Enrofloxacin IS addition, vortex(in the SRM 9a/3b 102 378* Three states: Erythromycin mixed 30 s; extraction mode) (Internal 10a/3b 102 < MQL Selangor, 13 a b standards: C3Flumequine triplicately in an 4 /1 92 1331* Veterinary Negeri Trimethoprim; a b Norfloxacin Homogenized ultrasonic bath for 10 8 /3 82 96* 13 C2 antibiotics Sembilan and [69] a b Sulfadiazine and sieved min (UAE), 7 /2 72 < MQL Erythromycin; and hormone Melaka located Tilmicosin centrifugation 4000 rpm, Ciprofloxacin-d8 10a/3b 93 < MQL in Peninsular Trimethoprim 10 min /Supernatant (20 hydrochloride; 2a/0.5b 102 60* 13 Malaysia C6 Tylosin mL) diluted by H2O to 9a/3b 103 679* Sulfamethazine; 13 Progesterone 500 mL, adjusted to pH 9a/3b 121 24* C6 2.3 and filtered was Thiabendazole) subjected to SPE (Oasis HLB) 5 mL 50% MgNO3 aqueous solution containing 4% aqueous ammonia, vortex-mix 10 min; extraction Guangdong triplicately in an province, a Enrofloxacin HPLC24.4* ultrasonic bath for 10 subtropical a Quinolone Ciprofloxacin Air-dried, (ESI)MS/MS 0.004 to 0.011 /0.001 42.0* min (UAE), 67 to 88 area located in [70] antibiotics Norfloxacin sieved (in the MRM to 0.003b 17.9* centrifugation 4500 rpm, Pearl River Lomefloxacin mode) 11.0* 5 min /Supernatant Delta region, concentrated to near Southern China dryness by rotary evaporated was subjected to SPE (Oasis HLB)
71
Veterinary antianxiety medications
4 Analytes including 2 NSAIDs
Acepromazine Azaperone Carazolol Chlorpromazine Fluphenazine Mesoridazine Metoprolol Perphenazine Prochlorperazine Promazine Propionylpromazine Propranolol Thioridazine Trifluoperazine Triflupromazine Xylazine
Diclofenac Naproxen
Air-dried, sieved
Air-dried, sieved
2 mL H2O, 2 mL 2 M aqueous NaOH, 10 mL EtOAc, vigorous shaking; extraction in an ultrasonic bath for 15 min (UAE), centrifugation 5000 rpm HPLC– 5 min/(LLE) HRMS Supernatant (5 mL) after (Accurate IS addition was dried mass under an N2 gas steam at 50 ◦C. The dried sample measurements of [M+H]+ dissolved in 1 mL ions) (Internal MeOH, vortex-mix with standard; 1 mL 1% aqueous FA acepromazine-d6(pH 3.5 adjusted with hydrochloride) NH4OH) was partitioned with 0.5 mL n-hexane and centrifuged at 5000 rpm for 5 min. The bottom layer was injected into the Orbitrap MS Sequentially extraction To using 35 mL freshly characterize prepared phosphate the extractable buffer (pH2):MOH (3:4, residue v/v) twice and 20 mL HPLC-UV MeOH once (each To identify extraction cycle 260 rpm transformatio for 1 h on a horizontal n products shaker and (UPLC -ESIcentrifugation at 2300 MS/MS rpm for 15 (in the MRM min)/Supernatant mixed mode) with 1200 mL of (Internal deionized water was standard: subjected to SPE (Oasis naproxen14labeled with C) HLB)
0.075c 0.25c 0.15c 0.075c 0.25c 0.15c 0.5c 0.25c 0.25c 0.5c 0.15c 0.15c 0.5c 0.5c 0.075c 0.25c
No data
89.6-94.7 92.3-102.6 85.2-93.5 88.7-102.9 94.8-99.9 78.6-88.8 83.0-90.8 91.1-102.4 96.7-98.2 78.3-94.6 89.1-93.6 94.3-101.3 58.9-81.5 93.6-94.5 86.3-94.3 93.9-100.3
61.7 74.5
No data. The method used for the establishme nt of extraction dissipation kinetics and adsorption– desorption isotherms
Dortmund and München, [71] Germany
No data. The method used for the study of California, CA, transformati Maricopa, AZ, [12] on and USA removal pathways of compounds in soil
72
15 Analytes NSAIDs Lipid regulators Antiepileptics β-blockers Antidepressan ts
Clofibric acid Ibuprofen Salicylic acid Allopurinol Paracetamol Gemfibrozil Fenoprofen Amitriptyline Metoprolol Naproxen Mefenamic acid Ketoprofen Carbamazepine Diclofenac Fenofibrate
Air-dried, sieved
Addition 3 g anhydrous sodium sulfate, left 60 min before extraction; addition 8 mL ACN containing 2% of NH4OH; 15 min in an ultrasonic water bath at room temperature (UAE). After extraction, the solvent evaporated and collected in graduated tubes, the samples washed with 1 mL of additional basic solvent (ACN containing 2% of NH4OH), and extracts evaporated to dryness. A second time extraction of the soil samples in the ultrasound bath (15 min) with 8 mL of ACN containing 2% of formic acid. Samples washed with 1 mL of acidic solvent. The extracts collected in the graduated tubes used in the first extraction step, evaporated to dryness, and reconstituted to 1 mL with ACN. An aliquot (100 μL) of the extract subjected to derivatization and GCMS analysis
GC-MS (in the SIM mode)
0.38a/0.14b 0.21a/0.07b 0.38a/0.14b 0.21a/0.07b 0.24a/0.07b 0.16a/0.04b 0.26a/0.09b 0.65a/0.24b 0.55a/0.18b 0.14a/0.04b 0.42a/0.16b 0.38a/0.14b 0.44a/0.16b 0.48a/0.16b 0.17a/0.53b
104.5-112.8 97.8-104.4 80.3-103.0 40.8-53.0 86.2-97.4 84.2-108.5 100.8-109.0 98.0-105.1 87.3-102.5 98.5-111.6 94.3-115.1 95.6-105.4 92.8-107.8 97.5-106.6 94.3-108.1
0.7 0.5±0.4 4.4±6.2 (37*) 1.3±16.2 (47*) 0.4±0.1 3.6±2.1 0.8±1.1 < MDL < MQL 0.7±2.2 1.5±0.8 < MDL 1.2±1.0 < MDL 7.0±1.0
Region Valencia and Murcia in Spain
[72]
73
NSAIDs Oestrogenic hormones
Salicylic acid Ibuprofen Paracetamol Flurbiprofen Naproxen Diflunisal Ketoprofen Diclofenac Diethylstilbestrol Estrone 17β-Estradiol 17α-Ethinylestradiol Estriol
11 Analytes including 6 hormones
Diethylstilbestrol Estrone 17β-Estradiol Testosterone 19-Norethindrone Progesterone
Freeze-dried, homogenised
Veterinary antibiotics: Tetracyclines (TCs)
Sulfadiazine SD Sulfamethoxazole (SMX) Sulfamonomethoxin
Freeze-dried, homogenized and sieved
Air-dried, sieved
10 mL H2O (adjusted to pH2) and 10 mL ACN, vortex-mix 1 min; addition 4 g of anhydrous magnesum sulphate and 1 g of sodium chloride, vortexmix 1 min; MAE extraction: 400 W, 8 GC-MS min to 115 °C, 15 min (in the SIM extraction at mode) 115 °C)/Organic layer evaporated to dryness in the nitrogen stream was dissolved in 100 mL distilled water, adjusted to pH2 using 1 M HCl and subjected to SPE (Oasis HLB) 10 mL Aceton:n-Hexane (70:30, v:v) solvent HPLCmixture using an ice (ESI)MS/MS bath, IS addition; (in the SRM sonication of 5 min at mode) 33% of power with (Internal pulse times on of 0.8 s standards: and pulse times off of [2H3]-17β0.2 s) Estradiol, (FUSLE)/Supernatant [2H9]filtered and evaporated Progesterone, to dryness was [2H4]reconstituted in ACN Nonylphenol, and subjected to dSPE [2H16](Envi-carb dSPE Bisphenol-A) protocol) Addition of surogates UPLCand 0.1 g NaF as the ion (ESI)MS/MS exchanger; 5 mL (in the MRM methanol:EDTA:citrate mode)
2.2a/0.7b 0.9a/0.3b 1.9a/0.6b 1.4a/0.5b 2.2a/0.7b 9.8a/3.3b 17.1a/5.7b 5.6a/1.9b 1.2a/0.4b 2.6a/0.9b 1.2a/0.4b 1.3a/0.4b 1.2a/0.4b
89.3 108.2 51.6 68.8 91.7 102.3 58.6 106.7 86.3 38.7 82.3 75.9 81.8
18.3* 8.0* < MDL 8.8 < MDL < MDL < MDL < MDL < MDL < MDL 9.0* < MDL < MDL
Northern Poland
[73]
1.0b 2.3b 3.2b 1.5b 2.8b 1.6b
5 (63) 9 (58) 7 (49) 13 (55) 30 (125) 13 (118)
All analytes < MDLs
Bilbao, Spain
[74]
65.6–90.0 for SAs 60.1–81.6 for TCs
1520.6±291 Liaoning and 4.8 TCs Tianjin areas of [75] 10 967.1* Northern China CTC
74
Sulfonamides e (SMN) (SAs) Sulfadimidine Fluoroquinolo (SM2) nes (FQs) sulfachlorpyridazine Macrolides (SCP) (MACs) Trimethoprim Nitrofurans (TMP) (NFs) Tetracycline (TC) Chlortetracycline (CTC) Oxytetracycline (OTC) Doxycycline (DOXY) Enrofloxacin (ENR Ciprofloxacin (CIP) Ofloxacin (OFL) Roxithromycin (ROX) Erythromycin (ERY) Tylosin (TYL) Furazolidone (FUR)
buffer (3:2:1, v/v/v), (Internal vortex-mix 30 s at 2500 standard: rpm; extraction Simeton; triplicately in an Surrogates: ultrasonic bath for 15 Meclocycline, min (UAE), Sulfadiazinecentrifugation 4000 rpm, phenyl-13C6, 5 min/Combined Lomefloxacin, Caffeine supernatant was trimethyldegreased by n-hexane, 13 C3) diluted to 250 mL with deionized sterile water, filtered, adjusted to pH4 and subjected to tandem SPE (SAX-HLB)
61.3–73.2 for FQs 47.3–73.4 for MACs, 58.2–67.4 for furazolidon e
12.3±16.5 SMX 20.9±13.2 SCP 43.0±48.4 SM2 32.9±28.0* CIP < 15 MACs < 15 FNs
* maximum concentration; ACN: acetonitrile; dSPE: dispersive solid-phase extraction; ESI: electrospray-ionisation; EtOAc: ethylacetate ;FA: formic acid; FUSLE: focused ultra-sonic solid–liquid extraction, HPLC: high-performance liquid chromatography; HRMS: high resolution mass spectrometry; LCL: lowest calibrated level; LLE: liquid-liquid extraction; MAE: microwave assisted extraction; MDL: method detection limit; MQL: method quantification limit; MRM: multiple reaction monitoring; MS: mass spectrometry; MS/MS: tandem mass spectrometry; NSAIDs: nonsteroidal anti-inflammatory drugs; SIM: selected ion monitoring; SPE: solid-phase extraction; SRM: selected reaction monitoring; UAE: ultrasound-assisted extraction; UPLC: ultra-performance liquid chromatography; UV: ultraviolet light.
75
Table 2. Maximal concentrations of selected pharmaceuticals detected in drinking waters around the world
Carbamazepine
Concentration (max) [ng L-1] 5.6
Atenolol Sotalol Hydrochlorthiaride Carbamaz epoxide Pherytoin
3 3 3 3 10
Spain (2011) [134]
Ibuprofen Indometacine Gemrozil Atorvastatin Carbamazepine Ranitidine Losartan
5 6 8 1 2 0.6 5
USA (2009) [135]
Sulfamethoxazole Carbamazepine Triclosan Ibuprofen
13.7 4.7 6.9 23.4
Portugal (2014) [136]
Carbamazepine Atenolol Propranolol Sulfonamides Erythromycin Ibuprofen Naproxen Gembrozil Indomethacin Diclofenac Paracetamol Amantadine Carbamazepine
14 2 6.7 1.9 5 21 6 18 37 11 47 9 25
Country (year) Ref. Canada (2009) [132] Spain (2008-2009) [133]
Japan (2015)
Pharmaceutical found
LOD [ng L-1] 3 5 0.1 1 0.01 0.02 UPLC-MS/MS 0.5 1.3 0.04 0.03 0.2 0.1 0.9 UPLC-MS/MS 0.3 0.2 1.2 1.6 LC-MS/MS No data UPLC-MS/MS
2.2 0.4
76
[137]
Diclofenak Epinastine Fenofibrate Ibuprofen Iopamidol
16 8 31 6 2400
China (2014) [138]
Atenolol Carbamazepine Clarithromycin Diclofenac Erythromycin Fluoxetine Ibuprofen Sulfametoxazole Trimetoprim
34.1 35.0 0.2 9.4 13.8 19.2 10.2 12.7 19.8
2.5 2.0 0.2 1.1 1.8 LC-MS, LC-MS/MS 0.5-10 LC-MS/MS
MCL - method confirmation limit
77
Table 3. Examples of methodology used for carbamazepine determination in raw and treated drinking water Technique SPE-GC-MS SPE-GC-MS SPE-LC-MS/MS SPE-LC-MS/MS SPE-UPLC-MS/MS On-line-SPE-LC-MS/MS
Sample type Treated drinking water (from wastewater) Raw and treated drinking water Treated drinking water Tap water Raw and treated drinking water Ground water
Sample volume [mL]
Detection limit [ng L-1]
Ref.
1000
5 (MQL)
[181]
100 1000 500 500 7.5
0.01 (MDL) 10 (MDL) 0.2 (MDL) 1.5 (MQL) 0.32 (MDL)
[159] [144] [135] [133] [182]
78
Table 4. Examples of ME, EE and AR obtained for pharmaceuticals determined in different environmental samples and techniques Analyte Sample type Matrix effect Extraction Absolute Ref. ME [%] efficiency EE, recovery ER [%] AR, PE [%] SPE-LC-MS/MS Ketoprofen sea water 59.4 92.9 37.8 [101] Trimetoprim sea water 54.2 92.6 45.8 [101] Flubendazole surface water 82.5 n.d. 90 [204] Tetracycline surface/ 89/56 n.d. 70/71 [158] drinking water Sulfamethoxazole surface/ 13/13 n.d. 90/96 [158] drinking water Diclofenac effluent 75 90 112 [205] wastewater SPE-GC-MS Propranolol wastewater 18.1 108.6 89.0 [187] Ketoprofen effluent 2 93 92 [177] wastewater
n.d. - no data
79
