Overview of Multiresidues Analytical Methods for the Quantitation of

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Overview of multi-residues analytical methods for the quantitation of pharmaceuticals in environmental solid matrices: comparison of analytical development strategy for sewage sludge, manure, soil and sediment samples. Audrey Larivière, Magali Casellas-Français, Marilyne Soubrand, and Sophie Lissalde Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.6b04382 • Publication Date (Web): 14 Nov 2016 Downloaded from http://pubs.acs.org on November 20, 2016

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Analytical Chemistry

Overview of multi-residues analytical methods for the quantitation of pharmaceuticals in environmental solid matrices: comparison of analytical development strategy for sewage sludge, manure, soil and sediment samples. Audrey Larivière†, Magali Casellas-Français‡, Marilyne Soubrand†, Sophie Lissalde*,† †

Research Group on Water, Soil and Environment (GRESE – EA 4330), University of Limoges, 123 Avenue Albert Thomas, 87060 Limoges Cedex, France

‡

Research Group on Water, Soil and Environment (GRESE – EA 4330), National Higher Engineering School of Limoges (ENSIL), Parc ESTER Technopole, 16 rue Atlantis 87720 Limoges, France

INTRODUCTION Pharmaceuticals are becoming a major concern of environmental pollution since the beginning of the century. They are employed in high proportion either in human or veterinary therapy.1 Unused pills or unabsorbed pharmaceuticals are delivered as parent molecules or metabolites in waste waters.2 Fate of pharmaceuticals entering waste water treatment plants (WWTPs) depends strongly on the chemical properties (i.e degradation, sorption on sludge or volatilization) of the pharmaceuticals as well as the treatment processes.3 Since WWTPs were not originally created to remove such pollutants, applied processes are sometimes inefficient in suppressing pharmaceuticals from wastewater and a more or less important part of these pharmaceutical compounds can be released in rivers.4 Another fate of some compounds is their sorption on sludge particles. Nowadays, around 50% of sewage sludge produced

in Europe is used as fertilizer in agriculture as a way of recycling this kind of waste.5 If pollutants such as metal elements or polycyclic aromatic hydrocarbons (PAH) and polychlorinated biphenyls (PCB) are currently regulated in spread biosolids, pharmaceuticals are part of emerging organic contaminants for which there is still no control or legislation.6 Into soils, pharmaceuticals can become bioavailable for fauna and flora or be transferred in soil solutions and contaminate groundwater. Pharmaceuticals can also join sea water by runoff of agricultural soils and be absorbed either by aquatic organisms or sediment.1 Associated risks of pharmaceutical residues are antibiotic resistance, changes in biological communities, contamination of food products by bioactive molecules and alteration of environmental quality.5

Figure 1. A/ Evolution of the number of publications dealing with pharmaceuticals analytes in solid environmental matrices (sewage sludge, manure, soil and sediment) since 2000 and B/ distribution of analytical methods depending on the matrix. Method to analyze sludge and soils represent about 70 % of the published papers, and then sediment and manure are less concerned. Statistics are based on 178 different analytical techniques present in 140 papers published from 2000 to 2015 (all references available in supplementary data).

Presence and persistence of these molecules in environmental compartments led to new challenges resulting in the increase, since the beginning of 2000’s, of studies dealing on the fate of pharmaceuticals in WWTPs or sludge, their mobility in amended soils and the ecological impact on leaving organ-

isms.7 Such studies require accurate and reliable analytical methods in order to identify and quantify such molecules present at very low concentrations ranging from a few pg.L-1 to several µg.L-1 either in liquid and solid matrices (i.e sludge, manure, soil or sediment) (Figure 1).

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Complexity of such analytical development is due to complex interactions between pharmaceuticals and solid particles as well as high organic materials content.8 These considerations lead to the search of an adequate extraction and clean-up techniques and the assessment of the involved matrix effects in mass spectrometry detection. The present manuscript should provide elements to carry out accurate multi-residues analysis of pharmaceuticals in complex solid matrices. All the steps of the analytical methods are discussed i.e. pretreatment, extraction, clean-up and detection thanks to the review of the last fifteen year literature on the determination of pharmaceuticals in environmental solid matrices.

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analytical procedure i.e. sampling, conditioning and storage of the samples.

Conditioning and storage. First of all sampling, should provide representative sample of a whole biosolid, manure, soil or sediment matrix.9 Sampling materials must be amber glass containing in order to avoid interaction of pharmaceuticals with plastic10 and photodegradation of molecules such as fluoroquinolones.7 During storage, bacterial activity should be stopped to preserve the integrity of the sample (i.e. physical form and chemical composition).11 For biological matrices like sewage sludge and manure, United State Environmental Protection Agency (USEPA) method 16979 recommends to store samples at a temperature less than 10 °C and begin the extracPretreatment/Extraction/Clean-up tion within 7 days of collection but within 48h is strongly Sampling, storage and preliminary treatments. Quality of recommended. Applied storage conditions for each kind of analytical results depends strongly on the first steps of the matrices are listed in the Table 1. Table 1: Storage temperatures after sampling for different matrixes and various authors

Sludge

Manure

< - 10°C Chen et al. 12 (2013); Diaz-Cruz et al.13 (2006); Gao et al.14 (2012); Jelic et al.15 (2009); Peysson et al.16 (2013); Radjenovic et al.17 (2009); Samaras et al.18 (2011) (5 days); Martin et al.19 (2010); Azzouz et al.20 (2012); Chu et al.21 (2007); Evans et al.22 (2015); Barron et al.23 (2008); Garcia-Galan et al.24 (2013); Pamreddy et al.25 (2013); Huang et al.26 (2013); Morales et al.27 (2005)(< 1 week); USEPA9, 2007 De Liguoro et al.34 (2003); Jacobsen et al.35 (2006); Huang et al.26 (2013); Ho et al.36 (2012); Tylova et al.37 (2010)

0 - 4 °C

Room temperature

Dobor et al.28 (2010); (< 1 week); Lillenberg et al.6 (2009); Yan et al.29 (2014); Wick et al.30 (2010) (< 1-2 days); Muller et al.31 (2008) (< 24h); Yu et al.32 (2012) (< 15h)

Golet et al.33 (2002)

Martinez-Caraballo et al.38 (2007); Campagnolo et al.39 (2002)

Soil

Aga et al.40 (2005) ; Azzouz et al.20 (2012) ; Bossio et al.41 (2008); Kay et al.42 (2004); Salvia et al.43 (2012); Duran-Alvarez et al.44 (2009) ; Raich-Montiu et al.45 (2011); Ho et al.36 (2012); Barron et al.23 (2008); GarciaGalan et al.24 (2013); Morales-Munoz et al.46 (2004)

Martinez-Carballo et al.38 (2007); Vazquez-Roig et al.47 (2010); Schlüsener et al.48 (2003); Cenzig et al.49 (2010); USEPA9, 2007

Sediment

Berlioz-Barbier et al.51 (2014); Martin et al.19 (2010); Jelic et al.15 (2009); Azzouz et al.20 (2012); MorenoGonzalez et al.52 (2015)(< 1 week); Labadie et al.53 (2007); Darwano et al.54 (2014); Morales et al.27 (2005)

Vazquez-Roig et al.47 (2010); Morales-Munoz et al.55 (2004); Yang et al.56 (2010) ; (> 2 weeks); Antonic et al.57 (2007); Cespedes et al.58 (2004); Bossio et al.41 (2008); USEPA9, 2007

As it can be seen storage time and temperature are less critical for soils and sediments. For these last ones, sterilization using ϒ-radiation45, autoclaving59, or amendment with poisons such as sodium azide29,35 or mercuric chloride solution60 is recommended to prevent molecules like ibuprofen or estrone to be transformed by present microorganisms.59,61 Pretreatment. After that, matrix pretreatment is an important step since it should provide a suitable homogeneous matrix guaranteeing repeatable extraction recovery rate.62 This step should not alter the matrix properties or provoke degradation of pharmaceuticals.63 Sediment and sludge are commonly freeze-dried, crushed and sieved at different cutoffs not exceeding 2 mm.51 Soil matrices are usually dried at room temperature and sieved to 2 mm.62 Oven drying should be limited to avoid thermal degradation.64 Most of the time, manures are extracted as untreated liquid slurries34 or after filtration to avoid long preparation step and possible losses of pharmaceuticals. These different pretreatments were gathered in Tables 2-a and Table 2-b.


Golet et al.33 (2002); Turiel et al.50 (2007)

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Table 2-a: Presentation of the different preparation steps before extraction for sludge and manure matrixes

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Matrix preparation before extraction No

Sludge

Manure

De Liguoro et al.34 (2003); MartínezCarballo et al.38 (2007); Ho et al.36 (2012); Blackwell et al.70 (2004); Tylová et al.37 (2010)

Filtration

Sterilization

Air drying + ground + sieve

Nie et al.65 (2009) (after centrifugation); Chu et al.21 (2007) (after centrifugation)

Yan et al.29 (2014) (Sodium azide); Muller et al.31 (2008) (Formaldehyde); Manso et al.66 (2014) (Sulfuric acid to pH 1.8); USEPA9 (2007) (Sulfuric acid to pH 5 or sodium hydroxyde to pH 9)

Gomes et al.61 (2004); Yu et al.67 (2012) (0.5 mm)

Shelver et al.71 (2010) (after centrifugation); Campagnolo et al.39 (2002) (0.45 µm glass fiber)

Loke et al.59 (2003) (Autoclaving)

Karci et al.72 (2009) (2 mm)

Oven drying + ground + sieve

Freeze-dry + ground + sieve

Centrifugation

Golet et al.33 (2002) (60°C, 72h, 0.5 mm); Samaras et al.18 (2011) (60°C, 48 h)

Chen et al.12 (2013) (0.45 mm); Díaz-Cruz et al.13 (2006) (0.5 mm); Dobor et al.28 (2010); Gao et al.14(2012) (0.45 mm); Peysson et al.16 (2013) (48h, 0;25 mm); Radjenović et al.17 (2009); Ternes et al.68 (2002) ; Ternes et al.69 (2005); Martín et al.19 (2010) (0.1 mm); Azzouz et al.20 (2012) (72h, 2 mm); Evans et al.22 (2015); García-Galán et al.24 (2013); Pamreddy et al.25 (2013) (0.425 mm); Morales et al.27 (2005) (0.3 mm); Jelić et al.15 (2009) ; USEPA9 (2007) (0.5 mm)

Wick et al.30 (2010) (freeze dry the solid phase) ; Chu et al.21 (2007); Nie et al.65 (2009)

Jacobsen et al.35 (2006) ; MartínezCarballo et al.38 (2007)

Shelver et al.71 (2010)



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Table 2-b: Presentation of the different preparation steps before extraction for soil and sediment matrixes

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Matrix preparation before extraction No

Soil

Sediment

Bossio et al.41 (2008); Kay et al.42 (2004); Ho et al.36 (2012)

Liu et al.77 (2014) ; Labadie et al.53 (2007); Cueva-Mestanza et al.78 (2008); Bossio et al.41 (2008); Loffler et al.79 (2003)

Filtra tration

Sterilization

Air drying + ground + sieve

Oven drying + ground + sieve

Freeze-dry + ground + sieve

Xu et al.60 (2008) (0.1 % HgCl2) ; Raich-Montiu et al.45 (2011) (ϒ-radiation)

Blackwell et al.70 (2004) (5.6 mm); Andreu et al.62 (2009) (2 mm); Jacobsen et al.73 (2004) (until 5 % humidity, 2 mm); PerezCarrera et al.74 (2010) (0.5 µm); Vazquez-Roig et al.47 (2010) (2 mm); Xu et al.60 (2008) (0.5 mm) ; Duran-Alvarez et al.44 (2009) (2 mm); Kumirska et al.75 (2015) (1 mm); Shlusener et al.48 (2003) (2 mm); Raich-Montiu et al.45 (2011) (2 mm); Turiel et al.50 (2007) (2 mm); Cengiz et al.49 (2010) (2 mm)

Golet et al.33 (2002) (40°C, 0.2 mm); Rice et al.76 (2007) (50°C); Salvia et al.43 (2012) (35 °C, 3 mm)

Azzouz et al.20 (2012) (72h, 2 mm); MartínezCarballo et al.38 (2007) (2 mm); García-Galán et al.24 (2013); USEPA9 (2007) (0.5 mm)

Hajkova et al.82 (2007) (30°C, 16h)

Vazquez-Roig et al.47 (2010) (2 mm); BerliozBarbier et al.51 (2014) (0.25 mm); Martín et al.19 (2010) (0.1 mm); Jelić et al.15 (2009); Azzouz et al.20 (2012) (72h, 2 mm); Ternes et al.68 (2002); Moreno-Gonzalez et al.52 (2015) (2 mm); MoralesMunoz et al.46 (2005) (0.5 mm); Yang et al.56 (2010) (0.5 mm); Darwano et al.54 (2014); Cespedes et al.58 (2004) (0.125 mm); Singer et al.83 (2002); USEPA9 (2007) (0.5 mm); Morales et al.27 (2005) (0.3 mm)

Wagil et al.80 (2015) (2 mm); Mutavdzic-Pavlovic et al.81 (2012) (2 mm); Antonić et al.57 (2007) (2 weeks, dark); Gomes et al.61 (2004)


Centrifugation

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Spiking and aging. Laboratory fortification is performed on control samples to determine the performances of the analytical method. Spiking concentrations should be selected to the amounts of each substance reported in literature. Consequently the method will provide representative data of the occurrence of pharmaceuticals in environmental solid samples.84 Spiking is most often realized on dry sample by adding a small volume of concentrated pharmaceuticals standard solutions in organic solvent. Then the solid is shaken manually or vortexed and solvent is evaporate in a cool and dark place allowing adsorption-desorption equilibrium to take place.79 The other spiking procedure reported in the literature was first introduced by Ternes et al.68 as the “slurry method”. Principle is to add spiking solution in excess in order to cover entirely the solid. Then the mixture is intensively stirred during 14h at room temperature and the solvent is allowed to evaporate.60,68,69,79 With regards to O’Connor et al.85 this procedure should facilitate homogeneous uptake and fast equilibration time in comparison of the previous cited method. However, due to the limitations in diffusion and kinetics of sorption process, spiked analytes will always be less retained in environmental matrices than the native ones.17 Consequently recoveries obtained for spike samples could overestimate the efficiency of the method for the native analytes.47 Thereby Jacobsen et al.73 recommended performing an adequate aging after spiking, superior to 24h. Stoob et al.86 have observed decreasing of extraction recoveries by half and more for several sulfonamides whose sulfamethoxazole spiked in soil samples when contact time is increased from 90h to 17 days. However, Vazquez-Roig et al.47 only observed a diminution of sulfamethoxazole recovery rates from 68 % to 58 % when comparing data for soils equilibrated for 24h and 3 months. Difference in soil properties can explain such a gap between

those two aging studies. In fact, whereas Vazquez-Roig et al.47 sampled soils in marsh areas, Stoob et al.86 took agricultural soils amended with manure, hence organic matter from manure could have sequestered sulfamethoxazole.87 These methods and their users were presented in Figure 2 and Table 3.

Figure 2: Spiking procedures for different matrixes: sludge, manure, soil and sediment

Table 3: Presentation of the different spiking procedures for different matrixes

Sludge

Method 1 : Small volume of contaminant in organic solvent

Method 2 : “Slurry method”

Aging more than 24 h

Albero et al.88 (2014) (24h, 4°C); Chen et al.12 (2013) (overnight); Ding et al.89 (2010) (overnight); Peysson et al.16 (2013) (overnight under N2); Azzouz et al.20 (2012) (1h under N2); Chu et al.21 (2007) (4h, room temperature, dark); Pamreddy et al.25 (2013) (overnight)

Ternes et al.68 (2002) (14h); Ternes et al.69 (2005) (14h)

Samaras et al.18 (2011) (2 weeks)

Manure

Soil

Vazquez-Roig et al.47 (2010); Azzouz et al.20 (2012) (1h under N2); Bossio et al.41 (2008) (24h); Rice et al.76 (2007) (22h); Salvia et al.43 (2012) (overnight); Shlusener et al.48 (2003) (1h or 24h) ; Raich-Montiu et al.45 (2011) (overnight) ; Turiel et al.50 (2007) (overnight, dark)

Sediment

Vazquez-Roig et al.47 (2010); Azzouz et al.20 (2012) (1h under N2); Liu et al.77 (2014) (2h); MoralesMunoz et al.46 (2005) ; Mutavdzic-Pavlovic et al.81 (2012) (24h, room temperature); Bossio et al.41 (2008) (24h); Yang et al.56 (2010) (overnight, 4°C)

Xu et al.60 (2008) (15h, room temperature, dark); O'Connor et al.85 (2007)

68

Ternes et al. (2002) (14h); Loffler et al.79 (2003) (14h)


Tylová et al.37 (2010) (3 days, 4 °C) Vazquez-Roig et al.47 (2010) (3 months); Gomes et al.61 (2004) (3 days); Raich-Montiu et al.45 (2011) (1 or 2.5 months); Morales-Munoz et al.55 (2004) (3 months) ; O'Connor85 et al. (2007) (2 days) Vazquez-Roig et al.47 (2010) (3 months); Gomes et al.61 (2004) (3 days); Wagil et al.80 (2015) (3 days, room temperature, dark)


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Extraction and clean-up procedures. Ideal extraction technique should provide selective total extraction of pharmaceutical analytes i.e high recovery of analytes and low extraction of matrix impurities. Moreover, the technique should be fast, easy, cheap and should require minimal organic solvent use. Clean-up is also a crucial step in pharmaceuticals analysis because there are present at very low levels (from pg.L-1 to µg.L-1) in environmental solid matrices such as manure, sewage sludge, soils and sediments. This step leads to remove some of co-extracted impurities in order to reduce matrix effect and fouling of analytical devices, both will result to considerably decrease limits of detection and quantification.62,90 Most popular techniques: USE, PLE, MAE coupled to SPE clean-up. Among existed extraction techniques, ultrasonicated extraction (USE) is the only technique that is used in the same proportion for solid sludge, manure, soil and sediment matrices, approximately one third of all the available techniques (Figure 3).

Figure 3. Difference in the distribution of extraction technics used for the extraction of pharmaceuticals from sewage sludge, manure, soil or sediment samples. Statistics were based on 65, 19, 62, and 32 different methods respectively for sewage sludge, manure, soil and sediment present in 140 publications from 2002 to 2015 (all references available in supplementary data).

USE using acetonitrile and phosphate buffer is the official USEPA method employed for the extraction of pharmaceuticals in freeze-dried sludge, soil or sediment samples.9 Several extraction cycles are performed in order to obtain better recoveries than a prolonging extraction time in a one-step extraction.91 This observation is explained by the fact that extraction of pharmaceuticals is controlled by distribution coefficients rather than kinetics of desorption processed.38 In second position, pressurized liquid extraction (PLE) is used in a large proportion especially for the extraction of pharmaceuticals from biosolids samples. PLE operates at temperatures above the normal boiling point of most solvents, using pressure to keep the solvents in the liquid phase during the extraction process. As the temperature is increased, the viscosity of the solvent is reduced, thereby increasing its ability to wet the matrix and solubilize the target analytes.47 If sonication produces a small elevation of the temperature of the extraction solvent, during PLE extraction, the temperature is most of the time set at 100 °C. Since multi-residues methods often include tetracycline, fluoroquinolone and sulfonamide families, 100°C allows the best compromise in term of extraction efficiencies because tetracyclines and fluoroquinolones are extracted with

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lower temperatures from ambient temperature to 100°C33,40,47,62,73,89 whereas high extraction temperatures ranging from 50°C to 200 °C are necessary to efficiently extract sulfonamides.13,24,86,89,92 High extraction temperatures are required to break strong interactions between pharmaceuticals and matrix components that could explain why PLE is more indicated for biosolids analysis than for other environmental solid matrices due to the complexity of organic matter responsible for pharmaceuticals sequestration. If the same extraction method is chosen for the extraction of different kind of matrices, conditions can be more drastic when dealing with biosolids samples than other samples. For example, Carvalho et al.93 have found that a two steps USE with Methanol/Acetone was sufficient to extract veterinary drugs from soil sample; however a three steps USE extraction with acid Methanol is required to obtain similar extraction yields in sludge samples. Otherwise thermal degradation of pharmaceuticals could occur at high temperatures when using either PLE or microwaveassisted extraction (MAE). Considering that and the equipment that is required to perform PLE or MAE, USE allows the best compromise of extraction efficiency/cost. MAE is mostly used for sediment even on wet sediment since sediment airdrying can take more than 2 weeks.57 In fact, water content of samples has been found to be very important in MAE to provide better extraction rates, resulting from the efficient heating of the samples as water absorbs microwave energy. MAE and USE techniques are efficiently employed for the extraction of critical compounds as tetracyclines and fluoroquinolones in soils samples. For instance it is known that tetracyclines tend to form chelate complex with metal ions and β-diketones and are strongly sorbed to soils. Fluoroquinolones are also known to sorb in particular to clay minerals via cation-bridging.93 Consequently, a common strategy to extract these particular families is to employ EDTA chelating agents and/or McIlvaine buffer containing citric acid. However the use of EDTA in PLE extraction is prohibited due to clogging of cells and device tubbings85 hence the use of other techniques as MAE and USE. These three techniques are especially efficient because they employed energy to extract pharmaceuticals. Yet a high proportion of matrix components as humic and fulvic substances, carbohydrates, proteins and lipids are extracted simultaneously. Sludges and manures extracts present an intense brown coloration due to co-extracted organic colloids especially after PLE extraction. This explains the need of a clean-up step to reduce matrix interferences and improve limits of detection (LOD).94 Also extraction of highly organic matrices are generally realized with less matrix; samples weight of sludge and manure are two to ten times less than soil or sediment samples for the same extraction method.61 For clean-up strategy, solidphase extraction (SPE) using hydrophilic and lipophilic balance (HLB) sorbent is clearly the purification technique most often employed (Figure 4). HLB cartridges present advantages in multi-residue analysis since both polar and non-polar pharmaceuticals residues can bind if they are neutral in the extract. The combination of strong-anion exchange (SAX) and HLB sorbent is also usual especially for the purification of soil extracts but is more expensive. In this case, negatively charged fulvic and humic acids will bound to SAX cartridge whereas pharmaceuticals will bound to the second HLB sorbent. SPE clean-up appears to be especially needed for sludge extracts since limits of quantification (LOQ) are often higher in sludge samples than soil or sediment samples.93,95 By adding a SPE


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Clean-up, Carvalho et al.93 have lower the LOD/LOQ by a factor of ten for tetracyclines and fluoroquinolones in sludge extracts. Authors also noticed loss of analytes during SPE step

however improving analytical performances is crucial when dealing with trace molecules.

Figure 4. Difference in the distribution of clean-up technics between sewage sludge, manure, soils and sediments after extraction. Since solid phase extraction is the technic most often used, a focus is made on the different adsorbent. Adsorbent in SPE is function of coextracted matrix components. Statistics were based on 65, 19, 62, and 32 different methods respectively for sewage sludge, manure, soil and sediment present in 140 publications from 2002 to 2015 (all references available in supplementary data).

Simple solid-liquid extractions. Solid liquid extractions (SLE) for sludge, manure, soil or sediment nearly represent the same proportion than MAE. SLE can be used either on a wet or dried sample and constitutes a very simple and fast extraction technique. Extraction yields for multi-residues analysis are of the same order in comparison of techniques requiring sophisticated equipment and often reach a total extraction.71,88,96 Since SLE requires no energy, few matrix components are extracted. However SLE is often coupled to SPE clean-up using HLB sorbent. In order to improve extraction efficiency and reducing handling time, salting-out extraction referred as QuEChERS extraction (i.e. Quick Easy Cheap Effective Rugged Safe) has been employed in a few studies. This technique was first introduce for the multi-residue extraction of pesticides from food samples and has since been used either for pesticides in soil, sediment, and sludge97 or for pharmaceuticals in food and biological matrices.98-100 Comparison of PLE and QuEChERS efficiencies for the extraction of 11 pharmaceuticals in vegetables highlights that QuEChERS extraction gives similar or better recovery rates than PLE in shorter time and with a reduced cost.98 However Kumirska et al.75 found better efficiencies for MAE extraction of nonsteroidal anti-inflammatory drugs and hormones in soil samples than for QuEChERS extraction. In this last study, simple SLE-SPE method also presented better efficiencies than extraction assisted by salts. These studies demonstrated that efficiency of QuEChERS extraction is matrix and molecule dependent as it is the case for the most common techniques but authors agree on the fact that QuEChERS is economic and efficient and can be used as a routine method for the multiresidue analysis of pharmaceuticals in environmental solid matrices.51,94,97,100 Originally QuEChERS technique employed a short clean-up step by dispersive solid phase extraction (dSPE). Different d-SPE sorbent are commercially available; Peysson et al.16 showed that PSA sorbent led to the best com-

promise for clean-up of sludge extract after QuEChERS extraction compared with GPC and C18 sorbent. Herrero et al.94, found that zirconium based sorbent was efficient to purified sludge extract of benzenesulfonamide since it has been specifically designed to remove interferences from complex matrices. However, according to Deschamps et al.101 and Westland et al.99, clean-up is not necessary since QuEChERS extraction only (i.e without d-SPE) also lead to a partial elimination of interferences causing increase of LOQ hence shorter handling time. Finally matrix-solid phase dispersion (MSPD) technique constitutes an original extraction method and has been efficiently used for the extraction of triclosan from sediment and sludge samples for examples.102 This technique is interesting since extraction and clean-up are realized simultaneously by placing the dried matrix in a preparative column with dispersive agent. Extraction of liquid samples. Extraction of liquid biosolid or manure are realized on untreated matrices in order to reduce handling time. Liquid liquid extraction (LLE) using a combination of ethyl acetate and a buffer constitutes the most common technique for the extraction of pharmaceuticals from manure. EDTA chelating agent can be added for the specific extraction of tetracycline molecules without complication as it is the case in PLE.37 Most of the time no clean-up is realized in order to perform a quick extraction but SPE clean-up can be used.71 Other recent technique is hollow fiber liquid phase microextraction (HF-LPME) and has currently only be used for the extraction of pharmaceuticals in sludge samples. It implies a hollow polypropylene fiber which is first immerged in the organic extraction solvent in order to immobilize solvent droplets in pores then the fiber is immersed in the liquid sample.63,103 Since very few organic solvent is used, HF-LPME allows very high enrichment factor which is interesting for the analysis of trace compounds.66 Pharmaceuticals from liquid manure and sludge can also be extracted by SPE. This solution



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presents the advantage of combining the extraction and the clean-up steps.39 A slurry of dried soil, sediment or sludge can also be made; then the extraction is realized by a sorptive stir bar (SBSE). This last technique constitutes an original and specific technique for the extraction of pharmaceuticals. However stirring time is long (1 hour), an additional desorption step is needed and commercially available coating of stir bar are few.10 Multi-residue analysis of pharmaceuticals

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followed by a detector. The aim of the separation device is to separate one pharmaceutical contained into solid extract from another so the detection could be specific.91 The combination of the two techniques should provide at least a selective qualitative analysis method and for the best a selective and sensible quantification technique for the analysis of pharmaceuticals trace residues in solid environmental matrices.53 At this point of this analysis, the choice of an adequate hyphenated techniques is determined by the molecules to analyze instead of the kind of matrix (Figure 5).

Hyphenated techniques. Hyphenated techniques for analysis of organic molecules are composed of a separation technique

Figure 5. Distribution of hyphenated technics for multi-residue pharmaceuticals analysis by GC and HPLC. Since HPLC separation technic is largely most often used a focus is made on HPLC columns currently employed to separate pharmaceuticals from sludge, manure, soil or sediment extracts. Statistics are based on 140 different papers dealing with pharmaceutical analysis in such matrices (all references available in supplementary data).

Separation techniques. The two separation techniques are HPLC and GC. GC technique is less often used for pharmaceuticals compounds since there are generally nonvolatile. A derivatization step can be employed to improve volatility but some pharmaceuticals do not present active hydrogen and do not undergo silylation. Estrogenic hormones are the only family to be separated as well by HPLC as GC after derivatization analysis.88 By using HPLC, parameters such as the column type, the nature and the gradient of the mobile phase can be optimized. In the context of multi pharmaceuticals residues analysis, reversed-phase liquid chromatography using a stationary phase with octyldecane silane binding provides better resolution of each species even with very different polarity properties12,15,104 (Figure 4). At a least extent, C8 and hydrophilic interaction liquid chromatography (HILIC) columns are used but their applications are preferable for more polar compounds such as sulfonamides.19,105 Mobile phase are generally a gradient of the combination of an organic solvent and water with some additives such as acids or salts. The pH of the mobile phase should not be too close from the pKa of the analytes.91 Acetic acid is commonly used in order to obtain a mobile phase pH between 2.5 and 4 for pharmaceuticals multiresidues analysis43,69,76,79,106 but formic acid will provides better sensitivity for MS detection.51 Ammonium formate additives reduce peaks width and consequently improve resolution of each compounds and the selectivity.51 Detection devices and performances. Simple detection techniques as ultraviolet (UV) and fluorescence light detection (FLD) can be used for determination of pharmaceuticals especially after HPLC separation (Figure 4). Their utilization can be limited in multi-residue analysis because of the lack of selectivity due to false positive.107 Consequently, these techniques are more often replace by MS employed with different

type of ionization processes (Figure 4). Detection by MS is based on ionization of eluted pharmaceuticals and detection on these species as ions fragments characterized by the mass ratio m/z.70,103 MS fragmentation yielded mostly to [M – H] - and [M – COOH] - in negative mode, or [M – H]+, [M – Na]+, and [M – K]+ adduct ions in positive mode. In most cases the chosen ionization mode for a compound could be predicted by its acidity, however compounds like bezafibrate (pka = 3.6) or ketoprofen (pka = 4.45) did not adhere to this assumption in the study of Barron et al..23 Performances of the analytical detection are characterized by the instrumental detection and quantification limits (respectively LOD and LOQ) which are function of the sensitivity of product ions in MS. A high instrumental LOQ could be the result of a poor yield of product ions.21 With regards to the ionization technique, electron impact (EI) is used in GC whereas different ionization techniques operating at atmospheric pressures are used after HPLC elution. Electrospray ionization interface (ESI) is often preferred to the atmospheric pressure chemical ionization one (APCI) since it provides better sensitivity.58 Matrix effects. One of the greatest drawbacks of pharmaceuticals analysis in environmental matrices by HPLC-MS and GC-MS at a least extent is suppression or enhancement of the analyte signals by co-extractive substances from the sample matrix.17 Comparing to other techniques like FLD and UV, method development by MS should include the determination of these matrix effect (ME) and consequently correct results to provide accurate quantification.80 Causes and consequences. ME cause a compound’s response to differ when analyzed in a matrix extract compared to a


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standard solution. Briefly this phenomenon is attributed to coextractive matrix components (principally nonvolatile) eluting at the same retention time than pharmaceuticals of interest.17 These endogenous compounds will mostly be responsible for the diminution of pharmaceuticals ionization yield hence partial suppression of the signals and under-estimation of environmental concentrations.108 ME in environmental solid samples as sludge, manure, soil and sediment will generally be more important than in water samples due to the large amount of endogenous components including carbohydrates, amines, lipids, peptides or even though metabolites of the pharmaceutical of interest.109 According to O’Connor et al.85, humic and fulvic acids should be responsible for signal suppression of tetracycline in soil extracts. Moreover, Salvia et al.110 found correlation between the high organic carbon content of the soil and the higher ME on steroid hormones. However, this correlation could not be proved for carbamazepine, trimethoprim or sulfonamides which highlights the fact that ME is compound dependent. Also prediction of the extent of ME between matrices should not be made before a specific ME evaluation procedure. For example, in the study of Bossio et al.41, sulfamethoxazole and pravastin experienced more signal suppression in digested sludge samples than in soil samples but meclofenamic acid and gemfibrozil behavior are reversed. Evaluation of matrix effects. This step of analytical development is only performed in approximately a quarter of the articles (Table 4). The assessment of ME extent during pharmaceutical analysis in environmental solid matrices is mostly performed by spiking post-extraction blank matrix and comparing the signals to an equivalent spiking in ultra-pure water111 (equation 1). − % = 100 × 1 where Ai, and Si are the peak areas of the analytes spiked in post-extraction blank matrix and the analytical standard respectively. Bi corresponds to the signals in unspiked postextraction matrix. At a least extent, authors used the comparison of calibration slopes between matrix-matched calibration curve (MMCC) and solvent calibration curve112 (equation 2). % ! = 100 × 1 − 2 "#$% $% Comparison between analytical methods and consequent ME extent is also difficult since ME interpretations is different depending on authors. Most often they agree on the fact that ion suppression/enhancement between 0 – 20 % corresponds to an absence of ME, whereas ion suppression/enhancement values between 20 and 40 refer to medium ME; outside these ranges there are major.26,104,113,114 Table 4. Percentages of articles with matrix effect study for different matrixes and type of method used to study these effects. Matrix effect study methods % of articles with matrix effect study

Method 1 : Matrix spike

Method 2 : Slope of MMCC

Method 3 (Other)

Sludge

34.4 %

73%

32%

5%

Manure

10.5 %

100%

0%

0%

Soil

25.8 %

36%

45%

19%

Sediment

28.1 %

82%

18%

0%

Analytical solutions to reduce matrix effects. Different simple actions can be taken concerning all the analytical steps (Figure 6, Table 5-a and Table 5-b) and 75% of the authors proposed various solutions to overcome this problem. Concerning the extraction, Chambers et al.115 concludes that acetonitrile is a better solvent choice than methanol due to less extraction of matrix compounds. High temperatures during PLE extraction also result in highly colored extracts and cleanup is highly recommended.51 Salvia et al.43 have compared ion suppression/enhancement for unpurified and purified extracts. Although signal suppression reaches 95 % for erythromycin in soil extracts, the suppression was nearly totally compensated with SPE purification use. Purification is the most often used technique for all the matrixes (Table 5). For highly organic matrix it is also possible to reduce sample mass to be extracted if pharmaceuticals concentration is enough to be quantitate.23,62 QuEChERS extraction can be efficiently used to extract multi pharmaceutical families with limited extraction of interferences.101 Finally to avoid ionization suppression in MS source additives or derivatization reagent concentrations should be limited.108 Other analytical solution available for any kind of environmental solid matrices concerns calibration solutions involving internal standard, surrogate or MMCC. Table 5 shows that internal calibration is the most often used correction implying the use of an adequate internal standard (IS), co-eluting (retention time difference < 0.1 min) with the target analyte.53,106 Principle is based on the addition of stable isotopic labeled internal standard (SIL-IS) in matrix extracts before analysis to compensate for ME due to ionization suppression or enhancement. Standard should have similar structure and identical fragmentation pattern than the pharmaceutical molecule to ensure accurate quantitation since ME will affect the two species in the same manner.61 It is important that the mass difference between the analyte and the SIL-IS is at least 3 mass units in order to avoid signal contribution of the abundance of the natural isotopes to the signal of the internal standard. Wang et al.116 have shown that a deuterium labeled IS was not able to entirely compensate for the observed ME and 13C, 15N or 17O-labeled IS may be more ideal than 2Hlabeled ones, since deuterium and hydrogen have greater differences in their physical properties than for example 12C and 13 C. However, SIL-IS are not commercially available for all pharmaceuticals analytes, and one SIL-IS will often be used to compensate ME for several compounds in multi-residues analysis.86,117 Internal standard can be added before cleanup step to correct for the loss during SPE and/or evaporation.33,68 However it is more frequent to add the IS before the extraction i.e. when spiking the matrix with other standards, thus IS will correct simultaneously ME and losses during sample preparation (Figure 6). Decreasing of ionization suppression during sulfonamides analysis in soils and sludge extracts by using sulfamethoxazole-d4 correction was reported in Garcia-Galan et al..24 Differences between surrogate correction and without correction ranged from 19 % to 103 %. Considerations about the nature of the IS are the same than previously. Isotopic dilution terms are used when the spiked IS before extraction corresponds exactly to the isotopic labelled pharmaceuticals. MMCC are also frequently used in order to correct ME especially during soil and sediment analysis20,48 (Table 5-b). The



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calibration curve is made by diluting standard stock solutions in blank matrix extract. The difficulty to find control sludge or manure matrix free from any pharmaceuticals of interest could explain why this solution is less often employed for the analysis of these kinds of matrices.36,117,118 MMCC constitute an interesting tool for the ME correction, especially if blank matrix has the same or a very similar composition than the real environmental sample to be analyzed, thus practically full compensation of ME may be achieved.117 These analytical solutions are often combined to improve the correction efficiency. In addition, dilutions of extracts are also realized to minimize quantity of endogenous compounds reaching MS detector.40 In fact, far from decreasing due to the

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dilution, pharmaceuticals signal intensities remained stable or in most cases increased at the same time the extract was diluted.17,57 Radjenovic et al.17 realized successive dilutions and considered the dilution suitable to compensate for ME when signals in spiked extract and for spiked solvent show less than 20 % differences. Dilution by a factor of two was enough to significantly decrease ME in sludge extracts without decreasing the sensitivity of quantitation17 but dilution factor study should be realize for other matrices even for other kind of sludge since the composition could differ.61 According to Bourdat-Deschamps et al.101, a 10-fold dilution should be realized as a maximum to limit the loss of sensitivity during analysis.

Figure 6. Presentation of the various -solutions proposed to overcome matrix effect for different matrixes (sludge, manure, soil or sediment). At each step, tables indicate the percentage of articles using the considered solution. Statistics were based from different solutions presented in 140 publications from 2002 to 2015 (all references available in supplementary data).


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Table 5-a: Presentation of the different analytical solutions to overcome matrix effects for sludge and manure matrixes

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Purification

Sludge

Díaz-Cruz et al.13 (2006); Albero et al.88 (2014); Chen et al.12 (2013); Ding et al.89 (2010); Dobor et al.28 (2010); Gao et al.14 (2012); Golet et al.33 (2002); Jelić et al.15 (2009); Lillenberg et al.6 (2009); Peysson et al.16 (2013); Radjenović et al.17 (2009); Ternes et al.68 (2002) (14h)/69(2005) (14h); Wick et al.30 (2010); Yan et al.29 (2014); Yu et al.67 (2012) ; Martín et al.19 (2010); Azzouz et al.20 (2012); Chu et al.21 (2007); Evans et al.22 (2015) ; Nie et al.65 (2009); Fernandez et al.119 (2009); Gomes et al.61 (2004); Labadie et al.53 (2007); Kim et al.120 (2005); Samaras et al.18 (2011); Subedi et al.121 (2015); Miao et al.122 (2005); Barron et al.23 (2008); Singer et al.83 (2002); García-Galán et al.24 (2013); Pamreddy et al. 25 (2013); Muller et al.31 (2008); García Valcarcel et al.123 (2011); Carballa et al.124 (2007); Kimura et al.125 (2007); Ho et al.36 (2012); Sanchez-Brunete et al.126 (2010); Huang et al.26 (2013); Gonzalez-Marino et al.102 (2010); USEPA9 (2007)

Manure

Blackwell et al.70 (2004); De Liguoro et al.34 (2003); Jacobsen et al.35 (2006); Martinez-Carballo et al.38 (2007); Shelver et al.71 (2010); Karci et al. 72(2009); Hu et al.127 (2010); Olsen et al.129 (2012); Blasco et al.130 (2009); Ho et al.36 (2012); Campagnolo et al.39 (2002); Huang et al.26 (2013)

Internal calibration

Surrogate before extraction or clean-up

MMCC

Dilution

Samaras et al.18 (2011); Sagrista et al.103 (2012); Jelić et al.15 (2009); Peysson et al.16 (2013); Radjenović et al.17 (2009); Hu et al.127 (2012); Labadie et al.53 (2007)

Chen et al.12 (2013); Ding et al.89 (2010); Gao et al.14 (2012); Lindberg et al.105 (2005); Ternes et al.69 (2005); Yu et al.67 (2012); Subedi et al.121 (2015); Miao et al.122 (2005); Wick et al.30 (2010); Huang et al.26 (2013); Eyser et al.128 (2015); García-Galán24 et al. (2013); Golet et al.33 (2002) (before clean-up); Ternes et al.68 (2002) (before clean-up) (cleanup)

Albero et al.88 (2014); Peysson et al.16 (2013)

Radjenović et al.17 (2009); García-Galán et al.24 (2013)

Ho et al.36 (2012); Huang et al.26 (2013); Shelver et al.71 (2010)



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Table 5-b: Presentation of the different analytical solutions to overcome matrix effects for soil and sediment matrixes

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Purification

Soil

Sediment

Xu et al.60 (2008); Shlusener et al.48 (2003); Salvia et al.43 (2012); Aga et al.40 (2005); Andreu et al.62 (2009); Blackwell et al.70 (2004); Azzouz et al.20 (2012); Bossio et al.41 (2008); De Liguoro et al.34 (2003); Golet et al.33 (2002); Jacobsen et al.73 (2004); Kay et al.42 (2004); Martinez-Carballo et al.38 (2007); Perez-Carrera et al.74 (2010); Rice et al.76 (2007); Shelver et al.71 (2010); Vazquez-Roig et al.47 (2010); Duran-Alvarez et al.44 (2009); Kumirska et al.75 (2015); Xu et al.32 (2015); Kim et al.120 (2005); Raich-Montiu et al.45 (2011); Turiel et al.50 (2007); Karci et al.72 (2009); Hu et al.127 (2010); Ho et al.36 (2012); Chen et al.131 (2010); Olsen et al.129 (2012); O'Connor et al.85 (2007); Chen et al.132 (2009); Sun et al.133 (2010); Bialk-Bielinska et al.134 (2010); Accinelli et al.135 (2007); USEPA9 (2007); Uslu et al.136 (2008); Kay et al.137 (2005); Barron et al.23 (2008); Cengiz et al.49 (2010); García-Galán et al.24 (2013); SanchezBrunete et al.126 (2010); Huang et al.26 (2013); Ferreira et al.10 (2011) Wagil et al.80 (2015); Berlioz-Barbier et al.51 (2014); Vazquez-Roig et al.47 (2010); Martín et al.19 (2010); Jelić et al.15 (2009); Azzouz et al.20 (2012); Liu et al.77 (2004); Hajkova et al.82 (2007); Ternes et al.68 (2002); Moreno-gonzalez et al.52 (2015); Labadie et al.53 (2007); Morales-Munoz et al.46 (2005); Mutavdzic Pavlovic et al.81 (2012); CuevaMestanza et al.78 (2008); Yang et al.56 (2010); Darwano et al.54 (2014); Antonić et al.57 (2007); Aguera et al.139 (2003); Singer et al.83 (2002); Cespedes et al.58 (2004); Loffler et al.79 (2003); Gomes et al.61 (2004); Gonzalez-Marino et al.102 (2010); USEPA9 (2007); Morales et al.27 (2005); Venkatesan et al.140 (2012)

Internal calibration

Surrogate before extraction or clean-up

MMCC

Dilution

Azzouz et al.20 (2012); Bossio et al.41 (2008); Schlusener et al.48 (2003); Chen et al.131 (2010); Sun et al.133 (2010); Stoob et al.86 (2006)

Aga et al.40 (2005); Andreu et al.62 (2009); Perez-Carrera et al.74 (2010); Vazquez-Roig et al.47 (2010); Huang et al.26 (2013); GarcíaGalán et al.24 (2013)

Andreu et al.62 (2009); Azzouz et al.20 (2012); Bragança et al.138 (2012); Schlusener et al.48 (2003); Chen et al.131 (2010); Salvia et al.43 (2012); Vazquez-Roig et al.47 (2010)

Aga et al.40 (2005)

Labadie et al.53 (2007); Cespedes et al.58 (2004)

Hajkova et al.82 (2007) ; Venkatesan et al.140 (2012); Singer et al.83 (2002); Yang et al.56 (2010); VazquezRoig et al.47 (2010); Ternes et al.69 (2002) (before clean-up)

Berlioz-Barbier et al.51 (2014); Hajkova et al.82 (2007); Loffler et al.79 (2003)

CONCLUSION We reviewed and commented all the steps that could be critical during the analysis of pharmaceuticals molecules in environmental solid matrices. The complexity of interactions between those molecules and matrix components makes the extraction a crucial step to recover the maximum amount of analyte. However extraction techniques using high temperature or energy are more susceptible to extract matrix components simultaneously. Considering that QuEChERS technique could present advantages since a large panel of molecules presenting different properties can be extracted without the extraction of a large amount of matrix components as it is the case in PLE extraction. If specific equipment is available USE represents a fast and efficient extraction technique. In this

case, SPE clean-up cannot be omitted since co-extracted matrix components lead to ME hence underestimation of environmental concentrations. During analysis of environmental complex matrices, ME assessment and calibration correction is hardly recommended in order to obtain accurate quantitation. Any analytical method is transferable from one solid matrix to another but since extraction efficiency and ME are strongly dependent on the matrix composition, it is hardly possible that the same method will provide same performances between different samples of sludge, manure, soil or sediment. If the extent of ME causes important differences in analytical performances, possible re-optimization can be the reduction of the matrix weight, an additional or modified clean-up step and the correction of the ME. If MMCC would be the proper correction, it is time consuming hence the combination of the


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dilution of the extract and the addition of SIL-IS appears to be a good solution in order to solve analytical problems present during analysis of pharmaceuticals in environmental complex solid matrices.

ASSOCIATED CONTENT

toring, the development of analytical methods to quantitate micropollutants and non-target screening analysis and its application in natural environment.

ACKNOWLEDGMENTS The authors would like to acknowledge the Regional Council of Limousin and the French Environment and Energy Management Agency for the study financial support.

Supporting Information Supporting information are available as two files. The Supporting Information is available free of charge on the ACS Publications website. Database on analytical workflow used in all the discussed articles (excel)

AUTHOR INFORMATION Corresponding Author *Phone: +33 5 55 45 73 60. Fax: +33 5 55 45 72 03. E-mail: [email protected]

Notes The authors declare no competing financial interest.

Biographies Audrey Larivière studied chemistry at the National School of Chemistry in Rennes (France) where she received her diploma in 2014. Since 2015 she is a PhD student in the Research Group on Water, Soil and Environment (GRESE) at the Limoges University. She works on the mobility of pharmaceuticals in sludge, manure and soil. Magali Casellas is an associate professor in the GRESE laboratory since 2002. Author of 30 international publications, her research is devoted to study the different mechanisms involved in the fate of metallic and organic micropollutants in wastes (Sludge, manure,..) and wastewater (hospital, urban, industrial,..) treatment processes. The methodology aims to determine the impacts of type of process and method of implementation on 1) biomass characteristics (physical, chemical, biochemical and microbiological) and on 2) micropollutants in terms of phase repartition and mechanisms associated (sorption, precipitation) and in terms of biodegradation. Most of the final products generated can be landspread, so the objective is to propose the best process implementation not only in terms overall performances, but also in terms of micropollutants concentrations and stability before their use as fertilizers. Marilyne Soubrand studied environmental chemistry at the University of Paris XII (France) then geochemistry at the INRA Paris. She received her Ph.D degrees in 2004 after works onto geochemistry of soils at the University of Limoges (France). After two years as a scientific assistant at the University of Amiens (France), she became associate professor of environmental geochemistry at the GRESE laboratory (France) since 2007. She is co-author of 21 international publications. Her current research activities are relative to the geochemistry of soils in natural and anthropic contexts, the role of soil constituents to prioritize soil parameters influencing sorption and transfer of pharmaceutical and trace elements compounds. Sophie Lissalde studied environmental chemistry at the Universities of Bordeaux and Strasbourg (France) where she received her diploma in 2006. From 2007-2010, she worked on her PhD in Irstea Cestas (France) on passive sampling and especially POCIS applicability to monitoring pesticides contamination in rivers. After finishing her PhD she stayed in Irstea for ten months as research engineer. Since 2011, she is a research engineer in analytical chemistry at the GRESE. Her current research activities included passive sampling development for environmental moni-

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(140) Venkatesan, A. K.; Pycke, B. F. G.; Barber, L. B.; Lee, K. E.; Halden, R. U. Journal of Hazardous Materials 2012, 229-230, 29-35.

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