Accepted Manuscript Title: RECENT ADVANCES IN SAMPLE PREPARATION TECHNIQUES AND METHODS OF SULFONAMIDES DETECTION - A REVIEW Author: Stanislava G. Dmitrienko Elena V. Kochuk Vladimir V. Apyari Veronika V. Tolmacheva Yury A. Zolotov PII: DOI: Reference:
S0003-2670(14)01006-X http://dx.doi.org/doi:10.1016/j.aca.2014.08.023 ACA 233423
To appear in:
Analytica Chimica Acta
Received date: Revised date: Accepted date:
25-3-2014 7-8-2014 11-8-2014
Please cite this article as: Stanislava G.Dmitrienko, Elena V.Kochuk, Vladimir V.Apyari, Veronika V.Tolmacheva, Yury A.Zolotov, RECENT ADVANCES IN SAMPLE PREPARATION TECHNIQUES AND METHODS OF SULFONAMIDES DETECTION - A REVIEW, Analytica Chimica Acta http://dx.doi.org/10.1016/j.aca.2014.08.023 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.
RECENT ADVANCES IN SAMPLE PREPARATION TECHNIQUES AND METHODS OF SULFONAMIDES DETECTION - A REVIEW Stanislava G. Dmitrienko*, Elena V. Kochuk, Vladimir V. Apyari, Veronika V.
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Tolmacheva, Yury A. Zolotov
Lomonosov Moscow State University, Chemistry Department, 119991 Leninskie gory, 1/3,
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Moscow, Russia
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* Corresponding author. Tel.: +7(495)939-46-08; Fax: +7(495)939-46-75; e-mail: [email protected]
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Graphical abstract
Highlights
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Ac ce pt e
An overview on recent trends in the sample preparation and determination of sulfonamides is given A comparison of different methods of real samples preparation is made The general chromatographic and other methods of SAs determination are discussed Examples of SAs determination in different matrices are given.
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ABSTRACT Sulfonamides (SAs) have been the most widely used antimicrobial drugs for more than 70 years, and their residues in foodstuffs and environmental samples pose serious health hazards. For this reason, sensitive and specific methods for the quantification of these compounds in numerous matrices have been developed. This review intends to provide an updated overview of the recent trends over the past five years in sample preparation techniques and methods for detecting SAs. Examples of the sample preparation techniques, including liquid-liquid and solid-phase extraction, dispersive liquid-liquid microextraction and QuEChERS, are given. Different methods of detecting the SAs present in food and feed and in environmental, pharmaceutical and biological samples are discussed. Keywords: Sulfonamides, Sample preparation, Extraction, Residue determination, Multi-class methods, Liquid chromatography–tandem mass spectrometry 1
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Abbreviations: Ac, Acetate; AD, Amperometric detection; ACN, Acetonitrile; CE, Capillary electrophoresis; DAD, Diode-array detector; DLLME, Dispersive liquid-liquid microextraction; DSPE, Dispersive solid-phase extraction; EDTA, Ethylenediaminetetraacetic acid; ELISA, Enzyme-linked immunosorbent assays; EMIS, Electrochemical magnetoimmunosensor; ESI, Electrospray ionization source; EtOH, Ethanol; F, Formate; FL, Fluorescence detection; HPLC, High-performance liquid chromatography; HPLC-MS/MS, High-performance liquid chromatography tandem mass spectrometry; LLE, Liquid–liquid extraction; LLME, Liquid-liquid microextraction; LOD, Limit of detection; LOQ, Limit of quantification; MeOH, Methanol; MIPs, Molecular imprinted polymers; MRLs, Maximum Page 1 of 76
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Contents 1. Intrroduction 2. Sample preparation 2.1. Food 2.2. Feed 2.3. Environmental samples 2.3.1. Waters 2.3.2. Soils, manure and sediments 2.4. Pharmaceutical and clinical samples 3. Analytical methods 3.1. Chromatographic methods 3.1.1. Detection with MS and multi-class analysis 3.1.2. Detection with other techniques 3.2. Electrophoretic methods 3.3. Microbiological assays 3.4. Immunoassays 3.5. Biosensors 3.6. Other methods 4. Conclusions and outlook Refferences
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1. Introduction
The problem of food and environmental sample contamination by veterinary drugs
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is of great concern [1 – 3]. There are systematised data on detection of antibiotics in
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foods of animal origin [4, 5], milk [6], honey [7], fish [8], and feed [9], as well as in environmental samples [10]. According to a previous review [5], sulfonamides (SAs) and fluoroquinolones are among the most commonly used veterinary antibiotics. For example, the frequency of cases in which SAs were detected in food is 20 %, whereas other antibiotics were detected as follows: fluoroquinolones – 19 %, aminoglycosides –
residue limits; MRM, Multiple reaction monitoring; MS, Mass spectrometry; MS/MS, Tandem mass spectrometry; MSPD, Matrix solid-phase dispersion; MWCNTs, multi-walled carbon nanotubes; PLE, Pressurised liquid extraction; PSA, Primary-secondary amine; QqLIT, Quadrupole linear ion-trap; QTOFMS, Quadrupole time of flight mass spectrometry; SAA, Sulfacetamide; SAM, Sulfanilamide; SAs, Sulfonamids; SCP, Sulfachloropyridazine; SDD, Sulfadimidine; SDM, Sulfadimethoxine; SDO, Sulfadoxine; SDZ, Sulfadiazine; SML, Sulfametrole; SMP, Sulfamethoxypyridazine; SMR, Sulfamerazine; SMT, Sulfamethizole; SMX, Sulfamethoxazole; SMZ, Sulfamethazine; SPE, Solid-phase extraction; SPME, Solid-phase microextraction; SPY, Sulfapyridine; SQX, Sulfaquinoxaline; SSA, Sulfisoxazole; SSZ, Sulfasalazine; STZ, Sulfathiazole; ToF-MS, Time-of-flight mass spectrometry; UHPLC-MS/MS, Ultra-high-performance liquid chromatography tandem mass spectrometry; UV, Ultraviolet detection.
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15 %, phenicols–15 %, β-lactams – 15 %, oxazolidinones – 8 % and tetracyclines – 8 % [5]. SAs are derivatives of sulfanilic acid (p-aminobenzenesulfonic acid) and are one of the oldest classes of antimicrobial drugs, which have been used for the treatment of
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humans and animals from the middle of the twentieth century. SAs act as bacteriostatic agents and possess chemotherapeutic activity against infections caused by gram-positive
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and gram-negative bacteria and some protozoa (causative agents of malaria,
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toxoplasmosis, etc.).
The precursor of SAs is sulfanilamide (p-aminobenzenesulfonamide), better
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known as streptocid, which was first synthesised in 1908 and was widely used as an intermediate in the production of dyes. SAs were discovered to have antibacterial
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properties in 1935 by G. Domagk. The basis for their bacteriostatic action is the structural
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similarity between the sulfanilamide moiety and p-aminobenzoic acid (PABA), which is
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involved in the biosynthesis of dihydrofolic and folic acids and other substances utilised by the microorganisms. SAs act as antimicrobials by blocking the synthesis of dihydrofolic acid by preventing the formation of dihydropteroic acid from dihydropteridine and PABA, which involves dihydropteroate synthetase. SAs compete with PABA, resulting in no formation of dihydrofolic acid but instead the formation of its analogue [11]. These features of the mechanism confer high sensitivity to SAs only to microorganisms that synthesise their own dihydrofolic acid, and microorganisms and cells that utilise dihydrofolic acid as a finished product are not sensitive to SAs. To date, more than 10000 sulfanilamide derivatives have been synthesised, and 40 of these are applied in medical and veterinary practices. The structures of the most commonly used SAs are represented in Fig. 1. Some patterns that illustrate the
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relationship between the chemical structure of these chemotherapeutic agents and their action are known, and the physiological activity of SAs has been found to be conditioned by the presence of an SO2NH group in the chemical structure that can be changed with the addition of various radicals at the R position:
H2N
S
NH R
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O
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O
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The most active SA derivatives contain heterocyclic radicals. Many SAs are based on pyrimidine, pyridazine and other heterocycles, and it turns out that the displacement of
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the para-amino group to the meta- or ortho-position deprives the compound of its bacteriostatic action. If the hydrogen atom in the amino group is replaced with different
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radicals, the compound loses its activity, but if these radicals are detached in the human
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body, the activity of the compound will be retained. Introduction of some additional
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substituents into the aromatic ring results in the decrease or complete loss of the physiological activity of the SA.
All SAs are white or slightly yellowish, odourless powders, and some have a bitter
taste. Most of these substances are poorly soluble or practically insoluble in water. The solubility of SAs in acids and alkalis is conditioned by their amphoteric properties, which are due to the presence of the basic aromatic amino group (pKa1 2–2.5) and the amide group, which contains a labile hydrogen atom with acidic properties (pKa2 5–8). The acidic properties of SAs are more pronounced than their basic properties, and thus SAs are positively charged in acidic medium at pH < 2, neutral at pH 3 – 5, and negatively charged at pH > 5 [2].
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The high efficiency of SAs and their relatively low cost have stimulated their ubiquitous use in veterinary practices. SAs are used in veterinary medicine in pure formulations or in combination with other antibiotics not only to combat infectious diseases, but as additives to animal feed in order to promote growth and to increase the
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productivity of livestock and poultry despite the fact that the use of antibiotics for this purpose is forbidden in several parts of the world. For example, according to the data
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given in a previous review [11], the 2009 consumption of SAs in mg per kilogram of
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meat produced in Denmark was 4.82 (pork), 17.2 (cattle), 0.033 (broilers) and 58.5 (fish). As a result of misconduct in the prophylaxis and treatment of animals or due to
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non-compliance with holding times before slaughter, traces of SA drugs can enter foods of animal origin. Strictly speaking, every human is a passive consumer of these drugs,
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which are obtained from meat and dairy products, eggs and honey that inherit SAs from
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the treatment of bacterial diseases in animals, poultry or bees. The systematic human
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intake of SAs through foods is dangerous, as SAs can have adverse effects that most commonly manifest in the form of allergic reactions, disbacteriosis, suppression of enzyme activity, alteration of the intestinal microflora, and promotion of sustainable forms of pathogens. In addition, there is evidence of hemotoxicity and carcinogenic effects of some SAs, particularly SMZ [12]. It should be noted that certain decomposition products of SAs can be active and potentially more toxic than the parent compounds [13]. The long-term use of SAs has resulted in a large number of SA-resistant bacterial strains, which has stimulated the production of combined SA preparations containing trimethoprim (Bactrim, Septrin, Biseptol, etc.) aimed at delaying proliferation of SAresistant microorganisms and enhancing the antibacterial effect of the SAs.
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SAs enter the soil and water from food chains that involve human and animal waste. A considerable portion of SAs enter the environment from flushing water from pharmaceutical companies as well as poultry and pig farms. Every year more than 20000 tons of SAs enter the environment worldwide, with maximum amounts of SAs being
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found in pig manure and soils. The SA content in other samples is as follows: sea water < groundwater < surface water < treated wastewater < untreated municipal wastewater
85%) than SPE, liquid extraction and MSPD. Furthermore, the sample preparation using QuEChERS was very
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fast and cheap due to the absence of the solvent evaporation and purification steps which are present in the other three extraction methods. Using this method, the preparation of 15 samples was completed in less than 1 h while the other extraction methods required at least 3 – 4 hours. The QuEChERS method meets requirements for today’s chemical
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analysis methodologies, as it allows for the quick and efficient extraction of SAs as well as other veterinary antibiotics from foods. For simplifying the conventional QuEChERS-
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like pretreatment, two straightforward extraction procedures named “STEMIT” (single-
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tube extraction with multisorbent impurity trapping) and “SEP/MAC” (single-tube extraction/partitioning multifunction adsorption clean-up) were evaluated [37].
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In recent years, the isolation of SAs from milk and honey has been performed using traditional liquid-liquid extraction (LLE) with ethyl acetate [53, 58, 86],
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chloroform:acetone mixture (65:35, v/v) [59], acetonitrile [79, 81, 82], hexane [83] along
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with cloud point extraction [63, 90] and different types of liquid-liquid microextraction
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(LLME) [115, 120, 121]. Among these methods, dispersive LLME (DLLME, developed in 2006) has attracted the greatest interest [33, 60, 61, 71, 78, 128]. The main idea of this method is to obtain a sub-micron emulsion of an extractant in the solution under analysis, which increases the surface of mass-exchange and decreases the time required for analysis. Equilibrium in such systems is usually achieved in less than 1 min. A poorly water-miscible or water-immiscible organic solvent is used in this method as the extractant and an organic polar solvent that is well miscible with water and capable of dissolving the extractant is used as a dispersant (dispersing solvent). The sample solution, the extractant and the dispersing solvent are mixed in a centrifuge tube, shaken, and the resulting emulsion is centrifuged. The use of ultrasound [78] or ionic liquids [60, 61, 101, 130] simplifies this method remarkably as it avoids the addition of a dispersant.
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As mentioned above, the solvent-based extraction of SAs from solid foodstuffs is often combined with SPE, which was used to preconcentrate SAs from meat [27, 39 − 42, 46], fish [96, 104], eggs [46, 107], honey [33, 116 – 118, 126] and milk [46, 65, 67, 72, 73, 75]. Commercially available cartridges filled with different polymeric sorbents are
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often used for this purpose and include the following: Oasis MCX [39, 116], Oasis HLB [46, 65, 73, 75, 107, 117], Nexus Abselul [27], BondElut SCX [33], Cleanert PEP [40],
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Strata SCX [41], LiChrolut C18 [42], HySphere C18 HD [96] and Sep-Pak C18 [126]. For
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the selective isolation of SAs from food, carbon nanomaterials [43] and molecular imprinted polymers (MIPs) [66, 67, 72, 104] have been used successfully. Acetonitrile
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[27], methanol [40], ammonium – acetonitrile [39] and ammonium – methanol solutions [41] as well as mixtures of acetonitrile or methanol with acetic acid [104, 118] are used
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as the eluents. Monolithic capillary columns provide an alternative to the use of SPE
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cartridges [76, 105]. The advantages of monolithic capillary columns are their high
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efficiency and stability combined with the convenience of their introduction into on-line flow preconcentration systems.
The routine monitoring of food products for residual amounts of SAs requires
rapid methods of analysis. Recently, solid-phase microextraction (SPME) has been increasingly used for this purpose [57, 77, 80]. Compared with the conventional methods of extraction such as LLE or SPE, SPME allows pure extracts to be obtained with less solvent consumption, which significantly improves the analytical signals. The adsorbents used in this method are different polymeric materials (polydimethylsiloxane, polyacrylate and carbowax/divinylbenzene, etc.) supported on a solid matrix. To improve the efficiency and selectivity by which analytes are isolated, the adsorbents are further modified, for instance, by molecular imprinted polymers (MIPs). Thus, Chen et al. [80]
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have developed a fast, selective and efficient method of SPME in which the adsorbent consists of MIP microbeads. The method was applied to the separation and preconcentration of SMZ from milk before its detection by capillary electrophoresis with a UV detector. The recoveries of SMZ from milk were 89 – 110 %. To isolate SAs from
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milk and meat, an SPME technique on a 1x1-cm polypropylene membrane containing a polymeric sorbent based on methacrylic acid and ethyleneglycoldimethacrylate was
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developed [57]. Using the porous membrane, the authors managed to avoid
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contamination of the sorbent by solid particles. For the detection of SAs in milk, a miniature device based on a medical syringe filled with 30 mg of water-compatible
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poly(hydroxyethyl methacrylate) was designed [74].
One of the newest techniques of food sample preparation is stir bar sorptive
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extraction in which glass magnetic stirrer bars coated with polydimethylsiloxane are
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used. The stir bar is placed in a vessel containing a sample that is placed on a magnetic
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stirrer and mixed for a certain time. Then, the bar is recovered, dried, and desorption of the compounds is performed. In several studies, this method of sample preparation was used for the isolation of SAs from meat [34, 35] and milk [64, 69]. To increase the efficiency of SAs sorption, the polydimethylsiloxane coating was further modified with MIPs [34], monolithic polymeric materials [35, 64] or C18 [69]. Among the other SPE methods, there is an interesting approach based on magnetic
particles coated with MIPs synthesised by grafting [26, 68, 119]. Particles of Fe 3O4 were treated with modifiers (ethylene glycol, polyvinyl alcohol or oleic acid), dipped into a solution containing all components necessary for the synthesis of MIP, and the polymerization was carried out. Composite materials based on Fe3O4 and MIPs retain all of the properties needed to recognise template molecules and can be easily separated
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from the solution by applying magnetic field. These were used for the selective extraction of SAs from meat [26], milk [68] and honey [119]. 2.2. Feed The practical use of SAs and other antibiotics as farm animal feed additives first
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became widespread in the 1950s. SAs are added to feed for therapeutic or prophylactic purposes and despite the fact that the antimicrobial effect of SAs is less than that of
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antibiotics, they are cheaper and more widely available in dealing with infectious
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livestock and poultry diseases. The concentration of SAs in feed ranges from 70 to 800 mg kg-1 [135], leading to their accumulation in the bodies of animals and contamination
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of animal-derived foods. SMZ, SQX and SDM are the most frequently detected in feed. A survey of the literature [53, 94, 135 – 148] has shown that the researchers have
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mainly focused on the search for express methods of feed sample preparation and their
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combination with the subsequent SA detection, which mostly has been performed by
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HPLC, HPLC-MS or HPLC-MS/MS. In recent years, many different extractants have been suggested for extracting SAs from feed, including acetonitrile [138, 142, 143], mixtures of acetonitrile and water (95:5, v/v) [53, 94, 135, 141, 142], mixtures of chloroform and acetone (50:50, v/v) [144] or ethylacetate and water (99:1, v/v) [145] as well as ternary mixtures methanol:acetonitrile:McIlvaine buffer (37.5:37.5:25, v/v/v) [137, 146]; and acetonirile:methanol:1%-formic acid (65:25:10, v/v/v [139] and 80:10:10, v/v/v [140]). In several papers, the sample preparation was carried out using an ultrasonic bath [139, 140, 146]. PLE [136, 148] and modified QuEChERS [147, 148] were also used. Further purification and preconcentration of the extracts was carried out using SPE with Oasis HLB [135, 148] and Strata SCX [144] cartridges or magnetic nanoparticles coated with SMZ-imprinted polymers (Fe3O4@MIPs) [142]. In most works
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[136, 137, 138 – 140, 146, 148], SAs were extracted from feed along with other antibiotics and medicines. 2.3. Environmental samples In the past decade, the interest in detecting SAs in the environment has
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significantly increased. These substances and their metabolites, along with surfactants, personal hygiene products and other compounds associated with the human life, enter the
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environment as complex mixtures and achieve penetrance primarily through the crude
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and treated city wastewater [149]. A considerable portion of SAs enter the environment through flushed water from pharmaceutical enterprises and poultry and pig farms.
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According to the data systematised in the reviews [11, 150], the content of SAs in untreated wastewaters ranges from 0.01 to 19.2 μg L-1, and in treated wastewaters ranges
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from 0.004 to 6.0 μg L-1. SMX has been the most frequently detected SA in the ground
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2.3.1. Waters
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water in many countries [150].
SAs have been detected in underground [151], surface [33, 61, 101, 152, 155, 157,
159, 160, 162 – 171] and wastewater [153, 154, 156 – 158, 161]. The preparation of these samples was often carried out by SPE using commercially available cartridges, such as Oasis HLB [151 – 159], Strata-X [160], or Bond Elut-ENV [161]. In some cases, to remove negatively charged humic and fulvic acids, a subsidiary anion exchange cartridge (SAX) has been used [155, 158].
The Oasis HLB, Hysphere C18 EC, and PRLP cartridges were compared for their efficiency in extracting SAs [152]. The best cartridge was Hysphere C18 EC, while the best eluents were methanol, acetone or a methanol – acetone mixture (1:1, v/v) in comparison to acetonitrile. The good sorption ability toward SAs was attributed to hyper-
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crosslinked polystyrene, which sorbed by 98–100% of SMZ, SMX, SMP and SCP using a microcolumn filled with 30 mg of this sorbent [162, 163]. Carbon nanotubes [164], magnetic iron oxide nanoparticles coated with octadecyltrimethylammonium bromide [165] and composites based on Fe3O4 and either carbon nanotubes [164] or graphene
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[166] were also suggested as the sorbents for isolating SAs from waters through SPE. A portable device based on a micropipette filled with 1 mg of graphene was developed for
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flow micro-SPE of SAs [167].
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Alternative miniaturised methods of extracting SAs from natural water before their chromatographic determination are single-drop liquid-phase microextraction into a drop
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of extractant formed at the tip of a syringe needle [168], membrane microextraction [169, 170] and dispersive liquid-liquid microextraction [61, 101, 171]. Ionic liquids are
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increasingly being used as the extractants [33, 61, 101, 168, 169].
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Other drug substances such as tetracyclines [154 – 157], quinolones [154, 171],
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macrolides [155, 158], trimethoprim [154, 160], chloramphenicol [154, 161] and hormones [155] have been found along with SAs in water. 2.3.2. Soils, manure and sediments
In recent years, interest in the determination of SAs in soils, manure and sediments
has grown remarkably [172 − 183]. The preparation of these environmental samples includes SA extraction with acetonitrile [172 – 175], methanol [176 – 178], nonionic surfactant Triton X-114 [179] and mixtures of these extractants with different buffers [175, 177, 178]. SAs were extracted from solid samples using ultrasonic extraction [174, 175, 177], microwave-assisted extraction [175, 179], PLE [175, 180 – 182] and MSPD [183].
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The extraction of six SAs (SDZ, SDD, STZ, SCP, SDM, and SQX) from soils was investigated by different extraction techniques, such as conventional mechanical shaking, microwave-assisted extraction, ultrasonic extraction and PLE [175]. The recoveries of SAs in an acetonitrile : pH 9 buffer (20:80, v/v) solution from overnight spiked soils
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ranged from 40 to 80%, depending on the SA and the soil, and did not depend on the extraction technique. Recoveries obtained from aged SA residues were lower and
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depended on the extraction technique applied, with the microwave-assisted extraction
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being the most efficient.
Additional clean-up of the samples is often carried out by SPE using anion-
2.4. Pharmaceutical and clinical samples
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exchange and polymer cartridges (Oasis HLB, Strata X) [172, 177, 178, 180].
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The preparation of sulfonamide-containing pharmaceuticals, in which the SA
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content is usually approximately 0.1 – 1 g, usually involves powdering a sample and
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dissolving a weighed portion of it in methanol [184 − 189]. The concentration levels of SAs in clinical samples vary within a quite broad range. SAs are usually detected at a rate of approximately 0.1 – 100 μg mL-1 in blood plasma and 0.001 – 1 μg mL-1 in urine. Liquid-liquid extraction is used for isolation of SAs from blood serum and plasma [61, 185, 190, 191] or urine [190, 192] and still remains the main method for preparation of biological samples prior to SA determination. Acetonitrile [185], ethylacetate [192], 1% phosphoric acid, [191] and a mixture of acetonitrile with phosphoric acid [190] are used as the extractants. Sedimentation of proteins in urine was performed using 2% trichloroacetic acid [192]. In some papers, liquid extraction was combined with SPE [190, 191]. For example, the aqueous phase was additionally purified on a Nexus Abselut SPE cartridge [190]. SAs were eluted with acetonitrile, preconcentrated by evaporation,
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derivatised by putrescine in sodium acetate buffer (pH 3.4) and analysed by HPLC-FL. The recoveries from serum and urine were 91.2 – 119.0 % and 91.3 – 117.0 %, respectively. For the simultaneous determination of SMX and trimethoprim in plasma by HPLC-MS, the isolation of the analytes was performed by SPE on Orpheous DVB-HL
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cartridges [191].
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3. Analytical methods
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Analytical methods for the detection and determination of SAs residues can be classified into three groups: quantitative, confirmatory and screening. Quantitative
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methods are mostly based on chromatography and capillary electrophoresis and allow for
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the quantification of SAs. However, these methods usually require complex samplepreparation procedures, multi-step clean-ups, complex laboratory equipment and trained
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operators. They are time-consuming and expensive. The main feature of confirmatory
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methods is their ability to reliably identify a compound. Screening methods can detect an analyte at the level of interest and usually provide semi-quantitative results. They are specifically designed to avoid false compliant results [193]. These methods must allow for the reliable checking of samples, and only those samples indicating the presence of the analyte should be selected for a thorough analysis. The ideal characteristics of a screening method are a low percentage of false compliant samples, short analysis time and high throughput, ease of use, good selectivity and low cost. In general, the reported methods of SA determination can be grouped depending on the type of analytical technique applied. The corresponding percentages are depicted in Fig. 4. As it can be seen, HPLC-MS(/MS) is the most employed analytical method (38 %), followed by HPLC with other detectors (22%) and electrophoresis (15 %).
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3.1. Chromatographic methods HPLC has been widely used for the quantification of SAs due to its high sensitivity and broad linear range. Currently, the most widely used analytical methods for SAs are based on a reversed-phase HPLC (RP-HPLC) separation. Among these methods,
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HPLC–MS/MS, which can also be considered to be a confirmatory method, has become the main analytical technique for the identification of SAs due to its higher selectivity
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and sensitivity than other instrumental methods.
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In addition to HPLC, ultra high-performance liquid chromatography (UHPLC) has increasingly been used for the rapid separation of SАs. This technique became possible
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due to the relatively new HPLC systems that tolerate ultra-high pressures and use columns with sub-2-μm-particles, improving chromatographic performance (e.g., speed,
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sensitivity and resolution) and reducing co-elution of interferences, thereby diminishing
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matrix effects when compared to conventional HPLC. Rapid multi-residue screening of
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veterinary antibiotics including SAs in food and environmental samples is one of the most promising applications of UHPLC technology. 3.1.1. Detection with MS and multi-class analysis
Table 4 represents a selection of analytical methods for the detection of SAs by
RP-HPLC and UHPLC with MS detection reported over the past 5 years. Being a confirmatory method, MS detection is used to identify and quantify a
substance and can be used to confirm a compound’s molecular structure. The basic principle of this detection technique is measurement of the mass-to-charge (m/z) ratio of ionised molecules. HPLC–MS/MS is often applied using a triple quadrupole analyser and a selected reaction monitoring mode. This mode allows for the confirmation of the composition of the compound and provides its structural information. In MS/MS, the
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most intensive ionic fragment from a precursor ion is used for the quantification. A less sensitive secondary transition is used as the second criterion in confirmation purposes. This mode also improves the precision and sensitivity of the analysis but does not collect the full scan data. This can limit the availability of the full scan data which could
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otherwise be used to both identify target analytes and detect additional unknown compounds. The choice of one or another MS approach to monitor certain substances and
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residues in live animals and animal products can be referred to the European Union
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Commission Decision 2002/657/EC, which established performance criteria and other requirements for analytical methods with different type detection, including MS
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[193].The first step in the tandem MS detection is the selection of a precursor ion. HPLC–MS/MS analysis of SAs is usually performed with the electrospray ionization
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(ESI) source operating in positive-ionization mode. The protonated molecule [M+H]+
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was chosen as a precursor ion for quantitation in all developed methods. The common
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fragment ion m/z 156 represents the sulfanyl ring and is used for the quantification of the majority of SAs [10].
One of the advantages of MS/MS is the fact that complete HPLC separation of the
target analytes is not necessary for selective detection. However, it is always advisable to have good chromatographic separation in order to reduce matrix effects that typically result in the suppression or, less frequently, in the enhancement of analyte signals. Therefore, short HPLC columns are generally used, considerably speeding up the analysis. As it is indicated in Table 4, C18 reversed phase based columns are widely used for HPLC multi-residue analytical methods. Because MS detection is incompatible with most mobile phases, volatile organic modifiers should be used when HPLC is coupled to MS. Thus, formic and acetic acid or
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their ammonium salts are added to acetonitrile–water or methanol–water mixtures. The typical concentrations of modifiers range from 2 to 20 mmol L-1. It has been observed that the higher concentrations lead to reduced signal intensities. The method of HPLC-MS/MS was successfully applied to the simultaneous
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quantification of SA residues in porcine liver [29], pork and chicken samples [35], milk and milk powder [69, 78], grass carp tissues [97], eggs [111], honey [117], feed [147] and
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soil [191]. Yu et al. [32] simultaneously determined 18 SA residues in poultry tissues,
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muscle, and the livers and kidneys of swine, cows and chickens.
A major drawback of a multi-residue method using HPLC–MS/MS is the high cost
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of the organic solvents and the HPLC-MS/MS equipment. The development of UHPLC has greatly reduced the analysis time. By reducing the particles of the stationary phase to
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less than 2 µm, the resolution can be increased up to 60 %, allowing good separation in
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less time. A highly selective and sensitive method was developed for the simultaneous
Ac ce pt e
detection of twelve SAs in beef and milk by immunoaffinity chromatography purification coupled to UHPLC-MS/MS [38]. The limit of detection (LOD) for the studied SAs ranged from 0.4 to 2.0 μg L-1 (1.6 – 8.0 μg kg-1 for beef and 1.8 – 6.4 μg kg-1for milk). She et al. [79] have developed a novel method for the rapid separation and determination of twenty-four SAs in bovine milk by UHPLC-MS/MS. The samples were treated with acetonitrile followed by homogenization, ultrasound treatment and centrifugation. The analytes were detected by multiple reaction monitoring (MRM) in the positive ion scan mode. Liu et al. [143] have presented a fast and sensitive UHPLC-MS/MS method for the simultaneous quantitative determination of 16 SAs in animal feeds. Recently, a hybrid triple quadrupole-linear ion trap (QqLIT) instrument has been developed. This is a powerful technique for the large-scale screening of SAs and their
Page 22 of 76
metabolites in real samples [37, 152, 181]. The method is based on a QqQ with the third quadrupole (Q3), which can be used as either a conventional quadrupole mass filter or a linear ion trap combining the advantages of the classical QqQ scanning functionality and the possibility of additional sensitive ion trap scans for structural analysis within the same
ip t
operating platform. Due to the high ion-accumulation capacity, this method has improved full-spectrum sensitivity that provides very promising modes such as enhanced full mass
cr
scan, enhanced product-ion and multi-stage scans. All of these features make the
us
technique very powerful for the identification of unknown or suspected analytes even with poor fragmentation and at low concentrations. Another attractive capability of
an
QqLIT for semi-targeted analysis is information-dependent acquisition that automatically
experiment.
M
combines a survey scan with the dependent (enhanced trap) scan during a single
d
The progress in chromatography and mass-spectrometry resulted in development
Ac ce pt e
of multi-class analytical methods, which are currently a significant trend in the detection of several classes of veterinary drugs in food and environmental samples that can be successfully applied for both quantification and screening purposes [133]. These methods are able to detect more than 200 different compounds and are of great interest to analytical laboratories due to their simplicity, high sample throughput and costeffectiveness.
A certain drawback of such procedures is the occurrence of abundant matrix
effects, which compromise the quantitative aspects and selectivity of the methods. The extracts from solid matrices usually have high contents of organic components, such as lipids, humic acids, etc. These interfering compounds compete with the analytes in reaching the droplet surface positions, which affects the maximum evaporation efficiency
Page 23 of 76
and hampers ionization of the analytes. These components also increase the viscosity of the sample and the surface tension of the droplets generated in ESI source, hindering the evaporation of the analytes. Different approaches have been developed to minimise the matrix effects. They
ip t
are based on the use of improved chromatography with better separation of the matrix compounds from the analytes (e.g., UHPLC). The dilution of the sample extracts and the
cr
use of internal standards or matrix matched calibration are also frequently used [37, 97,
us
181]. The main aspect in the multi-class residue analysis, however, is a sample preparation step that should effectively extract a broad range of compounds from the
an
samples. The different physico-chemical properties of target analytes as well as the
extraction and clean-up.
M
presence of the high concentrations of interferences in the matrices complicate the
d
A variety of sample pretreatment methodologies and several multi-class HPLC-
Ac ce pt e
MS/MS and UHPLC–MS/MS methods have been applied for the detection of SAs along with veterinary drugs in animal food (see Table 2, 3), feeds, waters, soils and sediments (see Table 5). Most multi-class methods involve simple liquid extraction and QuEChERS, while clean-up is carried out by SPE. The degree of clean-up provided by many of these methods is usually limited because the extensive purification would result in total loss of some residues. Other simple approaches such as “dilute-and-shoot” strategy, which utilises diminishing matrix effects in diluted samples and is usually exploited in the mass spectrometric analysis of SAs, as well as ultra-filtration or on-line column switching have also been developed. For instance, a rapid and simple method for both quantification and confirmation of nineteen antibiotics of five classes in muscle (SAs, tetracyclines, quinolones, β-lactams
Page 24 of 76
and macrolides) has been described [45]. The antibiotics were extracted by 70% methanol, diluted with water and injected in the HPLC–MS/MS system. Cronly et al. [138] have described a confirmatory method for the determination of fourteen prohibited medicinal
additives
(metronidazole,
dimetridazole,
ronidazole,
ipronidazole,
ip t
chloramphenicol, SMZ, SDZ, dinitolimide, ethopabate, carbadox, clopidol, tylosin, virginiamycin and avilamycin) in pig and poultry feed at levels of 100 µg kg−1. The
cr
compounds were extracted using acetonitrile with the addition of sodium sulfate and
us
cleaned with hexane before determination using HPLC–MS/MS. In another example, a fast and easy HPLC-MS/MS multiclass method was developed for the detection of fifty
an
antimicrobials from thirteen different families in animal feeds [146]. Analytes were extracted using a mixture of methanol, acetonitrile and McIlvaine buffer combined with
M
sonication. The feed extracts were simply diluted prior to injection. Analysis was carried
d
out by HPLC-MS/MS using an ESI source operating in the positive and negative modes.
Ac ce pt e
A multi-class UHPLC-MS/MS method has been developed for the determination of more than 160 regulated or banned compounds of various classes in eggs, honey and milk [47]. These compounds include anthelmintics such as benzimidazoles, avermectins and others; antibiotics including amphenicols, beta-lactams, macrolides, pyrimidines, quinolones,
SAs
and
tetracyclines;
beta-agonists;
corticosteroids;
ionophores;
nitroimidazoles; non-steroidal anti-inflammatory agents; steroids; and tranquillisers. The compounds were extracted with acetonitrile without any additional purification steps and analysed by UHPLC-MS/MS. In most cases, the target value was set at 5 mg kg-1 for unauthorised compounds. Furthermore, Zhan et al. have developed a simple and fast extraction procedure for the determination of 226 veterinary drugs and other contaminants in muscle [51]. The method is based on LLE, low temperature clean-up and
Page 25 of 76
dispersive SPE. The limit of quantification (LOQ) varied from 0.05 to 10 µg kg–1. Another work [108] describes a multiclass method for the determination of forty-one antimicrobial agents from seven families (SAs, diaminopyridine derivatives, quinolones, tetracyclines, macrolides, penicillins and lincosamides) in eggs. The method has been
ip t
validated according to the requirements of the European Commission Decision 2002/657. Compounds were extracted using PLE with a mixture of acetonitrile and succinic acid
cr
buffer (pH 6.0) (1:1, v/v) at 70◦C. No further clean-up was necessary. Analytes were
us
determined by UHPLC–MS/MS over a chromatographic run of 13 min. The LOQs were in the range of 0.5–3.8 µg kg−1 for non-authorised compounds. The proposed method
an
would enable to process about twenty-five samples per day.
A rapid and simple analytical method that was able to simultaneously determine
M
220 undesirable chemical residues (veterinary drugs, mycotoxins, pesticides, hormones
d
and other contaminants) in infant formula has been developed [132]. The method
Ac ce pt e
includes extraction with acetonitrile, low temperature clean-up by water precipitation and detection by UHPLC–MS/MS with ESI using the MRM mode. Most of the fat materials in the acetonitrile extract were eliminated by the low temperature clean-up. The LOQs were from 0.01 to 5 µg kg-1.
The QuEChERS multiresidue procedure simplifies extraction and clean-up and
reduces the time of the analysis (Table 3, 5). For example, the QuEChERS method has been developed for the determination of trace amounts of thirty-one substances including hormonal steroids, veterinary and human drugs in soil [172]. The analysis was performed using HPLC–MS/MS. This method allowed for the detection of substances at the sub-ng g-1 concentration level. The methodology was applied to real soil samples collected in the several areas of France that had received different treatments with manure or sludge.
Page 26 of 76
Veterinary antibiotics, which were mainly from the sulfonamide family, were found in the manure-treated soils (0.02 – 0.12 ng g-1). Another good possibility for the multi-component analysis is a sensitive full mass scan MS technique such as time-of-flight (ToF-MS) or quadrupole time-of-flight mass
ip t
spectrometry (QTOF-MS). These analysers provide high specificity due to both the high mass accuracy and the high mass resolution. The advantage of a ToF-MS analyser is its
cr
ability to analyse a sample for a large number of compounds. The HPLC–ToF-MS
us
approach is capable of high-sensitivity screening of several hundreds of compounds within a single run. Furthermore, the data can be acquired and processed without any
an
prior knowledge about the presence of certain compounds. In other words, no analytespecific information is required before injecting a sample, and the presence of newly
M
identified compounds can be confirmed in the previously analysed samples simply by
d
reprocessing the data. The advantage of ToF-MS can be further improved by combining
Ac ce pt e
it with UHPLC [46, 81, 94, 103]. A fast liquid chromatography ToF-MS method has been developed for the simultaneous multiclass determination of selected antibiotics and other veterinary drugs (benzalkonium chloride, ethoxyquin, leucomalachite green, malachite green, mebendazole, SDZ, SDM, SMZ, SMT, SAM, SPY, STZ and trimethoprim) in shrimps [103]. Different sample pretreatment methodologies based on either liquid partitioning with different solvents and SPE or MSPD were tested for the extraction of the targeted species. The extraction method that was finally selected was liquid extraction with acetonitrile followed by a clean-up step with PSA (QuEChERS). The LOD ranged from 0.06 to 7 µg kg−1. Deng et al. [46] have developed an UHPLC-QTOF-MS method for a comprehensive screening of 105 veterinary drugs and metabolites including beta-
Page 27 of 76
agonists, benzimidazoles, corticoids, triphenylmethane, nitromidazoles, quinolones, SAs, tetracyclines, and benzodiazepams in meat, milk, and eggs. Acetonitrile containing 0.1% formic acid was used to extract the drug residues from these matrices and to precipitate the proteins. Sample clean-up was then conducted on an Oasis HLB column. The
ip t
separation was achieved within 30 min at the optimised chromatographic conditions. A HPLC-QTOF-MS method has been developed to analyse veterinary drug residues in milk
cr
[81]. Drugs were extracted with acetonitrile and a molecular weight cut-off filter was the
us
only clean-up step used in the procedure. A set of target compounds (including representative SAs, tetracyclines, β-lactams, and macrolides) was used for validation.
an
Although the method was intended to be qualitative, the evaluation of the MS data indicated a linear response and the acceptable recoveries for a majority of target
M
compounds. Finally, milk samples from cows dosed with veterinary drugs including
d
SMZ, flunixin, cephapirin or enrofloxacin were analysed. In addition to the parent
Ac ce pt e
residues, several metabolites were detected in these samples. The proposed identification of these residues could be made by evaluating the MS and MS/MS data. For example, several plausible metabolites of enrofloxacin, which has not been previously observed in milk, were reported in this study.
3.1.2. Detection with other techniques Classical reversed-phase HPLC with ultraviolet (UV) [22, 25, 26, 33, 34, 41, 57,
58, 63, 64, 66, 72, 76, 77, 82, 101, 104, 112, 115,116, 135, 142, 159, 165, 166, 168, 169, 179], photodiode array (DAD) [23, 48, 59, 60, 62, 65, 67, 70, 95, 107, 128, 130, 144, 161,163, 178, 186] and fluorescence (FL) [24, 27, 28, 30, 61, 71, 74, 83, 95, 114, 117,121, 129, 145, 167, 175, 178, 190] detectors is still widely used for the routine quantification of SAs in different types of food, feed and environmental samples. All of
Page 28 of 76
these approaches are quantitative but not confirmatory, as they cannot provide direct evidence of the structure or composition of a substance. Electrochemical detection is used less frequently [105, 114, 163, 181]. UV detection is often carried out at 270–280 nm or in some cases at 255 nm. DAD detection is often performed at 267, 268 or 263 nm. FL
ip t
detection is carried out at the excitation wavelength of 405–420 nm and at the emission wavelength of 485–495 nm after pre-column derivatization with fluorescamine. UV
cr
detection is the most affordable and versatile but the least selective and sensitive. FL
us
detection is much more sensitive and selective, but its use is connected to the additional derivatization procedure for transformation of SAs into their fluorescent derivatives. The
an
less frequent use of electrochemical detection seems to be due to the complexity of selection of the detection conditions.
M
The vast majority of the chromatographic separations of SAs have been performed
d
with conventional silica-based reversed phased columns (mainly C18) with spherical
Ac ce pt e
sorbent particles of 3 – 5 μm in diameter. Some types of commercially available stationary phases used for the determination of SAs are represented in Table 6. The speed of the analysis can be increased through the use of a monolithic column
[27, 105], high temperature [159] or an ultra-high-pressure system [164, 171]. A fast analytical method based on HPLC-UV that provides pressure up to 600 bar, and a 150 mm column operated at high temperature (600C) was used for the separation and determination of nine SAs in surface and wastewater samples in the shortest possible time (3 min) [159]. Herrera et al. [164] used magnetic multi-walled carbon nanotubes combined with UHPLC-DAD to extract eleven SAs (i.e., SAM, SAA, SDZ, STZ, SMR, SDD, SMP, SDO, SMX, SSA and SDM) from different water samples [164]. A DLLME
Page 29 of 76
procedure combined with UHPLC-DAD has been developed for the determination of eleven SAs and fourteen quinolones in mineral and run-off water [171]. The mobile phases mainly consist of acetonitrile–water or methanol–water mixtures (Table 6). Furthermore, there are papers reporting the application of three-
ip t
component mixtures such as water:methanol:acetonitrile [58, 72, 144]. In most cases, the mobile phase was modified with acetic [41, 30, 79, 104, 119, 25, 165] or formic acid
cr
[119, 152, 168, 120], and acetate [27, 61], phosphate [72, 169] or formate buffer [146].
SAs in complex mixtures with other antibiotics.
an
3.2. Electrophoretic methods
us
The application an elution gradient allows the separation and simultaneous detection of
Capillary electrophoresis (CE) is another good quantitative analytical approach
M
that is mainly used when only small amounts of a sample are available. Some advantages
d
of CE are its high separation efficiency, ability to analyse several samples simultaneously
Ac ce pt e
in multicapillary systems, and low consumption of reagents and accessories (packaged columns are not required). Several CE methods for the analysis of SAs were published and reviewed in 2009 [17]. Recent advances in the analysis of antibiotics, including SAs, by CE from 2009 to 2011 are summarised in another review [194]. For the past five years, CE has been used for the determination of SAs in chicken
and edible pig tissues [25, 40, 43], milk [80], shrimp [99] and water samples [170]. Phosphate [40, 43] and borate [80, 99] buffers, which sometimes contain additional organic modifiers such as sodium polystyrene sulfonate [170], were used as a running buffer. The simultaneous determination of six SAs (SMZ, SDM, SMR, STZ, SDZ and SMX) in chicken and edible pig tissues was accomplished by CE with electrochemical
Page 30 of 76
detection [25]. The complete separation of SAs was achieved within 17 min, using 40 mmol L−1 Na2 B4O7/25 mmol L−1 KH2PO4 (pH 6.2) at the applied voltage of 18 kV. Chu et al. [40] used CE for the separation and detection of SMX, SMZ, SMR and SDM in chicken and beef tissue samples. The analysis was performed under the following
ip t
conditions: the stationary phase was a quartz capillary; the mobile phase was 45 mmol L-1 phosphate buffer (pH 6.3); detection was performed using a photodiode array; and the
cr
voltage was 20 kV. The LODs of the SAs were 4 – 6 μg kg-1. Four SAs were detected in
us
meat samples by CE following clean-up of the acetonitrile extracts on graphene-filled cartridges [43]. A hollow-fibre liquid-phase microextraction method was developed for
an
the preconcentration of six SAs, including SMZ, SMR, SDZ, SDM, SMX and STZ, which were detected by CE with electrochemical detection. Under the optimum
M
conditions, these compounds could achieve the baseline separation within 35 min. The
d
LODs were in the range of 0.033–0.44 ng mL-1 [170].
Ac ce pt e
Microfluidic chip electrophoresis is an alternative to the conventional capillary electrophoresis that usually has better performance [56, 185]. Wang et al. [56] have proposed a sensitive microchip electrophoresis method for the efficient separation and detection of four SAs (SMZ, SMX, SQX and SAM) in milk and chicken drumstick muscle using the laser-induced fluorescence detection. Separation of fluorescaminelabelled SAs was accomplished using a buffer containing 5 mmol L-1 boric acid and 1% (w/v) polyvinyl alcohol. Under optimised conditions, the separation of four SAs was achieved within 1 min with the LODs of 0.2−2.3 μg L-1. A compact and low-cost lightemitting diode-induced fluorescence detection coupled to a microchip electrophoresis system was applied to the detection of fluorescamine-labelled SAs in commercial
Page 31 of 76
preparations and in a rabbit plasma sample [185]. The LODs for SDZ, SMZ and SGD were 0.36–0.50 μg mL-1. Capillary electrochromatography is a hybrid separation technique that combines the stationary phase of HPLC and the electroosmotic flow of CE. Presently, capillary
ip t
electrochromatography is carried out on particle-packed or polymeric monolithic columns. For the separation and detection of nine SAs in meat samples, the authors [39]
cr
suggested using capillary electrochromatography with MS-detection. The separation was
us
carried out on several monolithic stationary phases, which were synthesised using onestep co-polymerization of divinylbenzene with different alkyl methacrylates (butyl-,
an
octyl-, lauryl- or stearyl methacrylate). Among these, the poly(divinylbenzene-octyl methacrylate) monolithic column gave the best results. Optimization of the mobile phase
M
composition and the gradient elution strategy allowed for the successful detection of
d
sulfonamide antibiotics in meat samples at levels of 10 μg L-1.
Ac ce pt e
A micellar electrokinetic capillary chromatographic method with UV detection was used for the simultaneous detection of SAs and amphenicols in poultry tissue [42]. The analytes were isolated from tissue samples by SPE with C18 cartridges followed by protein precipitation with acetonitrile. The compounds were separated on the unmodified quartz capillary (57 cm). A solution of 25 mmol L-1 sodium dodecylsulfate and 10 mmol L-1 sodium borate was used as the mobile phase. The total time of analysis was less than 8 min.
3.3. Microbiological assays The microbiological inhibition assays are based on the use of SA-sensitive bacteria as indicators. These assays assess the ability of microbes to reproduce in milk. When growth of these bacteria is suppressed, which is determined directly or indirectly by the
Page 32 of 76
metabolic activity of the bacteria, a conclusion is made about the presence of drugs. The presence of the residual substances is determined from inhibition plots of the bacterial growth obtained from an agar-diffusion method that uses cylinders, wells on the agar surface or discs of filter paper. The test microbes are streptococci, micrococci and aerobic
ip t
spore-forming bacteria. These types of techniques usually meet the requirements of a screening approach.
cr
The microbiological method was used for screening samples of milk for their SA and
us
antibiotic contents before these compounds could be detected by enzyme immunoassay [82] or HPLC [83]. Additional information on the application of microbial screening
an
methods for antibiotic residues, including SAs, can be found in a previous review [195]. That review presents an overview of the developments in the field of microbial screening
M
methods for antibiotic residues and the efforts expended to bring antibiotic screening
Ac ce pt e
3.4. Immunoassays
d
methods into compliance with EU legislation.
Immunoassays are semi-quantitative methods characterised by high specificity,
high sensitivity, simplicity and cost effectiveness, which make them particularly useful for routine uses. These assays are based on a specific reaction between an antibody and an antigen, and they are capable of detecting the low concentration of residues in short time and often do not require laborious extraction or clean-up steps. A large number of papers have been devoted to the detection and identification of SAs using different immuno-methods. Many of them are summarised in the reviews [14 – 16]. Enzyme-linked immunosorbent assays (ELISA) are the most widely used immunoassays due to their high sample throughput. These methods can drastically reduce the number of analyses required to detect sulfonamide contamination in food samples.
Page 33 of 76
Therefore, ELISA methods have been developed for sulfonamide screening in honey [53, 122], chicken muscle [54], fish [106], feed [53, 141], milk [82, 196] and farm animal hair samples [197]. For the high-throughput monitoring of SA residues in edible animal tissues, a
ip t
novel hapten and monoclonal-based indirect competitive ELISA has been developed. The novel hapten was synthesised and conjugated to a carrier protein as the immunogen. The
cr
spleen cells of the inoculated mice, which expressed group-specificity against SAs, were
us
used. The obtained monoclonal antibody showed cross-reactivity to 16 structurally different SAs. Based on this antibody, an optimised ELISA protocol with only
an
phosphate-buffered saline was carried out for the fast extraction of SAs from tissues. The LODs of SAs in chicken ranged from 1.5 to 22.3 µg kg-1. The developed ELISA method
M
would be a useful tool in screening for SAs residues in edible animal tissues [54].
d
A method of detecting the most commonly used SAs (SMR, SDM and SDZ) in
Ac ce pt e
commercial fish samples has been developed [106]. The important advantage of this method is that only one pair of immunoreagents is used for the detection of three analytes. Therefore, it is possible to use the same ELISA to determine the total concentration of SAs or quantify any of these analytes by using the calibration curves that correspond to each sulfonamide.
Currently, there are many commercially available immunoassay kits used for the
fast and highly specific detection of SAs and other veterinary drug residues. For example, ELISA test kits (RIDASCREEN, R-Biopharm AG, Darmstadt, Germany) were used to assess the contamination of milk with SAs, tetracyclines and quinolones residues [196]. The declared LODs were 1.5 μg L-1 for tetracyclines, 3.5 μg L-1 for sulfonamides, 10 μg L-1 for sulfamethazine and 0.25 μg L-1 for quinolones.
Page 34 of 76
One of the most useful immunoassay formats is the lateral flow immunoassay (LFIA). With respect to SAs, this method has been developed [123] in the competitive reaction format and applied to test for STZ residues in honey samples. To prepare the assay test, a hapten conjugate was used as the capture and goat antirabbit antiserum was
ip t
the control reagent. These reagents were dispensed on nitrocellulose membrane. A polyclonal antiserum against STZ was conjugated to colloidal gold nanoparticles and
cr
used as the detection reagent. The visual LOD (cut-off value) of STZ was 15 ng g-1. The
us
qualitative results were reached in 10 min, and the test was highly specific and showed no cross-reactivity to other chemically similar antibiotics.
an
Examples of immunoassays for the determination of SAs are given in Table 7. 3.5. Biosensors
M
Immunochemical methods, which use antibodies as the specific recognition
d
elements, are excellent complementary analytical alternatives for detecting SA residues
Ac ce pt e
in small sample volumes without complex sample preparation and purification steps. In fact, over the past five years, it has been demonstrated that the electrochemical and optical biosensors are excellent tools for detecting contaminants in food and environmental matrices [203, 204]. Their main advantages are their technical simplicity, low cost, and the possibility of being used in field analyses. Electrochemical sensors based on the use of receptors fabricated through different imprinting approaches have been developed for the detection of SAs [89, 91, 125 – 127, 205]. One of the prospective trends in this field is the development of miniaturised disposable electrodes which could potentially avoid a labour regeneration step simply by changing the electrode. The main role in this type of methods is played by screen-printed carbon electrodes. Thus, the authors [89, 91] have suggested an amperometric
Page 35 of 76
immunosensor based on an antibody covalently immobilised onto a 4-aminobenzoic acid film grafted onto disposable screen-printed carbon electrodes and a direct competitive immunoassay using horseradish peroxidase-labelled tracers. The developed methodology showed very low LOD (in the low ppb level) for SA antibiotics in milk samples and good
ip t
selectivity to other antibiotic residues frequently detected in milk and dairy products. Another interesting approach is the application of nanoparticles, quantum dots and
cr
nanocomposites. For example, an electrochemical immunosensor based on a
us
nanocomposite-modified glass carbon electrode has been developed [205]. The biospecific surface was a CeO2-chitosan-modified nanocomposite with an attached anti-
an
SMX polyclonal antibody. The presence of the CeO2-chitosan nanocomposite significantly enhanced the conductivity of the electrode. The large electroactive surface
M
area of the electrode resulted in high loading of the antibody. The LOD of SMX was
d
shown to be 3.25×10−7 mg mL−1. No cross-reactivity with other antibiotics of the
Ac ce pt e
sulfonamide family was found. The immunosensor was successfully applied to the analysis of milk, honey and egg samples. The immunosensor [125] was based on biofunctionalised magnetic particles and
electrochemical nanoprobes prepared by labelling the specific antibodies with CdS nanoparticles (CdSNPs). After the immunochemical reaction, the CdSNPs were dissolved and the released metal ions were reduced at the electrode and read in the form of the current or charge signal by using the well-known anodic stripping technique. Due to the amplification effect on the amperometric/coulombimetric signal produced by CdSNPs, high detectability could be reached. For example, SPY could be detected at 0.20 µg L-1. The immunosensor has been applied to the detection of residues of this antibiotic in
Page 36 of 76
honey samples. The use of magnetic particles minimised the matrix effect and allowed LOD values of up to 0.11 µg kg-1. This effect has conditioned the application of magnetic particles in immunosensing methods. The use of magnetic particles offers unique advantages such as
ip t
permitting interferences in the sample matrix, minimizing the matrix effect, improving immunoreaction kinetics, and ease of magnetic manipulation. For example, a new
cr
electrochemical magnetoimmunosensor (EMIS) has been developed [127] for the
us
detection of sulfonamide antimicrobials in honey samples. The improved EIMS was based on well-characterised immunoreagents, biofunctionalised magnetic beads and
an
homemade graphite–epoxy composite electrodes containing an internal magnet. The EMIS was able to detect SAs in honey at levels below 25 μg kg−1.
M
In a few articles [86 – 88], the application of aptamer-based sensors and assays for
d
the detection of SAs has been mentioned. Aptamers are single-stranded DNA or RNA
Ac ce pt e
oligonucleotides able to bind to their target with high affinity and specificity. The application of aptamers in biosensors offers the possibility of fast and easy detection of SAs. A polymer-based aptasensor using fluoresceinamidite-modified aptamers and coordination polymer nanobelts has been developed for detecting SDM residues in milk [86]. Using the fluorescence quenching effect, the proposed aptasensor showed high sensitivity for SDM (LOD = 10 ng mL-1). In another study [86], SDM-binding DNA aptamers and unmodified AuNPs have been proposed for the sensitive detection of SDM. The assay used aptamer-conjugated gold nanoparticles to combine the selectivity and affinity of aptamers and the spectroscopic advantages of gold nanoparticles. The red-toblue colour change of AuNPs in the presence of SDM was easily observed by the naked eye or measured using a UV–vis spectrometer. The linear dynamic range and the
Page 37 of 76
detection sensitivity were found to be 50 to 1000 ng mL-1 and 50 ng mL-1, respectively. Adrian et al. [88] have developed a portable wavelength-interrogated optical system (WIOS) exploiting class-selective bioreceptors for the fast screening of antibiotics (e.g., SAs, fluoroquinolones, b-lactams and tetracyclines) in milk. The label-free sensor used
ip t
the evanescent-wave principle. The changes in the refractive index close to the modified chip surface were detected by scanning the resonance conditions when a light wave was
cr
coupled in the waveguide through a conveniently designed grating. The bioreagents used
us
in this study were developed to detect a wide range of congeners of the each selected family of antibiotics below the MRL values established for milk samples.
an
3.6. Other methods
M
In addition to the methods described above, different physical-chemical methods have been used for the detection of SAs. These methods are all quantitative and include
d
fluorescence [73, 84, 85, 124, 184], spectrophotometry [90, 128, 188, 189, 206], surface
Ac ce pt e
enhanced Raman spectroscopy [207, 208] and electrochemical methods [55, 187, 209 – 215]. The use of these methods is justified when it is necessary to carry out the routine quality control of relatively simple sample compositions. The advantages of these methods include their simplicity, compactness, and relatively low cost of the analysis. Molecular fluorescence spectrometry can be used as a screening method to detect
SAs in milk [73, 84, 85], honey [124] and pharmaceuticals [184]. For the derivatization of SAs, fluorescamine [73, 84, 85] and β-cyclodextrins [124] have been employed. In a previous paper [184], a new, simple and accurate method has been proposed to detect SAs based on the direct quenching effect produced by several SAs (SSZ, SAM and SMX) on the luminescence of terbium (III). The proposed method allowed for the detection of up to 50 samples per hour.
Page 38 of 76
A net analyte signal standard addition method has been used for the simultaneous determination of SDZ and trimethoprim by spectrophotometry in some bovine milk and veterinary medicines. The method combines the advantages of a standard addition method with the net analyte signal concept that allows for the acquisition of information
ip t
about certain analytes from the spectra of multi-component mixtures. This method has some advantages, such as the use of a full spectrum realization. Therefore it does not
cr
require calibration and prediction steps and only a few measurements are required for
us
antibiotic detection [90].
A simple, sensitive and accurate spectrophotometric method for the detection of
an
SMX, SGD, SQX, SML and SDD in different pharmaceutical preparations has been developed [189]. The charge-transfer reactions between SAs as π-electron donors and
M
7,7,8,8-tetracyanoquinodimethane, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and 2,5-
d
dichloro-3,6-dihydroxy-1,4-benzoquinone as π-acceptors result in highly coloured
Ac ce pt e
complexes. p-Dimethylaminocinnamaldehyde (p-DAC) has been suggested [206] as a spectrophotometric reagent for the detection of SAs. It was shown that in acetonitrile medium, this reagent participated in a condensation reaction with SAM, SMP, SCP, SMX and SMZ, forming coloured products. The method was developed for the spectrophotometric detection of SAs with LODs of n·10-2 g mL-1. For the detection of SAs in honey samples, a screening method based on flow injection analysis coupled to a liquid waveguide capillary cell has been developed [128]. The proposed method was based on the reaction between SAs and p-DAC in the presence of sodium dodecylsulfate in dilute acid medium (hydrochloric acid), with the reaction product being measured spectrophotometrically at 565 nm. The non-compliant and false non-compliant samples
Page 39 of 76
were also analysed by a confirmatory HPLC method. The proposed system enables the screening of SAs in honey samples with a low number of the false non-compliant results. Electroanalytical techniques pose viable alternatives for the detection of SAs, which have advantages such as simplicity, portability and sensitivity that make them very
ip t
attractive for the monitoring of pharmaceutical compounds. Owing to the electroactive properties of SAs, the anodic oxidation of these substances occurs at the aromatic amino
cr
group with the formal oxidation–reduction potentials range of 0.75– 1.05 V. In the last
us
five years, there have been several reports concerning the electrochemical properties of SAs on different types of electrodes, such as a boron-doped diamond [187], a glassy
nanotubes-poly(1,5-diaminonapthalene)
an
carbon [209] and a multi-walled carbon nanotube paste electrode [210, 211], carbon [212] or
phthalocyanine
[213]
modified
M
electrodes, and a MIPs-modified carbon paste electrode [214]. These electrodes were
d
used to develop a variety of voltammetric methods for the detection of SDZ [209, 213],
Ac ce pt e
SMX [210], SAA [212] and SSZ [214] in commercial pharmaceutical formulations as well as SMT in human blood plasma [211] and SSZ in human serum [214]. Trace quantities of SMZ, SMT, SMM, SQX and SDM were successfully
preconcentrated, separated, and detected in a microfluidic device by employing electrokinetic separation and electrochemical detection using an Al2O3–AuNPs modified carbon paste electrode [55]. The method was used for the direct analysis of SAs in real meat samples.
A method based on a multicommutation stopped-flow system has been developed and applied to the simultaneous detection of SMX and trimethoprim in pharmaceutical formulations by using a differential pulse voltammetry with a boron-doped diamond electrode [187]. Almeida et al. [215] described the construction of an SDZ-selective
Page 40 of 76
electrode made from stainless steel tubular syringes of different lengths. The selective electrode was used as a potentiometric detector in a flow-injection analysis system for on-site detection of SDZ in aquaculture waters.
ip t
4. Conclusions and outlook Over the past five years, different methods for monitoring the residues of SAs in
cr
various types of samples (e.g., food, feed, environmental, clinical and pharmaceutical
us
samples) have been proposed. The key roles in these methods are played by sample preparation techniques, and the main efforts in this field have been focused on the
an
optimization of the preparation, extraction and clean-up steps and on the enhancement of the environmental safety of these procedures. The methods with the most promise in
M
achieving these goals are QuEChERS and SPE. The main advantages of these approaches are good compatibility with high throughput multi-residue analytical procedures and their
d
relatively low cost. Therefore, these techniques are expected to have the most
Ac ce pt e
pronounced development in the future.
The currently proposed analytical approaches for the detection of SAs are mainly
based on HPLC–MS or HPLC–MS/MS. Great advances in HPLC-MS/MS have made it a key technique for the determination of not only SAs but also other antibiotic residues. The main trend in this field is the combination of MS detectors with modern chromatographic approaches such as UHPLC and the application of the powerful QqTOF and Orbitrap instruments. These hybrid approaches have made a great contribution to the analysis of trace organic contaminants, including SAs, and have contributed to the development of multi-analyte techniques for the detection of a wide range of substances in a single analytical run. These methods seem poised to be the most frequently used techniques for the purposes of analysis in the future. The main disadvantages of these
Page 41 of 76
methods are their complex equipment and high costs. This fact currently stimulates a great interest in the development of screening methods based on microbiological, immunoassays and biosensors, which have the main advantages of low cost, short analysis times and the possibility of their on site use. The clear trend in this field is the miniaturization of the screening systems (chips, microarrays, microtiter plates) as well as
ip t
their automation. We think that these features will maintain the sustainable progress of
cr
these methods in the near future.
us
Acknowledgments
an
The work was financially supported by the Russian Foundation for Basic Research (grant N 1303-00100)
M
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Advantages
Disadvantages
References
Liquid-liquid extraction with fast partition at very low temperature (LLE-FPVLT)
Relatively low toxic solvent Low solvent consumption Free of additional purification
Extremely low temperature Requires liquid nitrogen Expansive
29, 44
Pressurized liquid extraction (PLE)
High performance Ease of automation Possibility to use water as an extractant
Requires high pressure Relatively complex equipment Expansive
32, 99, 108
Matrix solid-phase dispersion (MSPD)
Easy preparation of solid and viscous samples
Additional purification is usually required
30, 31, 48, 97
QuEChERS
Simplicity Quickness Low cost
Partial lack of the extraction selectivity
49, 50, 70, 71, 102, 103, 109, 110, 131
Additional solvent is required
33, 60, 61, 71, 78, 101, 128, 130
Quickness High efficiency
Ac ce pt e
Dispersive liquid-liquid microextraction (DLLME)
d
M
an
us
ip t
Extraction technique
cr
Table 1 .Non-classical extraction techniques for the sample preparation prior to the detection of SAs
Table 2 Examples of SAs extraction along with other veterinary drugs and their multiclass detection. Compounds
Matrix
Method
Detection
Ref.
37 veterinary drugs, including 16 SAs
Porcine muscle
Extraction with ACN at very low temperature
HPLC–MS/MS
44
19 veterinary drugs, including 4 SAs
Porcine and bovine muscle
Extraction with 70% methanol
HPLC–MS/MS
45
105 veterinary drugs, including 18 SAs
Meat, eggs
Extraction with ACN containing 0.1% formic acid
UHPLC–MS
46
160 veterinary drugs, including 16 SAs
Meat, eggs, honey
Extraction with ACN
UHPLC–MS/MS
47
Page 58 of 76
226 veterinary drugs, including 18 SAs
Meat
Extraction with ACN/EtOH (5:1, v/v) and Na2EDTA
UHPLC–MS/MS
51
120 veterinary drugs, including 21 SAs
Bovine kidney
Extraction with ACN/Н2О (4:1, v/v)
HPLC–MS/MS
52
25 veterinary drugs, including 8 SAs
Milk
Extraction with ACN
HPLC–MS
81
17 SAs, 5 tetracyclines
Fish
Extraction with acidic MeOH/ACN (50:50, v/v)
ip t
92
70 veterinary drugs, including 5 SAs
Fish fillets
Extraction with acidic ACN/Н2О (80:20, v/v)
UHPLC–MS
94
9 SAs,
Catfish
Extraction with acidic MeOH
HPLC–MS/MS
96
32 veterinary drugs, including 13 SAs
Fish
Extraction with acidic ACN
HPLC–MS/MS
98
100 veterinary drugs, including 15 SAs
Fish, eggs
UHRLC–MS
100
41 veterinary drugs, including 14 SAs
Eggs
Extraction with acidic ACN
HPLC–MS/MS
108
25 veterinary drugs, including 4 SAs
Eggs
Extraction with acidic ACN and Na2EDTA
UHPLC–MS/MS
109
220 veterinary drugs, including 18 SAs
Baby food
Extraction with ACN and Na2EDTA
UHPLC–MS/MS
132
us
cr
HPLC–MS/MS
M
an
5 tetracyclines
Ac ce pt e
d
Extraction with ACN/Н2О (6:4, v/v)
Page 59 of 76
Table 3 Examples of the QuEChERS methods used in the extraction and clean-up of SAs along with other veterinary drugs and their multi-class detection. Matrix
Method
Detection
Ref.
48 veterinary drugs, including 16 SAs
Chicken
Extraction with ACN containing 0.1% (v/v) acetic acid. Shaking with anhydrous Na2SO4. DSPE with Bondesil NH2 and Na2SO4. Filtration and evaporation of solvent. Dissolving in ACN – H2O (90:10, v/v)
HPLC–MS/MS
49
21 veterinary drugs, including 6 SAs
Chicken
Extraction with acidic ACN/Н2О (80:20, v/v). Shaking with sodium citrate dibasic sesquihydrate, sodium citrate dihydrate and anhydrous MgSO4. DSPE with PSA. Filtration and dilution with acidic ACN/Н2О (1:1, v/v)
UHPLC–MS/MS 50
32 veterinary drugs, including 13 SAs
Fish
Extraction with ACN/MeOH (75:25, v/v). Shaking with anhydrous MgSO4 and NaAc. Filtration and evaporation of solvent. Dissolving in acidic ACN/Н2О (1:1, v/v).
UHPLC–MS/MS 102
14 veterinary drugs, including 7 SAs
Shrimps
Extraction with acidic ACN. Shaking with anhydrous MgSO4 and NaCl. DSPE with PSA and anhydrous MgSO4. Filtration and evaporation of solvent. Dissolving in MeOH/Н2О (20:80, v/v)
HPLC–MS
103
21 veterinary drugs, including 3 SAs
Eggs
Extraction with acidic MeOH/Н2О (80:20, v/v). Shaking with anhydrous Na2SO4 and NaAc. Filtration
HPLC–MS/MS
110
29 veterinary drugs, including 5 SAs
Baby food
Extraction with acidic ACN. Shaking with anhydrous MgSO4 and NaAc. Filtration
UHPLC–MS/MS 131
Ac ce pt e
d
M
an
us
cr
ip t
Compounds
Page 60 of 76
Table 4 Examples of HPLC-MS/MS methods for the detection of SAs. Matrix
Sample preparation
Porcine liver
Extraction with Zorbax SB C18 fast partition at (250×4.6 mm, 5 very low μm) temperature with ACN
A: ACN/Н2О (5:95, 5.58 − 16.75 v/v) / 0.1% formic acid μg kg-1 B: ACN/Н2О (95:5, v/v)/ 0.1% formic acid
Pork
Extraction with Acquity BEH C18 phosphate buffer (100×2.1 mm, 1.7 (pH 6) μm)
A: 0.2% formic acid in 112 − 129 μg kg-1 31 Н2 О B: МеОН, gradient
Pork, mutton
cr
0.0012 − 0.0146 μg kg-1
35
Agilent-Plus C18 (100×2.1 mm, 1.8 μm)
А: 10 mmol L-1 ammonium formate / 0.1% formic acid B: ACN, gradient
0.1 − 0.3 μg kg-1
36
Kinetex C18 (100×3 mm, 2.6 μm)
Ac ce pt e
Monolith-based stir bar sorptive extraction
–
an
Extraction with ACN
Extraction with ACN SPE on AccuBONDII SCX cartridge
29
32
M
Pork, chicken
SPE on HLB cartridge.
Ref.
10 μg kg-1
Zorbax SB C18 A: ACN (250 mm×4.6 mm B: 0.1% formic acid, , 5 μm) gradient
d
PLE with ACN
us
SPE on multiwalled carbon nanotubes Porcine and swine liver, bovine muscle
LODs
ip t
Mobile phase
Analytical column
Pork, chicken, fish, honey, milk
STEMIT or SEP/MAC QuEChERS-like method
Agilent Zorbax Eclipse AAA (150×4.6 mm, 3.5 μm)
A: 0.02% formic acid in Н2О B: 0.02% formic acid in ACN, gradient
1.0 – 7.5 μg kg-1
37
Beef, milk
Extraction with Н2О/EtОН (20:80, v/v).
Acquity BEH C18 (100×2.1 mm, 1.7 μm)
A: 0.1% formic acid in 1.6 − 8.0 μg kg-1 Н2 О B: MeOH, gradient
38
Immunoaffinity chromatographic
Page 61 of 76
purification Magnetic SPE on magnetite/silica/ poly(methacryli c acid–co– ethylene glycol dimethacrylate) composite microspheres
Shim-pack VPODS (250×2 mm, 5 μm)
A: 0.2% formic acid in 0.0005 − 0.0495 Н2 О μg L-1 B: 0.2% formic acid in MeOH, gradient
Milk
C18-Stir bar sorptive extraction
Zorbax ODS C18 (150×2.1 mm, 3.5 μm)
МеОН/Н2О, gradient
Milk
Acidic deproteinization
Kinetex C18 core–shell
A: 0.1% formic acid in 8 − 96 μg kg-1 Н2 О B: 0.1% formic acid in ACN, gradient
69
us
cr
0.9 − 10.5 μg L-1
68
75
an
SPE on Oasis HLB cartridge
ip t
Milk
A: 0.1% formic acid in 12.5−25.5 μg kg-1 78 Н2 О B: 0.1% formic acid in ACN, gradient
Acidic deproteinization
Polar-RP 80A (50×2 mm, 4 μm)
Milk
Extraction with ACN
Acquity BEH C18 (100×2.1 mm, 1.7 μm)
A: 0.2% acetic acid in Н2 О B: ACN, gradient
0.04 – 1.35 μg kg- 79
Extraction with ACN
Acquity BEH C18 (100×2.1 mm, 1.7 μm)
A: 5 mМ formic acid in Н2О B: 5 mМ formic acid in ACN, gradient
3 − 6 μg kg-1
Extraction with ACN/water (50/50, v/v).
Halo fused-core C18 silica (50×2.1 mm, 2.7 μm)
A: 0.1% formic acid in 0.75 − 3.0 μg kg-1 97 Н2 О B: ACN, gradient
Grass carp
d
Ac ce pt e Clean-up with hexane
Fish
M
Milk
1
93
On-line MSPD Eggs
SPE on magnetic MWCNTs
Zorbax SB C18 (250×4.6 mm, 5 μm)
A: 0.5% acetic acid in Н2 О B: МеОН, gradient
1.4 − 2.8 μg kg-1
111
Honey
Extraction with ACN
MGIII C18 column (150 ×2.1 mm, 1.8 μm)
A: 50 mmol L-1 ammonium acetate (including 0.3%
1.0 μg kg-1
113
Page 62 of 76
formic acid) B: МеОН, gradient SPE on Oasis HLB
Kinetex XB C18 (100×3 mm, 2.6 μm)
0.1% formic acid in Н2О : ACN (80:20, v/v, pH 2.6)
0.01 − 0.5 μg kg-1 117
Honey
SPE on αzirconium phosphate intercalated by hexadecyl trimethyl ammonium bromide
Agilent SB-C18 (250×4.6 mm, 5 μm)
A: 0.15% formic acid in Н2О B: МеОН, gradient
0.25 − 0.5 μg kg-1 118
Honey
SPE on magnetic molecular imprinted polymer
XTerra C18
А: 0.5% acetic acid in Н2 О B: ACN, gradient
Honey
NovaPak C18 (150 А: МеОН Hollow fiber liquid membrane ×3.9 mm, 4μm) B:0.1% formic acid extraction and 10 mmol L−1 ammonium acetate, gradient
Feeds
Extraction with ACN.
1.5 − 4.3 μg kg-1
119
5.1 − 27.4 μg kg-1 120
A: 0.1% FAc in Н2О B: ACN, gradient
0.5 − 20 μg kg-1
143
Modified QuEChERS procedure including DSPE on PSA
Zorbax Eclipse XDB C18 (150×4.6 mm, 5 µm)
А: 0.1% formic acid in 0.5 − 4.2 μg kg-1 Н2О/ACN (95:5, v/v) B: 0.1% formic acid − Н2О/ACN (5:95, v/v), gradient
147
Online SPE on Oasis HLB cartridge
Atlantis C18 (150×2.1 mm, 3 µm)
A: 10 mМ formic acid in Н2О B: 10 mМ formic acid in ACN, gradient
0.00009 − 0.011 μg L-1
151
Online SPE on Oasis HLB, PLRP-s or Hysphere C18 EC cartridges
Atlantis C18 (150×2.1 mm, 3 µm)
A: 0.1% formic acid in 0.00005 − Н2 О 0.00784 μg L-1 B: 0.1% formic acid in ACN, gradient
Ac ce pt e
Eclipse Plus C18 (100×2.1 mm, 1.8 µm)
SPE on basic alumina column
Feeds
Ground water
Environ mental water
d
M
an
us
cr
ip t
Honey
152
Page 63 of 76
Soil
Microwave assisted extraction with ACN
Pinnacle II C18 (250×4.6 mm, 5 µm)
А: 0.2% acetic acid in Н2 О B: ACN, gradient
1.4 – 4.8 μg kg-1
Zorbax SB C18 (250×4.6 mm,5 μm)
А: 0.5% acetic acid in Н2 О B: ACN, gradient
0.37–6.74 μg kg-1 174
Gemini C18 and Gemini C6 (150×4.6 mm, 5 µm)
А: 1 mmol L-1 NH4Ac/acetic acid in Н2О/ACN (90:10, v/v, pH 3.5) B: ACN, gradient
173
Soil
Ultrasonic assisted extraction with ACN
ip t
SPE on alumina
Plasma
PLE with ACN/water (25:75, v/v) or MeOH/water (90:10, v/v) SPE on Oasis HLB.
Atlantis C18 (150×2.1 mm, 3 µm)
Acidic deproteinization
SPE on Orpheous DVBHL cartridge
us
A: 10 mmol L-1 formic acid in Н2О B: 10 mmol L-1 formic acid in ACN, gradient
0.01 − 4.2 μg kg-1 181
Hypersil Gold (50×4.6 mm, 5 µm)
2 mmol L-1 NH4Ac (pH 3, formic acid) in Н2О/ACN (40:60, v/v)
LOQs: 30; 880 μg L-1
Ac ce pt e
Soils and sewage sludge
0.31 – 2.74 μg L-1 176
an
Clean-up on Strata-X Polymeric Reversed Phase SPE-column
M
Extraction with MeOH
d
Soil
cr
Magnetic SPE on Fe3O4/Al2O3 nanoparticles
191
Page 64 of 76
Table 5 Examples of HPLC-MS/MS methods for the detection of SAs along with other veterinary drugs in feed and environmental samples. Compounds
Matrix
Method
Mobile phase
Analytical column
Ref.
18 veterinary Animal drugs, feed including 7 SAs
Extraction with C12 Hydro-RP Н2О/MeOH (95:5, v/v). (50×2 mm, 4 SPE (Hysphere C18 µm) HD)
A: 0.1% formic acid 136 in Н2О
33 veterinary Feeding drugs, stuffs including 1 SA
Extraction with Zorbax XDB MeOH/ACN/McIlvaine plus (150×2.1 buffer, pH 4.6 (37.5: mm, 3.5 µm) 37.5:25, v/v/v). SPE (C18 or HLB)
A: 0.1% formic acid 137 in Н2О B: 0.1% formic acid in ACN/МеОН (70:30, v/v), gradient
15veterinary drugs, including 2 SAs
Extraction with ACN. Shaking with anhydrous Na2SO4. Filtration. Extraction with hexane, evaporation of solvent. Dissolving in Н2О:ACN (85:15, v/v)
ip t
cr
us
an
Luna C18 (100×2 mm, 3 µm)
А: 0.2% acetic acid in Н2О B: 0.2% acetic acid in ACN, gradient
138
d
M
Pig and poultry compound feed
B: 0.1% formic acid in МеОН, gradient
Extraction with acidic ACN/MeOH/1% formic acid in Н2О (65 :25:10, v/v/v)
Altima HP C18 (150×3.2 mm, 5 µm)
A: 0.5% formic acid 139 in Н2О B: 0.5% formic acid in МеОН, gradient
96 veterinary Corn drugs, including 13 SAs
Extraction with ACN/MeOH/0.1% formic acid in Н2О (80:10:10, v/v/v)
Altima HP C18 (150×3.2 mm, 5 µm)
A: 0.5% formic acid 140 in Н2О B: 0.5% formic acid in МеОН, gradient
50 veterinary Animal drugs, feed including 11 SAs
Extraction with Kinetex XBMeOH/ACN/McIlvaine C18 (100×2.1 buffer (37.5:37.5:25, mm, 1.7 μm) v/v/v)
A: 5 mmol L-1 formic acid in Н2О B: 50 mmol L-1 formic acid in Н2О/ACN (10:90, v/v), gradient
22 veterinary Animal drugs, feed including 8 SAs
PLE with MeOH. SPE (Oasis HLB)
C12 Hydro-RP (50×2 mm, 4 μm)
A: 0.1% formic acid 148 in Н2О B: 0.1% formic acid in МеОН, gradient
13 veterinary Swine
SPE (Oasis HLB)
Dionex
A: ACN
Ac ce pt e
48 veterinary Pig feed drugs, including 12 SAs
146
154 Page 65 of 76
drugs, including 4 SAs
wastewater and environme ntal water
Acclaim C18 (150×2.1 mm, 4.6 μm)
B: 0.1% formic acid in Н2О, gradient
Extraction with ACN/citric acid buffer (pH 3) (1:1, v/v). SPE (Oasis HLB)
Zorbax eclipse plus C18 (100×2.1 mm, 1.8 μm)
A: 0.2% formic acid 155 and 2 mmol L-1 NH4Ac in Н2О B: ACN, gradient
5 veterinary drugs, including 3 SAs
SPE (Oasis HLB and MCX)
Shim-pack FC-ODS (75×3 mm, 3 μm)
A: 0.3% formic acid 156 and 0.1% NH4Ac in Н2О B: МеОН/ACN (50:50, v/v), gradient
11 veterinary Surface drugs, water, including 4 wastewater SAs
SPE (Oasis HLB)
Nucleodur C18 ISIS (125×2 mm, 3 μm)
A: 0.1% formic acid 157 in Н2О B: 0.1% formic acid in ACN, gradient
9 veterinary drugs, including 5 SAs
Extraction with МеОН/0.2 mol L-1 citric acid buffer (pH 4.7) (1:1, v/v). SPE (Oasis HLB and SAX)
Waters Symmetry C18 (150×2.1 mm, 5 μm)
A: 0.2% formic acid 158 in Н2О B: МеОН C: ACN, gradient
cr
us
an
M
Suspended solids of swine wastewater
d
Livestock wastewater
ip t
49 veterinary Wastewate drugs, r, sludge including 15 SAs
SPE (Strata-X)
Synergi Polar- A: 0.1% formic acid 160 RP (50×2 mm, in ACN 2.5 μm) B: 0.1% formic acid in Н2О, gradient
14 veterinary Soil drugs, including 7 SAs
Extraction with Н2О/ACN (1:1.5, v/v). SPE (SAX and StrataX)
Zorbax Eclipse A: 0.01% FAc in plus C18 Н2О (pH 3.3) (50×2.1 mm, B: МеОН, gradient 1.8 μm)
10 veterinary drugs, including 1 SA
Extraction with MeOH/ACN/0.1 mol L-1 EDTA/Mc Ilvaine buffer (pH 4), 30:20:25:25, v/v/v/v. SPE (Oasis HLB)
Xterra MS C18 (100×2.1 mm, 3.5 μm)
A: 0.3% formic acid 177 and 0.1% NH4F in Н2 О B: ACN/МеОН (1:1, v/v), gradient
PLE with water. SPE (SAX and Oasis HLB)
Sunfire C18 (150×4.6 mm, 3.5 μm)
A: 0.1% formic acid 180 in МеОН B: 0.1% formic acid in Н2О, gradient
Ac ce pt e
28 veterinary Surface drugs, water including 9 SAs
Broiler manure, soil, manure compost
17 veterinary Soils, drugs, sediments including 1 SA
172
Page 66 of 76
8 veterinary drugs, including 4 SAs
Biosolids
Luna C18 (150×4.6 mm, 5 μm)
A: 1% acetic acid in 182 Н2 О B: МеОН, gradient
MSPD (C18 and Florisil). Extraction with ACN/ 5% oxalic acid (6:4, v/v).
Synergy Fusion C18 (150×2 mm, 4 μm)
A: 0.1% formic acid 183 in Н2О B: 0.1% formic acid in ACN, gradient
ip t
12 veterinary Sediments drugs, including 4 SAs
PLE with МеОН/0.2 mol L-1 citric acid (pH 3) (50:50, v/v). SPE (Oasis HLB)
Sample preparation
us
Mightysil RP-18 A: ACN:1% (250×4.6 mm, 5 acetic acid (10:90, μm) v/v) B: ACN, gradient
C18 column (250×4.6 mm, 5 μm)
ACN:1% acetic acid (20:80, v/v)
Ac ce pt e
Poultry muscle, eggs
Extraction with acidic ACN
SPE on Nexus Abselut
Livers
Milk
MSPD with diatomaceous earth, silica gel or neutral alumina
Deproteinization with acidic ACN/water Polypropylene membrane protected micro-SPE on poly(methacrylic acidethylene glycol dimethacrylate)
Detection (LODs) DAD, 280 nm
23
(0.2 − 1.0 μg kg-1) UV, 270 nm
Chromolith Performance RP-18 (100×4.6 mm)
A: 0.05 mol L-1 acetate buffer (pH 3.4) B: MeOH, gradient
FL, 406 nm, 496 nm
Zorbax BonusRP (150×4.6 mm, 3.5 µm)
A: 2% acetic acid in Н2О B: ACN, gradient
FL, 401 nm, 495 nm
Belta ODS (150×3.9 mm, 5 μm)
Ref.
26 34
(0.1 − 0.5 μg L-1)
d
Pork, liver, chicken
Salting-out assisted extraction with ACN coupled with backextraction with water/ACN/dichlorom ethane SPE on magnetic molecular imprinted polymer
an
Swine muscle
Mobile phase
Analytical column
M
Matrix
cr
Table 6 Examples of HPLC–UV, HPLC–FL and HPLC–AD methods for the detection of SAs.
27
(2 − 17 μg kg-1) 30
(1.33 − 2.47 μg kg-1) MeOH : 1% acetic UV, acid (14:86, v:v) 260 nm
57
(0.38 − 0.62 μg L-1)
Page 67 of 76
Acidic deproteinization NovaPak C18 (150×3.9 mm, 5 Extraction with ethyl μm) acetate Centrifugation Restricted access media (RAM) octylbovine serum albumin column
Monolith-based stir bar Kromasil C18 sorptive extraction (250×4.6 mm, 5 μm)
DLLME and QuEChERS
C18 Ascentis™ (10cm×4.6cm, 3 μm)
A: 2% acetic acid in Н2О(pH 2.5) B: ACN, gradient
Centrifugation
Fish, shrimp
Extraction with 1% acetic acid in water. SPE on groupselective molecular imprinted polymer
Shrimp
Extraction with McIlvaine’s buffer. SPE on Oasis HLB cartridge
Honey
Sugaring-out assisted
AD, 1.25B
62
(15.0; 25.0 μg L-1) UV, 268 nm
64
(1.3 − 7.9 μg L-1) FL 405 nm, 495 nm
71
(0.6 − 2.7 μg L-1) UV, 268 nm
Venusil XBP C18 (250×4.6 mm, 5 μm)
А: acetic acid : Н2О (1:99, v/v) B: ACN, gradient
UV, 270 nm
Chromolith® Performance RP-18e (100×4.6 mm)
0.1M KH2PO4 (pH 3) : ACN:EtOH (80 : 15 : 5, v/v/v)
AD, 1.2B
Cosmosil 5C18AR-II (250×4.6
A: 2% acetic acid
FL, 405 nm,
Ac ce pt e
Restricted accessmolecular imprinted material
58
(–)
А: 0.1 mol L-1 phosphate buffer (pH 6.0)/МеОН (95:5, v/v) B: 0.1 mol L-1 phosphate buffer (pH 7.0)/ МеОН (83:17, v/v) C: 0.1 mol L-1 phosphate buffer (pH 8.0)/ МеОН (94:6, v/v)
Luna C18 (250×4.6 mm, 5 μm)
d
Milk
M
an
Milk
ACN:Н2О (35:75, v/v)
us
Milk
Luna octyl silica 0.05 mol L-1 (150×4.6 mm, KH2PO4 (pH 5) : 10 μm) ACN (82:18, v/v)
UV, 280 nm
ip t
Milk
А: NaAc (5mМ) B: ACN C: МеОН, gradient
cr
Milk
72
(0.8 μg L-1)
104
(8.4 − 10.9 μg kg-1) 105
(1.2 − 3.4 μg L-1) 114
Page 68 of 76
mm, 5 μm)
LLE
B: ACN, gradient
495 nm (0.6 − 0.9 μg kg-1)
Honey
Varian OmniSpher C18 (250×4.6 mm, 5 μm)
A: 25 mmol L-1 KH2PO4 in Н2О (pH 5) B: МеОН C: ACN, gradient
FL, 420 nm, 480 nm
C8 Inertsil (250×4.6 mm, 5 μm)
Ac ce pt e
d
Extraction with ACN. SPE on Oasis HLB, Bond Elut C18, Bond Elut Plexa, and Bond Elut Plexa PCX
Poultry feed
Feeds
Animal feeds
FL, 403 nm, 492 nm
A: 0.01 mol L-1 acetic acid in Н2О – NaAc buffer (pH 4.7) B: ACN, gradient
UV, 268nm
135
(5.0 − 18.0 μg L-1)
МеОН : Н2О : acetic acid (30:70:0.1, v/v/v)
UV, 270nm
Extraction with chloroform/acetone (50:50; v/v)
Luna C18 (250×4.6 mm, 5 μm)
А: 0.02 mol L-1 NH4Ac (pH 4.5) B: MeOH : ACN (50:50, v/v), gradient
DAD, 270 nm
LiChrospher 100 RP-18 (250×4 mm, 5 μm); Kinetex C18 (150×4.6 mm, 2.6 μm)
A: 0.01 mol L-1 formic acid − HCOONa (pH 3.4) B: ACN, gradient
FL, 405 nm, 485 nm
C18 column (70×4.6 mm, 5
МеОН : Н2О (55:45, v/v) (pH
DAD, 250 or 400
Environmental SPE on Bond Elutwater ENV, polystyrene-
129
(1.3 − 5.0 μg kg-1)
Shimadzu VPODS C18 (150×4.6 mm, 5 μm)
Extraction with AcEt/H2O (99:1, v/v)
117
(1.0 − 15.0 μg kg-1)
SPE on core-shell magnetic molecular imprinted polymers (Fe3O4@MIPs)
SPE on Strata SCX cartridge
115
(0.11 − 0.27 μg L-1)
ip t
A: 0.02 mol L-1 Ascentis RPAmide (250×4.6 NaAc (pH4.5) mm, 5 μm) B: ACN, gradient
Extraction with MeOH.
Animal feeds
UV, 260 nm
us
SPE on Oasis HLB, Strata-XL
МеОН:Н2О:NH4 Ac (15:75:1, v/v/v)
an
Honey
Belta ODS (150×3.9 mm, 5 μm)
cr
Salting-out LLE
M
Honey
142
(14.6 μg L-1 144
(390 − 640 μg kg-1) 145
(0.1 − 5.7 μg L-1) 161
Page 69 of 76
μm)
divinylbenzene
3.2)
nm (0.02 − 0.03 μg L-1)
Luna C18 (150×3.0 mm, 5 μm)
Environmental DSPE using magnetic water or non magnetic MWCNTs
Hypersil Gold A: 0.3% formic C18 (100×2.1 acid in Н2О mm and 1.9 μm) B: ACN, gradient
(3 μg L-1)
cr
us
DAD, 260 or 280 nm
Zorbax StableBond C18 (150×4.6 mm, 1.8 μm)
0.2% acetic acid:ACN (80:20, v/v)
DAD, 272 nm
Microwave-assisted extraction with nonionic surfactant Triton X-114
Zorbax SB C18 column (250×4.6 mm, 5 μm)
A: 1.0 % acetic acid in Н2О B: МеОН, gradient
UV, 270 nm
Extraction with acidic ACN.
Inertsil ODS-3 (250×4 mm, 5 μm)
A: 0.05 mol L-1 acetate buffer (pH 3.4) B: МеОН, gradient
FL, 406 nm, 496 nm
an
UV, 265 nm
d
SPE on Nexus Abselut
164
(0.008 − 0.032 μg L-1)
А: 0.1% formic acid in Н2О B: ACN, gradient
TC-C18 (150×4.6 mm, 5 μm)
Ac ce pt e
Biological fluids
163
UV, 269 nm
Environmental SPE on Oasis HLB water
Soil samples
AD, 1.2B
ACN : phosphate buffer solution (20 mmol L-1, pH 4.9) (25:75, v/v)
Environmental Ionic liquid-based water single-drop liquidphase microextraction
Inertsil ODS-4 (150×4.6 mm, 5 μm)
M
Environmental Magnetic SPE on water Fe3O4@SiO2/graphene
ACN : 2% acetic acid in Н2О (20:80, pH 3.2).
ip t
Environmental SPE on water hypercrosslinked polystyrene, Strata-X, Strata SDB-L, carbon nanomaterial Taunit or Diasorb-100C16T cartriges
166
(0.09 − 0.16 μg L-1) 168
(0.5 − 1.0 μg L-1) 159
(1 − 10 μg L-1) 179
(3.2 − 5.7 μg kg-1) 190
(0.1 − 0.3 μg L-1)
Page 70 of 76
LODs
Ref.
1.5 – 22.3 μg kg-1
54
cr
ip t
Table 7 Examples of immunoassays for the detection of SAs. Matrix Assay format Solid Immunogen and antibody support Edible Indirect 96-well 2-[[(4-aminophenyl)sulfonyl]animal competitive Maxisorp amino]-4-methyl)-5-pyrimidinetissues enzyme-linked microtitre carboxylic acid, 6-(4-aminoben(chicken) immunosorbent plates zensulfanylamino)pyridine-3assay (ELISA) carboxylic acid and (4-(4-aminobenzensulfonylamino)benzoic acid linked to bovine serum albumin (BSA); monoclonal antibodies (4E5) Fish Indirect Polystyrene Synthesized haptens against competitive 96-well sulfonamides and the ELISA microtiter commercial hapten N4plates phthalylsulfathiazole linked to BSA and OVA; peroxidaselabeled goat anti-rabbit immunoglobulins Honey Enzyme Costar N-sulfonyl-4-aminobutyric acid immunoassay 9018 linked to ovalbumin (OVA); (EIA) microplate rabbit polyclonal antibodies Feed ELISA Nunc 5-[4-aminophenylsulfonamide]Maxisorp 5-oxopentanoic acid linked to Microtiter OVA; female white New polystyrene Zealand rabbits antibodies plates Milk ELISA According to the RIDASCREEN ELISA test kits for sulfonamide (R3004) and sulfamethazine (R3001) Chicken Generic ELISA Polystyrene 6-(4-aminophenylsulfonamido)muscle microplate hexanoic acid, 4-(4-(4-aminophenylsulfonamido)phenylsulfonamido)benzoic acid and 4-(4(4-aminophenylsulfonamido)phenyl)butanoic acid linked to BSA; New Zealand white rabbits polyclonal antibodies Milk Hybrid The opaque Hapten-OVA conjugates; antiimmunosorbent white sulfonamide and anti-quinolone assay polystyrene broad-specificity monoclonal (fluorescence- microtiter antibodies linked plates and immunosorbent ELISA assay (FLISA) microtiter and ELISA) plates Milk DualMicrotiter 4-(4-(4-aminophenylsulfon-
106
0.05 μg L-1
122
40 –200 μg kg-1
141
3.5 – 10 μg L-1
196
~ 0.1 μg L-
198
Ac ce pt e
d
M
an
us
0.6 – 1 μg L-1
1
0.17 μg L-1
199
5.8 μg L-1
200
Page 71 of 76
Nitrocellul ose membrane (vivid 170)
Milk
4-aminobenzoic acid film grafted on a disposable electrode
201
0.12 – 8.41 μg L-1
202
Ac ce pt e
d
M
an
Integrated amperometric immunosensor based on direct competitive immunoassay
0.10 – 2.13 μg L-1
cr
Milk and Lateral flow Swine immunoassay Urine (LFA)
amido)phenyl)butanoic acid linked to BSA; monoclonal and polyclonal antibodies Hapten conjugate N1-[4(carboxymethyl)-2-thiazolyl] sulfanilamide linked to OVA; goat anti-rabbit antibody conjugated to colloidal gold particles Horseshoe crab hemocyanin linked to 5-(6-(4-aminophenylsulfonyl)pyridine-3-yl)-2methylpentanoic acid; female white New Zealand rabbits polyclonal antibody
ip t
plates
us
colorimetric ELISA
Page 72 of 76
O
O H2N
S
NH
NH2
H2N
S
NH2
O
S
N
O
Sulfadiazine (SDZ)
Sulfathiazole (STZ)
O
NH2 N
O S
NH2
N
H3C
O
CH3
H3C
N
NH O
S
Sulfamethazine (SMZ)
NH
NH
O
O
H3C
NH2
Sulfadoxine (SDO) NH2
S
NH2 N
O
Cl O
N
N
OH
N
S NH
d
O
Ac ce pt e
O
Sulfadimethoxine (SDM)
S N
OH
Sulfasalazine (SSZ)
H3C
H3C
O
N
O
M
O
N
O
N
N
Sulfamethoxypyridazine (SMP)
H3C
NH S
an
N
O O
H3C
S N
O
NH2
O H3C
NH
O
Sulfachlorpyridazine (SCP)
N
NH2
H2N
O O
N
H3C
S
NH
NH2
S NH
O
O
Sulfisoxazole (SSA)
O
NH
S O
O
Sulfamethoxazole (SMX) N
NH
CH3
O
O
O
NH2
O
O
O
S
Sulfamethizole (SMT)
us
NH2 N
NH
NH
Sulfamerazine (SMR)
CH3
O
cr
Sulfapyridine (SPY)
N S
O
N
N
H3C
ip t
NH S
N
NH
O
Sulfanilamide (SAM)
S
O
N
Sulfacetamide (SAA) CH3
CH3 NH2
S
O O NH
N
O
S
O
N
N NH2
Sulfaquinoxaline (SQX)
S H3C
N
NH
S
N
O
O
Sulfadimidine (SDD)
NH2
Sulfametrole (SML)
Fig. 1. Structures of the most commonly used sulfonamides.
Page 73 of 76
N
% 14
3000
12
2500
10 2000
8 6 1000
4
cr
500
2 0
us
20 11
Year
an
20 09
20 07
20 05
20 03
20 01
19 99
19 97
19 95
0 19 93
ip t
1500
Ac ce pt e
d
M
Fig. 2. The annual production of publications with titles, abstracts or keywords containing the term “sulfonamide” (■ histogram) and the percentage of these articles containing the term “sulfonamide” in the title (-♦- line).The data were derived from Scopus (on December 2013).
Page 74 of 76
Other 19%
Milk 23%
cr
ip t
Eggs 8%
us
Honey 10% Fish 11%
Meat 16%
d
M
an
Chicken 13%
Ac ce pt e
Fig. 3. Types of food samples that have usually been analysed for sulfonamides over the past 5 years.The data were derived from Scopus (on December 2013).
Page 75 of 76
Biosensors 3%
Fluorimetry 3%
ip t
Spectrophotometry, Colorimetry 9%
HPLC-MS(/MS) 38%
us
cr
Immunoassays 10%
an
Electrophoresis 15%
Ac ce pt e
d
M
HPLC-other 22%
Fig. 4. Analytical methods that have usually been applied to the detection of sulfonamides over the past 5 years.The data were derived from Scopus (on December 2013).
Page 76 of 76
S0003-2670(14)01006-X http://dx.doi.org/doi:10.1016/j.aca.2014.08.023 ACA 233423
To appear in:
Analytica Chimica Acta
Received date: Revised date: Accepted date:
25-3-2014 7-8-2014 11-8-2014
Please cite this article as: Stanislava G.Dmitrienko, Elena V.Kochuk, Vladimir V.Apyari, Veronika V.Tolmacheva, Yury A.Zolotov, RECENT ADVANCES IN SAMPLE PREPARATION TECHNIQUES AND METHODS OF SULFONAMIDES DETECTION - A REVIEW, Analytica Chimica Acta http://dx.doi.org/10.1016/j.aca.2014.08.023 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.
RECENT ADVANCES IN SAMPLE PREPARATION TECHNIQUES AND METHODS OF SULFONAMIDES DETECTION - A REVIEW Stanislava G. Dmitrienko*, Elena V. Kochuk, Vladimir V. Apyari, Veronika V.
ip t
Tolmacheva, Yury A. Zolotov
Lomonosov Moscow State University, Chemistry Department, 119991 Leninskie gory, 1/3,
cr
Moscow, Russia
us
* Corresponding author. Tel.: +7(495)939-46-08; Fax: +7(495)939-46-75; e-mail: [email protected]
an
Graphical abstract
Highlights
M
Ac ce pt e
An overview on recent trends in the sample preparation and determination of sulfonamides is given A comparison of different methods of real samples preparation is made The general chromatographic and other methods of SAs determination are discussed Examples of SAs determination in different matrices are given.
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ABSTRACT Sulfonamides (SAs) have been the most widely used antimicrobial drugs for more than 70 years, and their residues in foodstuffs and environmental samples pose serious health hazards. For this reason, sensitive and specific methods for the quantification of these compounds in numerous matrices have been developed. This review intends to provide an updated overview of the recent trends over the past five years in sample preparation techniques and methods for detecting SAs. Examples of the sample preparation techniques, including liquid-liquid and solid-phase extraction, dispersive liquid-liquid microextraction and QuEChERS, are given. Different methods of detecting the SAs present in food and feed and in environmental, pharmaceutical and biological samples are discussed. Keywords: Sulfonamides, Sample preparation, Extraction, Residue determination, Multi-class methods, Liquid chromatography–tandem mass spectrometry 1
1
Abbreviations: Ac, Acetate; AD, Amperometric detection; ACN, Acetonitrile; CE, Capillary electrophoresis; DAD, Diode-array detector; DLLME, Dispersive liquid-liquid microextraction; DSPE, Dispersive solid-phase extraction; EDTA, Ethylenediaminetetraacetic acid; ELISA, Enzyme-linked immunosorbent assays; EMIS, Electrochemical magnetoimmunosensor; ESI, Electrospray ionization source; EtOH, Ethanol; F, Formate; FL, Fluorescence detection; HPLC, High-performance liquid chromatography; HPLC-MS/MS, High-performance liquid chromatography tandem mass spectrometry; LLE, Liquid–liquid extraction; LLME, Liquid-liquid microextraction; LOD, Limit of detection; LOQ, Limit of quantification; MeOH, Methanol; MIPs, Molecular imprinted polymers; MRLs, Maximum Page 1 of 76
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Contents 1. Intrroduction 2. Sample preparation 2.1. Food 2.2. Feed 2.3. Environmental samples 2.3.1. Waters 2.3.2. Soils, manure and sediments 2.4. Pharmaceutical and clinical samples 3. Analytical methods 3.1. Chromatographic methods 3.1.1. Detection with MS and multi-class analysis 3.1.2. Detection with other techniques 3.2. Electrophoretic methods 3.3. Microbiological assays 3.4. Immunoassays 3.5. Biosensors 3.6. Other methods 4. Conclusions and outlook Refferences
M
1. Introduction
The problem of food and environmental sample contamination by veterinary drugs
d
is of great concern [1 – 3]. There are systematised data on detection of antibiotics in
Ac ce pt e
foods of animal origin [4, 5], milk [6], honey [7], fish [8], and feed [9], as well as in environmental samples [10]. According to a previous review [5], sulfonamides (SAs) and fluoroquinolones are among the most commonly used veterinary antibiotics. For example, the frequency of cases in which SAs were detected in food is 20 %, whereas other antibiotics were detected as follows: fluoroquinolones – 19 %, aminoglycosides –
residue limits; MRM, Multiple reaction monitoring; MS, Mass spectrometry; MS/MS, Tandem mass spectrometry; MSPD, Matrix solid-phase dispersion; MWCNTs, multi-walled carbon nanotubes; PLE, Pressurised liquid extraction; PSA, Primary-secondary amine; QqLIT, Quadrupole linear ion-trap; QTOFMS, Quadrupole time of flight mass spectrometry; SAA, Sulfacetamide; SAM, Sulfanilamide; SAs, Sulfonamids; SCP, Sulfachloropyridazine; SDD, Sulfadimidine; SDM, Sulfadimethoxine; SDO, Sulfadoxine; SDZ, Sulfadiazine; SML, Sulfametrole; SMP, Sulfamethoxypyridazine; SMR, Sulfamerazine; SMT, Sulfamethizole; SMX, Sulfamethoxazole; SMZ, Sulfamethazine; SPE, Solid-phase extraction; SPME, Solid-phase microextraction; SPY, Sulfapyridine; SQX, Sulfaquinoxaline; SSA, Sulfisoxazole; SSZ, Sulfasalazine; STZ, Sulfathiazole; ToF-MS, Time-of-flight mass spectrometry; UHPLC-MS/MS, Ultra-high-performance liquid chromatography tandem mass spectrometry; UV, Ultraviolet detection.
Page 2 of 76
15 %, phenicols–15 %, β-lactams – 15 %, oxazolidinones – 8 % and tetracyclines – 8 % [5]. SAs are derivatives of sulfanilic acid (p-aminobenzenesulfonic acid) and are one of the oldest classes of antimicrobial drugs, which have been used for the treatment of
ip t
humans and animals from the middle of the twentieth century. SAs act as bacteriostatic agents and possess chemotherapeutic activity against infections caused by gram-positive
cr
and gram-negative bacteria and some protozoa (causative agents of malaria,
us
toxoplasmosis, etc.).
The precursor of SAs is sulfanilamide (p-aminobenzenesulfonamide), better
an
known as streptocid, which was first synthesised in 1908 and was widely used as an intermediate in the production of dyes. SAs were discovered to have antibacterial
M
properties in 1935 by G. Domagk. The basis for their bacteriostatic action is the structural
d
similarity between the sulfanilamide moiety and p-aminobenzoic acid (PABA), which is
Ac ce pt e
involved in the biosynthesis of dihydrofolic and folic acids and other substances utilised by the microorganisms. SAs act as antimicrobials by blocking the synthesis of dihydrofolic acid by preventing the formation of dihydropteroic acid from dihydropteridine and PABA, which involves dihydropteroate synthetase. SAs compete with PABA, resulting in no formation of dihydrofolic acid but instead the formation of its analogue [11]. These features of the mechanism confer high sensitivity to SAs only to microorganisms that synthesise their own dihydrofolic acid, and microorganisms and cells that utilise dihydrofolic acid as a finished product are not sensitive to SAs. To date, more than 10000 sulfanilamide derivatives have been synthesised, and 40 of these are applied in medical and veterinary practices. The structures of the most commonly used SAs are represented in Fig. 1. Some patterns that illustrate the
Page 3 of 76
relationship between the chemical structure of these chemotherapeutic agents and their action are known, and the physiological activity of SAs has been found to be conditioned by the presence of an SO2NH group in the chemical structure that can be changed with the addition of various radicals at the R position:
H2N
S
NH R
cr
O
ip t
O
us
The most active SA derivatives contain heterocyclic radicals. Many SAs are based on pyrimidine, pyridazine and other heterocycles, and it turns out that the displacement of
an
the para-amino group to the meta- or ortho-position deprives the compound of its bacteriostatic action. If the hydrogen atom in the amino group is replaced with different
M
radicals, the compound loses its activity, but if these radicals are detached in the human
d
body, the activity of the compound will be retained. Introduction of some additional
Ac ce pt e
substituents into the aromatic ring results in the decrease or complete loss of the physiological activity of the SA.
All SAs are white or slightly yellowish, odourless powders, and some have a bitter
taste. Most of these substances are poorly soluble or practically insoluble in water. The solubility of SAs in acids and alkalis is conditioned by their amphoteric properties, which are due to the presence of the basic aromatic amino group (pKa1 2–2.5) and the amide group, which contains a labile hydrogen atom with acidic properties (pKa2 5–8). The acidic properties of SAs are more pronounced than their basic properties, and thus SAs are positively charged in acidic medium at pH < 2, neutral at pH 3 – 5, and negatively charged at pH > 5 [2].
Page 4 of 76
The high efficiency of SAs and their relatively low cost have stimulated their ubiquitous use in veterinary practices. SAs are used in veterinary medicine in pure formulations or in combination with other antibiotics not only to combat infectious diseases, but as additives to animal feed in order to promote growth and to increase the
ip t
productivity of livestock and poultry despite the fact that the use of antibiotics for this purpose is forbidden in several parts of the world. For example, according to the data
cr
given in a previous review [11], the 2009 consumption of SAs in mg per kilogram of
us
meat produced in Denmark was 4.82 (pork), 17.2 (cattle), 0.033 (broilers) and 58.5 (fish). As a result of misconduct in the prophylaxis and treatment of animals or due to
an
non-compliance with holding times before slaughter, traces of SA drugs can enter foods of animal origin. Strictly speaking, every human is a passive consumer of these drugs,
M
which are obtained from meat and dairy products, eggs and honey that inherit SAs from
d
the treatment of bacterial diseases in animals, poultry or bees. The systematic human
Ac ce pt e
intake of SAs through foods is dangerous, as SAs can have adverse effects that most commonly manifest in the form of allergic reactions, disbacteriosis, suppression of enzyme activity, alteration of the intestinal microflora, and promotion of sustainable forms of pathogens. In addition, there is evidence of hemotoxicity and carcinogenic effects of some SAs, particularly SMZ [12]. It should be noted that certain decomposition products of SAs can be active and potentially more toxic than the parent compounds [13]. The long-term use of SAs has resulted in a large number of SA-resistant bacterial strains, which has stimulated the production of combined SA preparations containing trimethoprim (Bactrim, Septrin, Biseptol, etc.) aimed at delaying proliferation of SAresistant microorganisms and enhancing the antibacterial effect of the SAs.
Page 5 of 76
SAs enter the soil and water from food chains that involve human and animal waste. A considerable portion of SAs enter the environment from flushing water from pharmaceutical companies as well as poultry and pig farms. Every year more than 20000 tons of SAs enter the environment worldwide, with maximum amounts of SAs being
ip t
found in pig manure and soils. The SA content in other samples is as follows: sea water < groundwater < surface water < treated wastewater < untreated municipal wastewater
85%) than SPE, liquid extraction and MSPD. Furthermore, the sample preparation using QuEChERS was very
Page 11 of 76
fast and cheap due to the absence of the solvent evaporation and purification steps which are present in the other three extraction methods. Using this method, the preparation of 15 samples was completed in less than 1 h while the other extraction methods required at least 3 – 4 hours. The QuEChERS method meets requirements for today’s chemical
ip t
analysis methodologies, as it allows for the quick and efficient extraction of SAs as well as other veterinary antibiotics from foods. For simplifying the conventional QuEChERS-
cr
like pretreatment, two straightforward extraction procedures named “STEMIT” (single-
us
tube extraction with multisorbent impurity trapping) and “SEP/MAC” (single-tube extraction/partitioning multifunction adsorption clean-up) were evaluated [37].
an
In recent years, the isolation of SAs from milk and honey has been performed using traditional liquid-liquid extraction (LLE) with ethyl acetate [53, 58, 86],
M
chloroform:acetone mixture (65:35, v/v) [59], acetonitrile [79, 81, 82], hexane [83] along
d
with cloud point extraction [63, 90] and different types of liquid-liquid microextraction
Ac ce pt e
(LLME) [115, 120, 121]. Among these methods, dispersive LLME (DLLME, developed in 2006) has attracted the greatest interest [33, 60, 61, 71, 78, 128]. The main idea of this method is to obtain a sub-micron emulsion of an extractant in the solution under analysis, which increases the surface of mass-exchange and decreases the time required for analysis. Equilibrium in such systems is usually achieved in less than 1 min. A poorly water-miscible or water-immiscible organic solvent is used in this method as the extractant and an organic polar solvent that is well miscible with water and capable of dissolving the extractant is used as a dispersant (dispersing solvent). The sample solution, the extractant and the dispersing solvent are mixed in a centrifuge tube, shaken, and the resulting emulsion is centrifuged. The use of ultrasound [78] or ionic liquids [60, 61, 101, 130] simplifies this method remarkably as it avoids the addition of a dispersant.
Page 12 of 76
As mentioned above, the solvent-based extraction of SAs from solid foodstuffs is often combined with SPE, which was used to preconcentrate SAs from meat [27, 39 − 42, 46], fish [96, 104], eggs [46, 107], honey [33, 116 – 118, 126] and milk [46, 65, 67, 72, 73, 75]. Commercially available cartridges filled with different polymeric sorbents are
ip t
often used for this purpose and include the following: Oasis MCX [39, 116], Oasis HLB [46, 65, 73, 75, 107, 117], Nexus Abselul [27], BondElut SCX [33], Cleanert PEP [40],
cr
Strata SCX [41], LiChrolut C18 [42], HySphere C18 HD [96] and Sep-Pak C18 [126]. For
us
the selective isolation of SAs from food, carbon nanomaterials [43] and molecular imprinted polymers (MIPs) [66, 67, 72, 104] have been used successfully. Acetonitrile
an
[27], methanol [40], ammonium – acetonitrile [39] and ammonium – methanol solutions [41] as well as mixtures of acetonitrile or methanol with acetic acid [104, 118] are used
M
as the eluents. Monolithic capillary columns provide an alternative to the use of SPE
d
cartridges [76, 105]. The advantages of monolithic capillary columns are their high
Ac ce pt e
efficiency and stability combined with the convenience of their introduction into on-line flow preconcentration systems.
The routine monitoring of food products for residual amounts of SAs requires
rapid methods of analysis. Recently, solid-phase microextraction (SPME) has been increasingly used for this purpose [57, 77, 80]. Compared with the conventional methods of extraction such as LLE or SPE, SPME allows pure extracts to be obtained with less solvent consumption, which significantly improves the analytical signals. The adsorbents used in this method are different polymeric materials (polydimethylsiloxane, polyacrylate and carbowax/divinylbenzene, etc.) supported on a solid matrix. To improve the efficiency and selectivity by which analytes are isolated, the adsorbents are further modified, for instance, by molecular imprinted polymers (MIPs). Thus, Chen et al. [80]
Page 13 of 76
have developed a fast, selective and efficient method of SPME in which the adsorbent consists of MIP microbeads. The method was applied to the separation and preconcentration of SMZ from milk before its detection by capillary electrophoresis with a UV detector. The recoveries of SMZ from milk were 89 – 110 %. To isolate SAs from
ip t
milk and meat, an SPME technique on a 1x1-cm polypropylene membrane containing a polymeric sorbent based on methacrylic acid and ethyleneglycoldimethacrylate was
cr
developed [57]. Using the porous membrane, the authors managed to avoid
us
contamination of the sorbent by solid particles. For the detection of SAs in milk, a miniature device based on a medical syringe filled with 30 mg of water-compatible
an
poly(hydroxyethyl methacrylate) was designed [74].
One of the newest techniques of food sample preparation is stir bar sorptive
M
extraction in which glass magnetic stirrer bars coated with polydimethylsiloxane are
d
used. The stir bar is placed in a vessel containing a sample that is placed on a magnetic
Ac ce pt e
stirrer and mixed for a certain time. Then, the bar is recovered, dried, and desorption of the compounds is performed. In several studies, this method of sample preparation was used for the isolation of SAs from meat [34, 35] and milk [64, 69]. To increase the efficiency of SAs sorption, the polydimethylsiloxane coating was further modified with MIPs [34], monolithic polymeric materials [35, 64] or C18 [69]. Among the other SPE methods, there is an interesting approach based on magnetic
particles coated with MIPs synthesised by grafting [26, 68, 119]. Particles of Fe 3O4 were treated with modifiers (ethylene glycol, polyvinyl alcohol or oleic acid), dipped into a solution containing all components necessary for the synthesis of MIP, and the polymerization was carried out. Composite materials based on Fe3O4 and MIPs retain all of the properties needed to recognise template molecules and can be easily separated
Page 14 of 76
from the solution by applying magnetic field. These were used for the selective extraction of SAs from meat [26], milk [68] and honey [119]. 2.2. Feed The practical use of SAs and other antibiotics as farm animal feed additives first
ip t
became widespread in the 1950s. SAs are added to feed for therapeutic or prophylactic purposes and despite the fact that the antimicrobial effect of SAs is less than that of
cr
antibiotics, they are cheaper and more widely available in dealing with infectious
us
livestock and poultry diseases. The concentration of SAs in feed ranges from 70 to 800 mg kg-1 [135], leading to their accumulation in the bodies of animals and contamination
an
of animal-derived foods. SMZ, SQX and SDM are the most frequently detected in feed. A survey of the literature [53, 94, 135 – 148] has shown that the researchers have
M
mainly focused on the search for express methods of feed sample preparation and their
d
combination with the subsequent SA detection, which mostly has been performed by
Ac ce pt e
HPLC, HPLC-MS or HPLC-MS/MS. In recent years, many different extractants have been suggested for extracting SAs from feed, including acetonitrile [138, 142, 143], mixtures of acetonitrile and water (95:5, v/v) [53, 94, 135, 141, 142], mixtures of chloroform and acetone (50:50, v/v) [144] or ethylacetate and water (99:1, v/v) [145] as well as ternary mixtures methanol:acetonitrile:McIlvaine buffer (37.5:37.5:25, v/v/v) [137, 146]; and acetonirile:methanol:1%-formic acid (65:25:10, v/v/v [139] and 80:10:10, v/v/v [140]). In several papers, the sample preparation was carried out using an ultrasonic bath [139, 140, 146]. PLE [136, 148] and modified QuEChERS [147, 148] were also used. Further purification and preconcentration of the extracts was carried out using SPE with Oasis HLB [135, 148] and Strata SCX [144] cartridges or magnetic nanoparticles coated with SMZ-imprinted polymers (Fe3O4@MIPs) [142]. In most works
Page 15 of 76
[136, 137, 138 – 140, 146, 148], SAs were extracted from feed along with other antibiotics and medicines. 2.3. Environmental samples In the past decade, the interest in detecting SAs in the environment has
ip t
significantly increased. These substances and their metabolites, along with surfactants, personal hygiene products and other compounds associated with the human life, enter the
cr
environment as complex mixtures and achieve penetrance primarily through the crude
us
and treated city wastewater [149]. A considerable portion of SAs enter the environment through flushed water from pharmaceutical enterprises and poultry and pig farms.
an
According to the data systematised in the reviews [11, 150], the content of SAs in untreated wastewaters ranges from 0.01 to 19.2 μg L-1, and in treated wastewaters ranges
M
from 0.004 to 6.0 μg L-1. SMX has been the most frequently detected SA in the ground
Ac ce pt e
2.3.1. Waters
d
water in many countries [150].
SAs have been detected in underground [151], surface [33, 61, 101, 152, 155, 157,
159, 160, 162 – 171] and wastewater [153, 154, 156 – 158, 161]. The preparation of these samples was often carried out by SPE using commercially available cartridges, such as Oasis HLB [151 – 159], Strata-X [160], or Bond Elut-ENV [161]. In some cases, to remove negatively charged humic and fulvic acids, a subsidiary anion exchange cartridge (SAX) has been used [155, 158].
The Oasis HLB, Hysphere C18 EC, and PRLP cartridges were compared for their efficiency in extracting SAs [152]. The best cartridge was Hysphere C18 EC, while the best eluents were methanol, acetone or a methanol – acetone mixture (1:1, v/v) in comparison to acetonitrile. The good sorption ability toward SAs was attributed to hyper-
Page 16 of 76
crosslinked polystyrene, which sorbed by 98–100% of SMZ, SMX, SMP and SCP using a microcolumn filled with 30 mg of this sorbent [162, 163]. Carbon nanotubes [164], magnetic iron oxide nanoparticles coated with octadecyltrimethylammonium bromide [165] and composites based on Fe3O4 and either carbon nanotubes [164] or graphene
ip t
[166] were also suggested as the sorbents for isolating SAs from waters through SPE. A portable device based on a micropipette filled with 1 mg of graphene was developed for
cr
flow micro-SPE of SAs [167].
us
Alternative miniaturised methods of extracting SAs from natural water before their chromatographic determination are single-drop liquid-phase microextraction into a drop
an
of extractant formed at the tip of a syringe needle [168], membrane microextraction [169, 170] and dispersive liquid-liquid microextraction [61, 101, 171]. Ionic liquids are
M
increasingly being used as the extractants [33, 61, 101, 168, 169].
d
Other drug substances such as tetracyclines [154 – 157], quinolones [154, 171],
Ac ce pt e
macrolides [155, 158], trimethoprim [154, 160], chloramphenicol [154, 161] and hormones [155] have been found along with SAs in water. 2.3.2. Soils, manure and sediments
In recent years, interest in the determination of SAs in soils, manure and sediments
has grown remarkably [172 − 183]. The preparation of these environmental samples includes SA extraction with acetonitrile [172 – 175], methanol [176 – 178], nonionic surfactant Triton X-114 [179] and mixtures of these extractants with different buffers [175, 177, 178]. SAs were extracted from solid samples using ultrasonic extraction [174, 175, 177], microwave-assisted extraction [175, 179], PLE [175, 180 – 182] and MSPD [183].
Page 17 of 76
The extraction of six SAs (SDZ, SDD, STZ, SCP, SDM, and SQX) from soils was investigated by different extraction techniques, such as conventional mechanical shaking, microwave-assisted extraction, ultrasonic extraction and PLE [175]. The recoveries of SAs in an acetonitrile : pH 9 buffer (20:80, v/v) solution from overnight spiked soils
ip t
ranged from 40 to 80%, depending on the SA and the soil, and did not depend on the extraction technique. Recoveries obtained from aged SA residues were lower and
cr
depended on the extraction technique applied, with the microwave-assisted extraction
us
being the most efficient.
Additional clean-up of the samples is often carried out by SPE using anion-
2.4. Pharmaceutical and clinical samples
an
exchange and polymer cartridges (Oasis HLB, Strata X) [172, 177, 178, 180].
M
The preparation of sulfonamide-containing pharmaceuticals, in which the SA
d
content is usually approximately 0.1 – 1 g, usually involves powdering a sample and
Ac ce pt e
dissolving a weighed portion of it in methanol [184 − 189]. The concentration levels of SAs in clinical samples vary within a quite broad range. SAs are usually detected at a rate of approximately 0.1 – 100 μg mL-1 in blood plasma and 0.001 – 1 μg mL-1 in urine. Liquid-liquid extraction is used for isolation of SAs from blood serum and plasma [61, 185, 190, 191] or urine [190, 192] and still remains the main method for preparation of biological samples prior to SA determination. Acetonitrile [185], ethylacetate [192], 1% phosphoric acid, [191] and a mixture of acetonitrile with phosphoric acid [190] are used as the extractants. Sedimentation of proteins in urine was performed using 2% trichloroacetic acid [192]. In some papers, liquid extraction was combined with SPE [190, 191]. For example, the aqueous phase was additionally purified on a Nexus Abselut SPE cartridge [190]. SAs were eluted with acetonitrile, preconcentrated by evaporation,
Page 18 of 76
derivatised by putrescine in sodium acetate buffer (pH 3.4) and analysed by HPLC-FL. The recoveries from serum and urine were 91.2 – 119.0 % and 91.3 – 117.0 %, respectively. For the simultaneous determination of SMX and trimethoprim in plasma by HPLC-MS, the isolation of the analytes was performed by SPE on Orpheous DVB-HL
ip t
cartridges [191].
cr
3. Analytical methods
us
Analytical methods for the detection and determination of SAs residues can be classified into three groups: quantitative, confirmatory and screening. Quantitative
an
methods are mostly based on chromatography and capillary electrophoresis and allow for
M
the quantification of SAs. However, these methods usually require complex samplepreparation procedures, multi-step clean-ups, complex laboratory equipment and trained
d
operators. They are time-consuming and expensive. The main feature of confirmatory
Ac ce pt e
methods is their ability to reliably identify a compound. Screening methods can detect an analyte at the level of interest and usually provide semi-quantitative results. They are specifically designed to avoid false compliant results [193]. These methods must allow for the reliable checking of samples, and only those samples indicating the presence of the analyte should be selected for a thorough analysis. The ideal characteristics of a screening method are a low percentage of false compliant samples, short analysis time and high throughput, ease of use, good selectivity and low cost. In general, the reported methods of SA determination can be grouped depending on the type of analytical technique applied. The corresponding percentages are depicted in Fig. 4. As it can be seen, HPLC-MS(/MS) is the most employed analytical method (38 %), followed by HPLC with other detectors (22%) and electrophoresis (15 %).
Page 19 of 76
3.1. Chromatographic methods HPLC has been widely used for the quantification of SAs due to its high sensitivity and broad linear range. Currently, the most widely used analytical methods for SAs are based on a reversed-phase HPLC (RP-HPLC) separation. Among these methods,
ip t
HPLC–MS/MS, which can also be considered to be a confirmatory method, has become the main analytical technique for the identification of SAs due to its higher selectivity
cr
and sensitivity than other instrumental methods.
us
In addition to HPLC, ultra high-performance liquid chromatography (UHPLC) has increasingly been used for the rapid separation of SАs. This technique became possible
an
due to the relatively new HPLC systems that tolerate ultra-high pressures and use columns with sub-2-μm-particles, improving chromatographic performance (e.g., speed,
M
sensitivity and resolution) and reducing co-elution of interferences, thereby diminishing
d
matrix effects when compared to conventional HPLC. Rapid multi-residue screening of
Ac ce pt e
veterinary antibiotics including SAs in food and environmental samples is one of the most promising applications of UHPLC technology. 3.1.1. Detection with MS and multi-class analysis
Table 4 represents a selection of analytical methods for the detection of SAs by
RP-HPLC and UHPLC with MS detection reported over the past 5 years. Being a confirmatory method, MS detection is used to identify and quantify a
substance and can be used to confirm a compound’s molecular structure. The basic principle of this detection technique is measurement of the mass-to-charge (m/z) ratio of ionised molecules. HPLC–MS/MS is often applied using a triple quadrupole analyser and a selected reaction monitoring mode. This mode allows for the confirmation of the composition of the compound and provides its structural information. In MS/MS, the
Page 20 of 76
most intensive ionic fragment from a precursor ion is used for the quantification. A less sensitive secondary transition is used as the second criterion in confirmation purposes. This mode also improves the precision and sensitivity of the analysis but does not collect the full scan data. This can limit the availability of the full scan data which could
ip t
otherwise be used to both identify target analytes and detect additional unknown compounds. The choice of one or another MS approach to monitor certain substances and
cr
residues in live animals and animal products can be referred to the European Union
us
Commission Decision 2002/657/EC, which established performance criteria and other requirements for analytical methods with different type detection, including MS
an
[193].The first step in the tandem MS detection is the selection of a precursor ion. HPLC–MS/MS analysis of SAs is usually performed with the electrospray ionization
M
(ESI) source operating in positive-ionization mode. The protonated molecule [M+H]+
d
was chosen as a precursor ion for quantitation in all developed methods. The common
Ac ce pt e
fragment ion m/z 156 represents the sulfanyl ring and is used for the quantification of the majority of SAs [10].
One of the advantages of MS/MS is the fact that complete HPLC separation of the
target analytes is not necessary for selective detection. However, it is always advisable to have good chromatographic separation in order to reduce matrix effects that typically result in the suppression or, less frequently, in the enhancement of analyte signals. Therefore, short HPLC columns are generally used, considerably speeding up the analysis. As it is indicated in Table 4, C18 reversed phase based columns are widely used for HPLC multi-residue analytical methods. Because MS detection is incompatible with most mobile phases, volatile organic modifiers should be used when HPLC is coupled to MS. Thus, formic and acetic acid or
Page 21 of 76
their ammonium salts are added to acetonitrile–water or methanol–water mixtures. The typical concentrations of modifiers range from 2 to 20 mmol L-1. It has been observed that the higher concentrations lead to reduced signal intensities. The method of HPLC-MS/MS was successfully applied to the simultaneous
ip t
quantification of SA residues in porcine liver [29], pork and chicken samples [35], milk and milk powder [69, 78], grass carp tissues [97], eggs [111], honey [117], feed [147] and
cr
soil [191]. Yu et al. [32] simultaneously determined 18 SA residues in poultry tissues,
us
muscle, and the livers and kidneys of swine, cows and chickens.
A major drawback of a multi-residue method using HPLC–MS/MS is the high cost
an
of the organic solvents and the HPLC-MS/MS equipment. The development of UHPLC has greatly reduced the analysis time. By reducing the particles of the stationary phase to
M
less than 2 µm, the resolution can be increased up to 60 %, allowing good separation in
d
less time. A highly selective and sensitive method was developed for the simultaneous
Ac ce pt e
detection of twelve SAs in beef and milk by immunoaffinity chromatography purification coupled to UHPLC-MS/MS [38]. The limit of detection (LOD) for the studied SAs ranged from 0.4 to 2.0 μg L-1 (1.6 – 8.0 μg kg-1 for beef and 1.8 – 6.4 μg kg-1for milk). She et al. [79] have developed a novel method for the rapid separation and determination of twenty-four SAs in bovine milk by UHPLC-MS/MS. The samples were treated with acetonitrile followed by homogenization, ultrasound treatment and centrifugation. The analytes were detected by multiple reaction monitoring (MRM) in the positive ion scan mode. Liu et al. [143] have presented a fast and sensitive UHPLC-MS/MS method for the simultaneous quantitative determination of 16 SAs in animal feeds. Recently, a hybrid triple quadrupole-linear ion trap (QqLIT) instrument has been developed. This is a powerful technique for the large-scale screening of SAs and their
Page 22 of 76
metabolites in real samples [37, 152, 181]. The method is based on a QqQ with the third quadrupole (Q3), which can be used as either a conventional quadrupole mass filter or a linear ion trap combining the advantages of the classical QqQ scanning functionality and the possibility of additional sensitive ion trap scans for structural analysis within the same
ip t
operating platform. Due to the high ion-accumulation capacity, this method has improved full-spectrum sensitivity that provides very promising modes such as enhanced full mass
cr
scan, enhanced product-ion and multi-stage scans. All of these features make the
us
technique very powerful for the identification of unknown or suspected analytes even with poor fragmentation and at low concentrations. Another attractive capability of
an
QqLIT for semi-targeted analysis is information-dependent acquisition that automatically
experiment.
M
combines a survey scan with the dependent (enhanced trap) scan during a single
d
The progress in chromatography and mass-spectrometry resulted in development
Ac ce pt e
of multi-class analytical methods, which are currently a significant trend in the detection of several classes of veterinary drugs in food and environmental samples that can be successfully applied for both quantification and screening purposes [133]. These methods are able to detect more than 200 different compounds and are of great interest to analytical laboratories due to their simplicity, high sample throughput and costeffectiveness.
A certain drawback of such procedures is the occurrence of abundant matrix
effects, which compromise the quantitative aspects and selectivity of the methods. The extracts from solid matrices usually have high contents of organic components, such as lipids, humic acids, etc. These interfering compounds compete with the analytes in reaching the droplet surface positions, which affects the maximum evaporation efficiency
Page 23 of 76
and hampers ionization of the analytes. These components also increase the viscosity of the sample and the surface tension of the droplets generated in ESI source, hindering the evaporation of the analytes. Different approaches have been developed to minimise the matrix effects. They
ip t
are based on the use of improved chromatography with better separation of the matrix compounds from the analytes (e.g., UHPLC). The dilution of the sample extracts and the
cr
use of internal standards or matrix matched calibration are also frequently used [37, 97,
us
181]. The main aspect in the multi-class residue analysis, however, is a sample preparation step that should effectively extract a broad range of compounds from the
an
samples. The different physico-chemical properties of target analytes as well as the
extraction and clean-up.
M
presence of the high concentrations of interferences in the matrices complicate the
d
A variety of sample pretreatment methodologies and several multi-class HPLC-
Ac ce pt e
MS/MS and UHPLC–MS/MS methods have been applied for the detection of SAs along with veterinary drugs in animal food (see Table 2, 3), feeds, waters, soils and sediments (see Table 5). Most multi-class methods involve simple liquid extraction and QuEChERS, while clean-up is carried out by SPE. The degree of clean-up provided by many of these methods is usually limited because the extensive purification would result in total loss of some residues. Other simple approaches such as “dilute-and-shoot” strategy, which utilises diminishing matrix effects in diluted samples and is usually exploited in the mass spectrometric analysis of SAs, as well as ultra-filtration or on-line column switching have also been developed. For instance, a rapid and simple method for both quantification and confirmation of nineteen antibiotics of five classes in muscle (SAs, tetracyclines, quinolones, β-lactams
Page 24 of 76
and macrolides) has been described [45]. The antibiotics were extracted by 70% methanol, diluted with water and injected in the HPLC–MS/MS system. Cronly et al. [138] have described a confirmatory method for the determination of fourteen prohibited medicinal
additives
(metronidazole,
dimetridazole,
ronidazole,
ipronidazole,
ip t
chloramphenicol, SMZ, SDZ, dinitolimide, ethopabate, carbadox, clopidol, tylosin, virginiamycin and avilamycin) in pig and poultry feed at levels of 100 µg kg−1. The
cr
compounds were extracted using acetonitrile with the addition of sodium sulfate and
us
cleaned with hexane before determination using HPLC–MS/MS. In another example, a fast and easy HPLC-MS/MS multiclass method was developed for the detection of fifty
an
antimicrobials from thirteen different families in animal feeds [146]. Analytes were extracted using a mixture of methanol, acetonitrile and McIlvaine buffer combined with
M
sonication. The feed extracts were simply diluted prior to injection. Analysis was carried
d
out by HPLC-MS/MS using an ESI source operating in the positive and negative modes.
Ac ce pt e
A multi-class UHPLC-MS/MS method has been developed for the determination of more than 160 regulated or banned compounds of various classes in eggs, honey and milk [47]. These compounds include anthelmintics such as benzimidazoles, avermectins and others; antibiotics including amphenicols, beta-lactams, macrolides, pyrimidines, quinolones,
SAs
and
tetracyclines;
beta-agonists;
corticosteroids;
ionophores;
nitroimidazoles; non-steroidal anti-inflammatory agents; steroids; and tranquillisers. The compounds were extracted with acetonitrile without any additional purification steps and analysed by UHPLC-MS/MS. In most cases, the target value was set at 5 mg kg-1 for unauthorised compounds. Furthermore, Zhan et al. have developed a simple and fast extraction procedure for the determination of 226 veterinary drugs and other contaminants in muscle [51]. The method is based on LLE, low temperature clean-up and
Page 25 of 76
dispersive SPE. The limit of quantification (LOQ) varied from 0.05 to 10 µg kg–1. Another work [108] describes a multiclass method for the determination of forty-one antimicrobial agents from seven families (SAs, diaminopyridine derivatives, quinolones, tetracyclines, macrolides, penicillins and lincosamides) in eggs. The method has been
ip t
validated according to the requirements of the European Commission Decision 2002/657. Compounds were extracted using PLE with a mixture of acetonitrile and succinic acid
cr
buffer (pH 6.0) (1:1, v/v) at 70◦C. No further clean-up was necessary. Analytes were
us
determined by UHPLC–MS/MS over a chromatographic run of 13 min. The LOQs were in the range of 0.5–3.8 µg kg−1 for non-authorised compounds. The proposed method
an
would enable to process about twenty-five samples per day.
A rapid and simple analytical method that was able to simultaneously determine
M
220 undesirable chemical residues (veterinary drugs, mycotoxins, pesticides, hormones
d
and other contaminants) in infant formula has been developed [132]. The method
Ac ce pt e
includes extraction with acetonitrile, low temperature clean-up by water precipitation and detection by UHPLC–MS/MS with ESI using the MRM mode. Most of the fat materials in the acetonitrile extract were eliminated by the low temperature clean-up. The LOQs were from 0.01 to 5 µg kg-1.
The QuEChERS multiresidue procedure simplifies extraction and clean-up and
reduces the time of the analysis (Table 3, 5). For example, the QuEChERS method has been developed for the determination of trace amounts of thirty-one substances including hormonal steroids, veterinary and human drugs in soil [172]. The analysis was performed using HPLC–MS/MS. This method allowed for the detection of substances at the sub-ng g-1 concentration level. The methodology was applied to real soil samples collected in the several areas of France that had received different treatments with manure or sludge.
Page 26 of 76
Veterinary antibiotics, which were mainly from the sulfonamide family, were found in the manure-treated soils (0.02 – 0.12 ng g-1). Another good possibility for the multi-component analysis is a sensitive full mass scan MS technique such as time-of-flight (ToF-MS) or quadrupole time-of-flight mass
ip t
spectrometry (QTOF-MS). These analysers provide high specificity due to both the high mass accuracy and the high mass resolution. The advantage of a ToF-MS analyser is its
cr
ability to analyse a sample for a large number of compounds. The HPLC–ToF-MS
us
approach is capable of high-sensitivity screening of several hundreds of compounds within a single run. Furthermore, the data can be acquired and processed without any
an
prior knowledge about the presence of certain compounds. In other words, no analytespecific information is required before injecting a sample, and the presence of newly
M
identified compounds can be confirmed in the previously analysed samples simply by
d
reprocessing the data. The advantage of ToF-MS can be further improved by combining
Ac ce pt e
it with UHPLC [46, 81, 94, 103]. A fast liquid chromatography ToF-MS method has been developed for the simultaneous multiclass determination of selected antibiotics and other veterinary drugs (benzalkonium chloride, ethoxyquin, leucomalachite green, malachite green, mebendazole, SDZ, SDM, SMZ, SMT, SAM, SPY, STZ and trimethoprim) in shrimps [103]. Different sample pretreatment methodologies based on either liquid partitioning with different solvents and SPE or MSPD were tested for the extraction of the targeted species. The extraction method that was finally selected was liquid extraction with acetonitrile followed by a clean-up step with PSA (QuEChERS). The LOD ranged from 0.06 to 7 µg kg−1. Deng et al. [46] have developed an UHPLC-QTOF-MS method for a comprehensive screening of 105 veterinary drugs and metabolites including beta-
Page 27 of 76
agonists, benzimidazoles, corticoids, triphenylmethane, nitromidazoles, quinolones, SAs, tetracyclines, and benzodiazepams in meat, milk, and eggs. Acetonitrile containing 0.1% formic acid was used to extract the drug residues from these matrices and to precipitate the proteins. Sample clean-up was then conducted on an Oasis HLB column. The
ip t
separation was achieved within 30 min at the optimised chromatographic conditions. A HPLC-QTOF-MS method has been developed to analyse veterinary drug residues in milk
cr
[81]. Drugs were extracted with acetonitrile and a molecular weight cut-off filter was the
us
only clean-up step used in the procedure. A set of target compounds (including representative SAs, tetracyclines, β-lactams, and macrolides) was used for validation.
an
Although the method was intended to be qualitative, the evaluation of the MS data indicated a linear response and the acceptable recoveries for a majority of target
M
compounds. Finally, milk samples from cows dosed with veterinary drugs including
d
SMZ, flunixin, cephapirin or enrofloxacin were analysed. In addition to the parent
Ac ce pt e
residues, several metabolites were detected in these samples. The proposed identification of these residues could be made by evaluating the MS and MS/MS data. For example, several plausible metabolites of enrofloxacin, which has not been previously observed in milk, were reported in this study.
3.1.2. Detection with other techniques Classical reversed-phase HPLC with ultraviolet (UV) [22, 25, 26, 33, 34, 41, 57,
58, 63, 64, 66, 72, 76, 77, 82, 101, 104, 112, 115,116, 135, 142, 159, 165, 166, 168, 169, 179], photodiode array (DAD) [23, 48, 59, 60, 62, 65, 67, 70, 95, 107, 128, 130, 144, 161,163, 178, 186] and fluorescence (FL) [24, 27, 28, 30, 61, 71, 74, 83, 95, 114, 117,121, 129, 145, 167, 175, 178, 190] detectors is still widely used for the routine quantification of SAs in different types of food, feed and environmental samples. All of
Page 28 of 76
these approaches are quantitative but not confirmatory, as they cannot provide direct evidence of the structure or composition of a substance. Electrochemical detection is used less frequently [105, 114, 163, 181]. UV detection is often carried out at 270–280 nm or in some cases at 255 nm. DAD detection is often performed at 267, 268 or 263 nm. FL
ip t
detection is carried out at the excitation wavelength of 405–420 nm and at the emission wavelength of 485–495 nm after pre-column derivatization with fluorescamine. UV
cr
detection is the most affordable and versatile but the least selective and sensitive. FL
us
detection is much more sensitive and selective, but its use is connected to the additional derivatization procedure for transformation of SAs into their fluorescent derivatives. The
an
less frequent use of electrochemical detection seems to be due to the complexity of selection of the detection conditions.
M
The vast majority of the chromatographic separations of SAs have been performed
d
with conventional silica-based reversed phased columns (mainly C18) with spherical
Ac ce pt e
sorbent particles of 3 – 5 μm in diameter. Some types of commercially available stationary phases used for the determination of SAs are represented in Table 6. The speed of the analysis can be increased through the use of a monolithic column
[27, 105], high temperature [159] or an ultra-high-pressure system [164, 171]. A fast analytical method based on HPLC-UV that provides pressure up to 600 bar, and a 150 mm column operated at high temperature (600C) was used for the separation and determination of nine SAs in surface and wastewater samples in the shortest possible time (3 min) [159]. Herrera et al. [164] used magnetic multi-walled carbon nanotubes combined with UHPLC-DAD to extract eleven SAs (i.e., SAM, SAA, SDZ, STZ, SMR, SDD, SMP, SDO, SMX, SSA and SDM) from different water samples [164]. A DLLME
Page 29 of 76
procedure combined with UHPLC-DAD has been developed for the determination of eleven SAs and fourteen quinolones in mineral and run-off water [171]. The mobile phases mainly consist of acetonitrile–water or methanol–water mixtures (Table 6). Furthermore, there are papers reporting the application of three-
ip t
component mixtures such as water:methanol:acetonitrile [58, 72, 144]. In most cases, the mobile phase was modified with acetic [41, 30, 79, 104, 119, 25, 165] or formic acid
cr
[119, 152, 168, 120], and acetate [27, 61], phosphate [72, 169] or formate buffer [146].
SAs in complex mixtures with other antibiotics.
an
3.2. Electrophoretic methods
us
The application an elution gradient allows the separation and simultaneous detection of
Capillary electrophoresis (CE) is another good quantitative analytical approach
M
that is mainly used when only small amounts of a sample are available. Some advantages
d
of CE are its high separation efficiency, ability to analyse several samples simultaneously
Ac ce pt e
in multicapillary systems, and low consumption of reagents and accessories (packaged columns are not required). Several CE methods for the analysis of SAs were published and reviewed in 2009 [17]. Recent advances in the analysis of antibiotics, including SAs, by CE from 2009 to 2011 are summarised in another review [194]. For the past five years, CE has been used for the determination of SAs in chicken
and edible pig tissues [25, 40, 43], milk [80], shrimp [99] and water samples [170]. Phosphate [40, 43] and borate [80, 99] buffers, which sometimes contain additional organic modifiers such as sodium polystyrene sulfonate [170], were used as a running buffer. The simultaneous determination of six SAs (SMZ, SDM, SMR, STZ, SDZ and SMX) in chicken and edible pig tissues was accomplished by CE with electrochemical
Page 30 of 76
detection [25]. The complete separation of SAs was achieved within 17 min, using 40 mmol L−1 Na2 B4O7/25 mmol L−1 KH2PO4 (pH 6.2) at the applied voltage of 18 kV. Chu et al. [40] used CE for the separation and detection of SMX, SMZ, SMR and SDM in chicken and beef tissue samples. The analysis was performed under the following
ip t
conditions: the stationary phase was a quartz capillary; the mobile phase was 45 mmol L-1 phosphate buffer (pH 6.3); detection was performed using a photodiode array; and the
cr
voltage was 20 kV. The LODs of the SAs were 4 – 6 μg kg-1. Four SAs were detected in
us
meat samples by CE following clean-up of the acetonitrile extracts on graphene-filled cartridges [43]. A hollow-fibre liquid-phase microextraction method was developed for
an
the preconcentration of six SAs, including SMZ, SMR, SDZ, SDM, SMX and STZ, which were detected by CE with electrochemical detection. Under the optimum
M
conditions, these compounds could achieve the baseline separation within 35 min. The
d
LODs were in the range of 0.033–0.44 ng mL-1 [170].
Ac ce pt e
Microfluidic chip electrophoresis is an alternative to the conventional capillary electrophoresis that usually has better performance [56, 185]. Wang et al. [56] have proposed a sensitive microchip electrophoresis method for the efficient separation and detection of four SAs (SMZ, SMX, SQX and SAM) in milk and chicken drumstick muscle using the laser-induced fluorescence detection. Separation of fluorescaminelabelled SAs was accomplished using a buffer containing 5 mmol L-1 boric acid and 1% (w/v) polyvinyl alcohol. Under optimised conditions, the separation of four SAs was achieved within 1 min with the LODs of 0.2−2.3 μg L-1. A compact and low-cost lightemitting diode-induced fluorescence detection coupled to a microchip electrophoresis system was applied to the detection of fluorescamine-labelled SAs in commercial
Page 31 of 76
preparations and in a rabbit plasma sample [185]. The LODs for SDZ, SMZ and SGD were 0.36–0.50 μg mL-1. Capillary electrochromatography is a hybrid separation technique that combines the stationary phase of HPLC and the electroosmotic flow of CE. Presently, capillary
ip t
electrochromatography is carried out on particle-packed or polymeric monolithic columns. For the separation and detection of nine SAs in meat samples, the authors [39]
cr
suggested using capillary electrochromatography with MS-detection. The separation was
us
carried out on several monolithic stationary phases, which were synthesised using onestep co-polymerization of divinylbenzene with different alkyl methacrylates (butyl-,
an
octyl-, lauryl- or stearyl methacrylate). Among these, the poly(divinylbenzene-octyl methacrylate) monolithic column gave the best results. Optimization of the mobile phase
M
composition and the gradient elution strategy allowed for the successful detection of
d
sulfonamide antibiotics in meat samples at levels of 10 μg L-1.
Ac ce pt e
A micellar electrokinetic capillary chromatographic method with UV detection was used for the simultaneous detection of SAs and amphenicols in poultry tissue [42]. The analytes were isolated from tissue samples by SPE with C18 cartridges followed by protein precipitation with acetonitrile. The compounds were separated on the unmodified quartz capillary (57 cm). A solution of 25 mmol L-1 sodium dodecylsulfate and 10 mmol L-1 sodium borate was used as the mobile phase. The total time of analysis was less than 8 min.
3.3. Microbiological assays The microbiological inhibition assays are based on the use of SA-sensitive bacteria as indicators. These assays assess the ability of microbes to reproduce in milk. When growth of these bacteria is suppressed, which is determined directly or indirectly by the
Page 32 of 76
metabolic activity of the bacteria, a conclusion is made about the presence of drugs. The presence of the residual substances is determined from inhibition plots of the bacterial growth obtained from an agar-diffusion method that uses cylinders, wells on the agar surface or discs of filter paper. The test microbes are streptococci, micrococci and aerobic
ip t
spore-forming bacteria. These types of techniques usually meet the requirements of a screening approach.
cr
The microbiological method was used for screening samples of milk for their SA and
us
antibiotic contents before these compounds could be detected by enzyme immunoassay [82] or HPLC [83]. Additional information on the application of microbial screening
an
methods for antibiotic residues, including SAs, can be found in a previous review [195]. That review presents an overview of the developments in the field of microbial screening
M
methods for antibiotic residues and the efforts expended to bring antibiotic screening
Ac ce pt e
3.4. Immunoassays
d
methods into compliance with EU legislation.
Immunoassays are semi-quantitative methods characterised by high specificity,
high sensitivity, simplicity and cost effectiveness, which make them particularly useful for routine uses. These assays are based on a specific reaction between an antibody and an antigen, and they are capable of detecting the low concentration of residues in short time and often do not require laborious extraction or clean-up steps. A large number of papers have been devoted to the detection and identification of SAs using different immuno-methods. Many of them are summarised in the reviews [14 – 16]. Enzyme-linked immunosorbent assays (ELISA) are the most widely used immunoassays due to their high sample throughput. These methods can drastically reduce the number of analyses required to detect sulfonamide contamination in food samples.
Page 33 of 76
Therefore, ELISA methods have been developed for sulfonamide screening in honey [53, 122], chicken muscle [54], fish [106], feed [53, 141], milk [82, 196] and farm animal hair samples [197]. For the high-throughput monitoring of SA residues in edible animal tissues, a
ip t
novel hapten and monoclonal-based indirect competitive ELISA has been developed. The novel hapten was synthesised and conjugated to a carrier protein as the immunogen. The
cr
spleen cells of the inoculated mice, which expressed group-specificity against SAs, were
us
used. The obtained monoclonal antibody showed cross-reactivity to 16 structurally different SAs. Based on this antibody, an optimised ELISA protocol with only
an
phosphate-buffered saline was carried out for the fast extraction of SAs from tissues. The LODs of SAs in chicken ranged from 1.5 to 22.3 µg kg-1. The developed ELISA method
M
would be a useful tool in screening for SAs residues in edible animal tissues [54].
d
A method of detecting the most commonly used SAs (SMR, SDM and SDZ) in
Ac ce pt e
commercial fish samples has been developed [106]. The important advantage of this method is that only one pair of immunoreagents is used for the detection of three analytes. Therefore, it is possible to use the same ELISA to determine the total concentration of SAs or quantify any of these analytes by using the calibration curves that correspond to each sulfonamide.
Currently, there are many commercially available immunoassay kits used for the
fast and highly specific detection of SAs and other veterinary drug residues. For example, ELISA test kits (RIDASCREEN, R-Biopharm AG, Darmstadt, Germany) were used to assess the contamination of milk with SAs, tetracyclines and quinolones residues [196]. The declared LODs were 1.5 μg L-1 for tetracyclines, 3.5 μg L-1 for sulfonamides, 10 μg L-1 for sulfamethazine and 0.25 μg L-1 for quinolones.
Page 34 of 76
One of the most useful immunoassay formats is the lateral flow immunoassay (LFIA). With respect to SAs, this method has been developed [123] in the competitive reaction format and applied to test for STZ residues in honey samples. To prepare the assay test, a hapten conjugate was used as the capture and goat antirabbit antiserum was
ip t
the control reagent. These reagents were dispensed on nitrocellulose membrane. A polyclonal antiserum against STZ was conjugated to colloidal gold nanoparticles and
cr
used as the detection reagent. The visual LOD (cut-off value) of STZ was 15 ng g-1. The
us
qualitative results were reached in 10 min, and the test was highly specific and showed no cross-reactivity to other chemically similar antibiotics.
an
Examples of immunoassays for the determination of SAs are given in Table 7. 3.5. Biosensors
M
Immunochemical methods, which use antibodies as the specific recognition
d
elements, are excellent complementary analytical alternatives for detecting SA residues
Ac ce pt e
in small sample volumes without complex sample preparation and purification steps. In fact, over the past five years, it has been demonstrated that the electrochemical and optical biosensors are excellent tools for detecting contaminants in food and environmental matrices [203, 204]. Their main advantages are their technical simplicity, low cost, and the possibility of being used in field analyses. Electrochemical sensors based on the use of receptors fabricated through different imprinting approaches have been developed for the detection of SAs [89, 91, 125 – 127, 205]. One of the prospective trends in this field is the development of miniaturised disposable electrodes which could potentially avoid a labour regeneration step simply by changing the electrode. The main role in this type of methods is played by screen-printed carbon electrodes. Thus, the authors [89, 91] have suggested an amperometric
Page 35 of 76
immunosensor based on an antibody covalently immobilised onto a 4-aminobenzoic acid film grafted onto disposable screen-printed carbon electrodes and a direct competitive immunoassay using horseradish peroxidase-labelled tracers. The developed methodology showed very low LOD (in the low ppb level) for SA antibiotics in milk samples and good
ip t
selectivity to other antibiotic residues frequently detected in milk and dairy products. Another interesting approach is the application of nanoparticles, quantum dots and
cr
nanocomposites. For example, an electrochemical immunosensor based on a
us
nanocomposite-modified glass carbon electrode has been developed [205]. The biospecific surface was a CeO2-chitosan-modified nanocomposite with an attached anti-
an
SMX polyclonal antibody. The presence of the CeO2-chitosan nanocomposite significantly enhanced the conductivity of the electrode. The large electroactive surface
M
area of the electrode resulted in high loading of the antibody. The LOD of SMX was
d
shown to be 3.25×10−7 mg mL−1. No cross-reactivity with other antibiotics of the
Ac ce pt e
sulfonamide family was found. The immunosensor was successfully applied to the analysis of milk, honey and egg samples. The immunosensor [125] was based on biofunctionalised magnetic particles and
electrochemical nanoprobes prepared by labelling the specific antibodies with CdS nanoparticles (CdSNPs). After the immunochemical reaction, the CdSNPs were dissolved and the released metal ions were reduced at the electrode and read in the form of the current or charge signal by using the well-known anodic stripping technique. Due to the amplification effect on the amperometric/coulombimetric signal produced by CdSNPs, high detectability could be reached. For example, SPY could be detected at 0.20 µg L-1. The immunosensor has been applied to the detection of residues of this antibiotic in
Page 36 of 76
honey samples. The use of magnetic particles minimised the matrix effect and allowed LOD values of up to 0.11 µg kg-1. This effect has conditioned the application of magnetic particles in immunosensing methods. The use of magnetic particles offers unique advantages such as
ip t
permitting interferences in the sample matrix, minimizing the matrix effect, improving immunoreaction kinetics, and ease of magnetic manipulation. For example, a new
cr
electrochemical magnetoimmunosensor (EMIS) has been developed [127] for the
us
detection of sulfonamide antimicrobials in honey samples. The improved EIMS was based on well-characterised immunoreagents, biofunctionalised magnetic beads and
an
homemade graphite–epoxy composite electrodes containing an internal magnet. The EMIS was able to detect SAs in honey at levels below 25 μg kg−1.
M
In a few articles [86 – 88], the application of aptamer-based sensors and assays for
d
the detection of SAs has been mentioned. Aptamers are single-stranded DNA or RNA
Ac ce pt e
oligonucleotides able to bind to their target with high affinity and specificity. The application of aptamers in biosensors offers the possibility of fast and easy detection of SAs. A polymer-based aptasensor using fluoresceinamidite-modified aptamers and coordination polymer nanobelts has been developed for detecting SDM residues in milk [86]. Using the fluorescence quenching effect, the proposed aptasensor showed high sensitivity for SDM (LOD = 10 ng mL-1). In another study [86], SDM-binding DNA aptamers and unmodified AuNPs have been proposed for the sensitive detection of SDM. The assay used aptamer-conjugated gold nanoparticles to combine the selectivity and affinity of aptamers and the spectroscopic advantages of gold nanoparticles. The red-toblue colour change of AuNPs in the presence of SDM was easily observed by the naked eye or measured using a UV–vis spectrometer. The linear dynamic range and the
Page 37 of 76
detection sensitivity were found to be 50 to 1000 ng mL-1 and 50 ng mL-1, respectively. Adrian et al. [88] have developed a portable wavelength-interrogated optical system (WIOS) exploiting class-selective bioreceptors for the fast screening of antibiotics (e.g., SAs, fluoroquinolones, b-lactams and tetracyclines) in milk. The label-free sensor used
ip t
the evanescent-wave principle. The changes in the refractive index close to the modified chip surface were detected by scanning the resonance conditions when a light wave was
cr
coupled in the waveguide through a conveniently designed grating. The bioreagents used
us
in this study were developed to detect a wide range of congeners of the each selected family of antibiotics below the MRL values established for milk samples.
an
3.6. Other methods
M
In addition to the methods described above, different physical-chemical methods have been used for the detection of SAs. These methods are all quantitative and include
d
fluorescence [73, 84, 85, 124, 184], spectrophotometry [90, 128, 188, 189, 206], surface
Ac ce pt e
enhanced Raman spectroscopy [207, 208] and electrochemical methods [55, 187, 209 – 215]. The use of these methods is justified when it is necessary to carry out the routine quality control of relatively simple sample compositions. The advantages of these methods include their simplicity, compactness, and relatively low cost of the analysis. Molecular fluorescence spectrometry can be used as a screening method to detect
SAs in milk [73, 84, 85], honey [124] and pharmaceuticals [184]. For the derivatization of SAs, fluorescamine [73, 84, 85] and β-cyclodextrins [124] have been employed. In a previous paper [184], a new, simple and accurate method has been proposed to detect SAs based on the direct quenching effect produced by several SAs (SSZ, SAM and SMX) on the luminescence of terbium (III). The proposed method allowed for the detection of up to 50 samples per hour.
Page 38 of 76
A net analyte signal standard addition method has been used for the simultaneous determination of SDZ and trimethoprim by spectrophotometry in some bovine milk and veterinary medicines. The method combines the advantages of a standard addition method with the net analyte signal concept that allows for the acquisition of information
ip t
about certain analytes from the spectra of multi-component mixtures. This method has some advantages, such as the use of a full spectrum realization. Therefore it does not
cr
require calibration and prediction steps and only a few measurements are required for
us
antibiotic detection [90].
A simple, sensitive and accurate spectrophotometric method for the detection of
an
SMX, SGD, SQX, SML and SDD in different pharmaceutical preparations has been developed [189]. The charge-transfer reactions between SAs as π-electron donors and
M
7,7,8,8-tetracyanoquinodimethane, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and 2,5-
d
dichloro-3,6-dihydroxy-1,4-benzoquinone as π-acceptors result in highly coloured
Ac ce pt e
complexes. p-Dimethylaminocinnamaldehyde (p-DAC) has been suggested [206] as a spectrophotometric reagent for the detection of SAs. It was shown that in acetonitrile medium, this reagent participated in a condensation reaction with SAM, SMP, SCP, SMX and SMZ, forming coloured products. The method was developed for the spectrophotometric detection of SAs with LODs of n·10-2 g mL-1. For the detection of SAs in honey samples, a screening method based on flow injection analysis coupled to a liquid waveguide capillary cell has been developed [128]. The proposed method was based on the reaction between SAs and p-DAC in the presence of sodium dodecylsulfate in dilute acid medium (hydrochloric acid), with the reaction product being measured spectrophotometrically at 565 nm. The non-compliant and false non-compliant samples
Page 39 of 76
were also analysed by a confirmatory HPLC method. The proposed system enables the screening of SAs in honey samples with a low number of the false non-compliant results. Electroanalytical techniques pose viable alternatives for the detection of SAs, which have advantages such as simplicity, portability and sensitivity that make them very
ip t
attractive for the monitoring of pharmaceutical compounds. Owing to the electroactive properties of SAs, the anodic oxidation of these substances occurs at the aromatic amino
cr
group with the formal oxidation–reduction potentials range of 0.75– 1.05 V. In the last
us
five years, there have been several reports concerning the electrochemical properties of SAs on different types of electrodes, such as a boron-doped diamond [187], a glassy
nanotubes-poly(1,5-diaminonapthalene)
an
carbon [209] and a multi-walled carbon nanotube paste electrode [210, 211], carbon [212] or
phthalocyanine
[213]
modified
M
electrodes, and a MIPs-modified carbon paste electrode [214]. These electrodes were
d
used to develop a variety of voltammetric methods for the detection of SDZ [209, 213],
Ac ce pt e
SMX [210], SAA [212] and SSZ [214] in commercial pharmaceutical formulations as well as SMT in human blood plasma [211] and SSZ in human serum [214]. Trace quantities of SMZ, SMT, SMM, SQX and SDM were successfully
preconcentrated, separated, and detected in a microfluidic device by employing electrokinetic separation and electrochemical detection using an Al2O3–AuNPs modified carbon paste electrode [55]. The method was used for the direct analysis of SAs in real meat samples.
A method based on a multicommutation stopped-flow system has been developed and applied to the simultaneous detection of SMX and trimethoprim in pharmaceutical formulations by using a differential pulse voltammetry with a boron-doped diamond electrode [187]. Almeida et al. [215] described the construction of an SDZ-selective
Page 40 of 76
electrode made from stainless steel tubular syringes of different lengths. The selective electrode was used as a potentiometric detector in a flow-injection analysis system for on-site detection of SDZ in aquaculture waters.
ip t
4. Conclusions and outlook Over the past five years, different methods for monitoring the residues of SAs in
cr
various types of samples (e.g., food, feed, environmental, clinical and pharmaceutical
us
samples) have been proposed. The key roles in these methods are played by sample preparation techniques, and the main efforts in this field have been focused on the
an
optimization of the preparation, extraction and clean-up steps and on the enhancement of the environmental safety of these procedures. The methods with the most promise in
M
achieving these goals are QuEChERS and SPE. The main advantages of these approaches are good compatibility with high throughput multi-residue analytical procedures and their
d
relatively low cost. Therefore, these techniques are expected to have the most
Ac ce pt e
pronounced development in the future.
The currently proposed analytical approaches for the detection of SAs are mainly
based on HPLC–MS or HPLC–MS/MS. Great advances in HPLC-MS/MS have made it a key technique for the determination of not only SAs but also other antibiotic residues. The main trend in this field is the combination of MS detectors with modern chromatographic approaches such as UHPLC and the application of the powerful QqTOF and Orbitrap instruments. These hybrid approaches have made a great contribution to the analysis of trace organic contaminants, including SAs, and have contributed to the development of multi-analyte techniques for the detection of a wide range of substances in a single analytical run. These methods seem poised to be the most frequently used techniques for the purposes of analysis in the future. The main disadvantages of these
Page 41 of 76
methods are their complex equipment and high costs. This fact currently stimulates a great interest in the development of screening methods based on microbiological, immunoassays and biosensors, which have the main advantages of low cost, short analysis times and the possibility of their on site use. The clear trend in this field is the miniaturization of the screening systems (chips, microarrays, microtiter plates) as well as
ip t
their automation. We think that these features will maintain the sustainable progress of
cr
these methods in the near future.
us
Acknowledgments
an
The work was financially supported by the Russian Foundation for Basic Research (grant N 1303-00100)
M
References
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[2] K. Kűmmerer, Chemosphere. 75 (2009) 417–434.
Ac ce pt e
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Advantages
Disadvantages
References
Liquid-liquid extraction with fast partition at very low temperature (LLE-FPVLT)
Relatively low toxic solvent Low solvent consumption Free of additional purification
Extremely low temperature Requires liquid nitrogen Expansive
29, 44
Pressurized liquid extraction (PLE)
High performance Ease of automation Possibility to use water as an extractant
Requires high pressure Relatively complex equipment Expansive
32, 99, 108
Matrix solid-phase dispersion (MSPD)
Easy preparation of solid and viscous samples
Additional purification is usually required
30, 31, 48, 97
QuEChERS
Simplicity Quickness Low cost
Partial lack of the extraction selectivity
49, 50, 70, 71, 102, 103, 109, 110, 131
Additional solvent is required
33, 60, 61, 71, 78, 101, 128, 130
Quickness High efficiency
Ac ce pt e
Dispersive liquid-liquid microextraction (DLLME)
d
M
an
us
ip t
Extraction technique
cr
Table 1 .Non-classical extraction techniques for the sample preparation prior to the detection of SAs
Table 2 Examples of SAs extraction along with other veterinary drugs and their multiclass detection. Compounds
Matrix
Method
Detection
Ref.
37 veterinary drugs, including 16 SAs
Porcine muscle
Extraction with ACN at very low temperature
HPLC–MS/MS
44
19 veterinary drugs, including 4 SAs
Porcine and bovine muscle
Extraction with 70% methanol
HPLC–MS/MS
45
105 veterinary drugs, including 18 SAs
Meat, eggs
Extraction with ACN containing 0.1% formic acid
UHPLC–MS
46
160 veterinary drugs, including 16 SAs
Meat, eggs, honey
Extraction with ACN
UHPLC–MS/MS
47
Page 58 of 76
226 veterinary drugs, including 18 SAs
Meat
Extraction with ACN/EtOH (5:1, v/v) and Na2EDTA
UHPLC–MS/MS
51
120 veterinary drugs, including 21 SAs
Bovine kidney
Extraction with ACN/Н2О (4:1, v/v)
HPLC–MS/MS
52
25 veterinary drugs, including 8 SAs
Milk
Extraction with ACN
HPLC–MS
81
17 SAs, 5 tetracyclines
Fish
Extraction with acidic MeOH/ACN (50:50, v/v)
ip t
92
70 veterinary drugs, including 5 SAs
Fish fillets
Extraction with acidic ACN/Н2О (80:20, v/v)
UHPLC–MS
94
9 SAs,
Catfish
Extraction with acidic MeOH
HPLC–MS/MS
96
32 veterinary drugs, including 13 SAs
Fish
Extraction with acidic ACN
HPLC–MS/MS
98
100 veterinary drugs, including 15 SAs
Fish, eggs
UHRLC–MS
100
41 veterinary drugs, including 14 SAs
Eggs
Extraction with acidic ACN
HPLC–MS/MS
108
25 veterinary drugs, including 4 SAs
Eggs
Extraction with acidic ACN and Na2EDTA
UHPLC–MS/MS
109
220 veterinary drugs, including 18 SAs
Baby food
Extraction with ACN and Na2EDTA
UHPLC–MS/MS
132
us
cr
HPLC–MS/MS
M
an
5 tetracyclines
Ac ce pt e
d
Extraction with ACN/Н2О (6:4, v/v)
Page 59 of 76
Table 3 Examples of the QuEChERS methods used in the extraction and clean-up of SAs along with other veterinary drugs and their multi-class detection. Matrix
Method
Detection
Ref.
48 veterinary drugs, including 16 SAs
Chicken
Extraction with ACN containing 0.1% (v/v) acetic acid. Shaking with anhydrous Na2SO4. DSPE with Bondesil NH2 and Na2SO4. Filtration and evaporation of solvent. Dissolving in ACN – H2O (90:10, v/v)
HPLC–MS/MS
49
21 veterinary drugs, including 6 SAs
Chicken
Extraction with acidic ACN/Н2О (80:20, v/v). Shaking with sodium citrate dibasic sesquihydrate, sodium citrate dihydrate and anhydrous MgSO4. DSPE with PSA. Filtration and dilution with acidic ACN/Н2О (1:1, v/v)
UHPLC–MS/MS 50
32 veterinary drugs, including 13 SAs
Fish
Extraction with ACN/MeOH (75:25, v/v). Shaking with anhydrous MgSO4 and NaAc. Filtration and evaporation of solvent. Dissolving in acidic ACN/Н2О (1:1, v/v).
UHPLC–MS/MS 102
14 veterinary drugs, including 7 SAs
Shrimps
Extraction with acidic ACN. Shaking with anhydrous MgSO4 and NaCl. DSPE with PSA and anhydrous MgSO4. Filtration and evaporation of solvent. Dissolving in MeOH/Н2О (20:80, v/v)
HPLC–MS
103
21 veterinary drugs, including 3 SAs
Eggs
Extraction with acidic MeOH/Н2О (80:20, v/v). Shaking with anhydrous Na2SO4 and NaAc. Filtration
HPLC–MS/MS
110
29 veterinary drugs, including 5 SAs
Baby food
Extraction with acidic ACN. Shaking with anhydrous MgSO4 and NaAc. Filtration
UHPLC–MS/MS 131
Ac ce pt e
d
M
an
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cr
ip t
Compounds
Page 60 of 76
Table 4 Examples of HPLC-MS/MS methods for the detection of SAs. Matrix
Sample preparation
Porcine liver
Extraction with Zorbax SB C18 fast partition at (250×4.6 mm, 5 very low μm) temperature with ACN
A: ACN/Н2О (5:95, 5.58 − 16.75 v/v) / 0.1% formic acid μg kg-1 B: ACN/Н2О (95:5, v/v)/ 0.1% formic acid
Pork
Extraction with Acquity BEH C18 phosphate buffer (100×2.1 mm, 1.7 (pH 6) μm)
A: 0.2% formic acid in 112 − 129 μg kg-1 31 Н2 О B: МеОН, gradient
Pork, mutton
cr
0.0012 − 0.0146 μg kg-1
35
Agilent-Plus C18 (100×2.1 mm, 1.8 μm)
А: 10 mmol L-1 ammonium formate / 0.1% formic acid B: ACN, gradient
0.1 − 0.3 μg kg-1
36
Kinetex C18 (100×3 mm, 2.6 μm)
Ac ce pt e
Monolith-based stir bar sorptive extraction
–
an
Extraction with ACN
Extraction with ACN SPE on AccuBONDII SCX cartridge
29
32
M
Pork, chicken
SPE on HLB cartridge.
Ref.
10 μg kg-1
Zorbax SB C18 A: ACN (250 mm×4.6 mm B: 0.1% formic acid, , 5 μm) gradient
d
PLE with ACN
us
SPE on multiwalled carbon nanotubes Porcine and swine liver, bovine muscle
LODs
ip t
Mobile phase
Analytical column
Pork, chicken, fish, honey, milk
STEMIT or SEP/MAC QuEChERS-like method
Agilent Zorbax Eclipse AAA (150×4.6 mm, 3.5 μm)
A: 0.02% formic acid in Н2О B: 0.02% formic acid in ACN, gradient
1.0 – 7.5 μg kg-1
37
Beef, milk
Extraction with Н2О/EtОН (20:80, v/v).
Acquity BEH C18 (100×2.1 mm, 1.7 μm)
A: 0.1% formic acid in 1.6 − 8.0 μg kg-1 Н2 О B: MeOH, gradient
38
Immunoaffinity chromatographic
Page 61 of 76
purification Magnetic SPE on magnetite/silica/ poly(methacryli c acid–co– ethylene glycol dimethacrylate) composite microspheres
Shim-pack VPODS (250×2 mm, 5 μm)
A: 0.2% formic acid in 0.0005 − 0.0495 Н2 О μg L-1 B: 0.2% formic acid in MeOH, gradient
Milk
C18-Stir bar sorptive extraction
Zorbax ODS C18 (150×2.1 mm, 3.5 μm)
МеОН/Н2О, gradient
Milk
Acidic deproteinization
Kinetex C18 core–shell
A: 0.1% formic acid in 8 − 96 μg kg-1 Н2 О B: 0.1% formic acid in ACN, gradient
69
us
cr
0.9 − 10.5 μg L-1
68
75
an
SPE on Oasis HLB cartridge
ip t
Milk
A: 0.1% formic acid in 12.5−25.5 μg kg-1 78 Н2 О B: 0.1% formic acid in ACN, gradient
Acidic deproteinization
Polar-RP 80A (50×2 mm, 4 μm)
Milk
Extraction with ACN
Acquity BEH C18 (100×2.1 mm, 1.7 μm)
A: 0.2% acetic acid in Н2 О B: ACN, gradient
0.04 – 1.35 μg kg- 79
Extraction with ACN
Acquity BEH C18 (100×2.1 mm, 1.7 μm)
A: 5 mМ formic acid in Н2О B: 5 mМ formic acid in ACN, gradient
3 − 6 μg kg-1
Extraction with ACN/water (50/50, v/v).
Halo fused-core C18 silica (50×2.1 mm, 2.7 μm)
A: 0.1% formic acid in 0.75 − 3.0 μg kg-1 97 Н2 О B: ACN, gradient
Grass carp
d
Ac ce pt e Clean-up with hexane
Fish
M
Milk
1
93
On-line MSPD Eggs
SPE on magnetic MWCNTs
Zorbax SB C18 (250×4.6 mm, 5 μm)
A: 0.5% acetic acid in Н2 О B: МеОН, gradient
1.4 − 2.8 μg kg-1
111
Honey
Extraction with ACN
MGIII C18 column (150 ×2.1 mm, 1.8 μm)
A: 50 mmol L-1 ammonium acetate (including 0.3%
1.0 μg kg-1
113
Page 62 of 76
formic acid) B: МеОН, gradient SPE on Oasis HLB
Kinetex XB C18 (100×3 mm, 2.6 μm)
0.1% formic acid in Н2О : ACN (80:20, v/v, pH 2.6)
0.01 − 0.5 μg kg-1 117
Honey
SPE on αzirconium phosphate intercalated by hexadecyl trimethyl ammonium bromide
Agilent SB-C18 (250×4.6 mm, 5 μm)
A: 0.15% formic acid in Н2О B: МеОН, gradient
0.25 − 0.5 μg kg-1 118
Honey
SPE on magnetic molecular imprinted polymer
XTerra C18
А: 0.5% acetic acid in Н2 О B: ACN, gradient
Honey
NovaPak C18 (150 А: МеОН Hollow fiber liquid membrane ×3.9 mm, 4μm) B:0.1% formic acid extraction and 10 mmol L−1 ammonium acetate, gradient
Feeds
Extraction with ACN.
1.5 − 4.3 μg kg-1
119
5.1 − 27.4 μg kg-1 120
A: 0.1% FAc in Н2О B: ACN, gradient
0.5 − 20 μg kg-1
143
Modified QuEChERS procedure including DSPE on PSA
Zorbax Eclipse XDB C18 (150×4.6 mm, 5 µm)
А: 0.1% formic acid in 0.5 − 4.2 μg kg-1 Н2О/ACN (95:5, v/v) B: 0.1% formic acid − Н2О/ACN (5:95, v/v), gradient
147
Online SPE on Oasis HLB cartridge
Atlantis C18 (150×2.1 mm, 3 µm)
A: 10 mМ formic acid in Н2О B: 10 mМ formic acid in ACN, gradient
0.00009 − 0.011 μg L-1
151
Online SPE on Oasis HLB, PLRP-s or Hysphere C18 EC cartridges
Atlantis C18 (150×2.1 mm, 3 µm)
A: 0.1% formic acid in 0.00005 − Н2 О 0.00784 μg L-1 B: 0.1% formic acid in ACN, gradient
Ac ce pt e
Eclipse Plus C18 (100×2.1 mm, 1.8 µm)
SPE on basic alumina column
Feeds
Ground water
Environ mental water
d
M
an
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cr
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Honey
152
Page 63 of 76
Soil
Microwave assisted extraction with ACN
Pinnacle II C18 (250×4.6 mm, 5 µm)
А: 0.2% acetic acid in Н2 О B: ACN, gradient
1.4 – 4.8 μg kg-1
Zorbax SB C18 (250×4.6 mm,5 μm)
А: 0.5% acetic acid in Н2 О B: ACN, gradient
0.37–6.74 μg kg-1 174
Gemini C18 and Gemini C6 (150×4.6 mm, 5 µm)
А: 1 mmol L-1 NH4Ac/acetic acid in Н2О/ACN (90:10, v/v, pH 3.5) B: ACN, gradient
173
Soil
Ultrasonic assisted extraction with ACN
ip t
SPE on alumina
Plasma
PLE with ACN/water (25:75, v/v) or MeOH/water (90:10, v/v) SPE on Oasis HLB.
Atlantis C18 (150×2.1 mm, 3 µm)
Acidic deproteinization
SPE on Orpheous DVBHL cartridge
us
A: 10 mmol L-1 formic acid in Н2О B: 10 mmol L-1 formic acid in ACN, gradient
0.01 − 4.2 μg kg-1 181
Hypersil Gold (50×4.6 mm, 5 µm)
2 mmol L-1 NH4Ac (pH 3, formic acid) in Н2О/ACN (40:60, v/v)
LOQs: 30; 880 μg L-1
Ac ce pt e
Soils and sewage sludge
0.31 – 2.74 μg L-1 176
an
Clean-up on Strata-X Polymeric Reversed Phase SPE-column
M
Extraction with MeOH
d
Soil
cr
Magnetic SPE on Fe3O4/Al2O3 nanoparticles
191
Page 64 of 76
Table 5 Examples of HPLC-MS/MS methods for the detection of SAs along with other veterinary drugs in feed and environmental samples. Compounds
Matrix
Method
Mobile phase
Analytical column
Ref.
18 veterinary Animal drugs, feed including 7 SAs
Extraction with C12 Hydro-RP Н2О/MeOH (95:5, v/v). (50×2 mm, 4 SPE (Hysphere C18 µm) HD)
A: 0.1% formic acid 136 in Н2О
33 veterinary Feeding drugs, stuffs including 1 SA
Extraction with Zorbax XDB MeOH/ACN/McIlvaine plus (150×2.1 buffer, pH 4.6 (37.5: mm, 3.5 µm) 37.5:25, v/v/v). SPE (C18 or HLB)
A: 0.1% formic acid 137 in Н2О B: 0.1% formic acid in ACN/МеОН (70:30, v/v), gradient
15veterinary drugs, including 2 SAs
Extraction with ACN. Shaking with anhydrous Na2SO4. Filtration. Extraction with hexane, evaporation of solvent. Dissolving in Н2О:ACN (85:15, v/v)
ip t
cr
us
an
Luna C18 (100×2 mm, 3 µm)
А: 0.2% acetic acid in Н2О B: 0.2% acetic acid in ACN, gradient
138
d
M
Pig and poultry compound feed
B: 0.1% formic acid in МеОН, gradient
Extraction with acidic ACN/MeOH/1% formic acid in Н2О (65 :25:10, v/v/v)
Altima HP C18 (150×3.2 mm, 5 µm)
A: 0.5% formic acid 139 in Н2О B: 0.5% formic acid in МеОН, gradient
96 veterinary Corn drugs, including 13 SAs
Extraction with ACN/MeOH/0.1% formic acid in Н2О (80:10:10, v/v/v)
Altima HP C18 (150×3.2 mm, 5 µm)
A: 0.5% formic acid 140 in Н2О B: 0.5% formic acid in МеОН, gradient
50 veterinary Animal drugs, feed including 11 SAs
Extraction with Kinetex XBMeOH/ACN/McIlvaine C18 (100×2.1 buffer (37.5:37.5:25, mm, 1.7 μm) v/v/v)
A: 5 mmol L-1 formic acid in Н2О B: 50 mmol L-1 formic acid in Н2О/ACN (10:90, v/v), gradient
22 veterinary Animal drugs, feed including 8 SAs
PLE with MeOH. SPE (Oasis HLB)
C12 Hydro-RP (50×2 mm, 4 μm)
A: 0.1% formic acid 148 in Н2О B: 0.1% formic acid in МеОН, gradient
13 veterinary Swine
SPE (Oasis HLB)
Dionex
A: ACN
Ac ce pt e
48 veterinary Pig feed drugs, including 12 SAs
146
154 Page 65 of 76
drugs, including 4 SAs
wastewater and environme ntal water
Acclaim C18 (150×2.1 mm, 4.6 μm)
B: 0.1% formic acid in Н2О, gradient
Extraction with ACN/citric acid buffer (pH 3) (1:1, v/v). SPE (Oasis HLB)
Zorbax eclipse plus C18 (100×2.1 mm, 1.8 μm)
A: 0.2% formic acid 155 and 2 mmol L-1 NH4Ac in Н2О B: ACN, gradient
5 veterinary drugs, including 3 SAs
SPE (Oasis HLB and MCX)
Shim-pack FC-ODS (75×3 mm, 3 μm)
A: 0.3% formic acid 156 and 0.1% NH4Ac in Н2О B: МеОН/ACN (50:50, v/v), gradient
11 veterinary Surface drugs, water, including 4 wastewater SAs
SPE (Oasis HLB)
Nucleodur C18 ISIS (125×2 mm, 3 μm)
A: 0.1% formic acid 157 in Н2О B: 0.1% formic acid in ACN, gradient
9 veterinary drugs, including 5 SAs
Extraction with МеОН/0.2 mol L-1 citric acid buffer (pH 4.7) (1:1, v/v). SPE (Oasis HLB and SAX)
Waters Symmetry C18 (150×2.1 mm, 5 μm)
A: 0.2% formic acid 158 in Н2О B: МеОН C: ACN, gradient
cr
us
an
M
Suspended solids of swine wastewater
d
Livestock wastewater
ip t
49 veterinary Wastewate drugs, r, sludge including 15 SAs
SPE (Strata-X)
Synergi Polar- A: 0.1% formic acid 160 RP (50×2 mm, in ACN 2.5 μm) B: 0.1% formic acid in Н2О, gradient
14 veterinary Soil drugs, including 7 SAs
Extraction with Н2О/ACN (1:1.5, v/v). SPE (SAX and StrataX)
Zorbax Eclipse A: 0.01% FAc in plus C18 Н2О (pH 3.3) (50×2.1 mm, B: МеОН, gradient 1.8 μm)
10 veterinary drugs, including 1 SA
Extraction with MeOH/ACN/0.1 mol L-1 EDTA/Mc Ilvaine buffer (pH 4), 30:20:25:25, v/v/v/v. SPE (Oasis HLB)
Xterra MS C18 (100×2.1 mm, 3.5 μm)
A: 0.3% formic acid 177 and 0.1% NH4F in Н2 О B: ACN/МеОН (1:1, v/v), gradient
PLE with water. SPE (SAX and Oasis HLB)
Sunfire C18 (150×4.6 mm, 3.5 μm)
A: 0.1% formic acid 180 in МеОН B: 0.1% formic acid in Н2О, gradient
Ac ce pt e
28 veterinary Surface drugs, water including 9 SAs
Broiler manure, soil, manure compost
17 veterinary Soils, drugs, sediments including 1 SA
172
Page 66 of 76
8 veterinary drugs, including 4 SAs
Biosolids
Luna C18 (150×4.6 mm, 5 μm)
A: 1% acetic acid in 182 Н2 О B: МеОН, gradient
MSPD (C18 and Florisil). Extraction with ACN/ 5% oxalic acid (6:4, v/v).
Synergy Fusion C18 (150×2 mm, 4 μm)
A: 0.1% formic acid 183 in Н2О B: 0.1% formic acid in ACN, gradient
ip t
12 veterinary Sediments drugs, including 4 SAs
PLE with МеОН/0.2 mol L-1 citric acid (pH 3) (50:50, v/v). SPE (Oasis HLB)
Sample preparation
us
Mightysil RP-18 A: ACN:1% (250×4.6 mm, 5 acetic acid (10:90, μm) v/v) B: ACN, gradient
C18 column (250×4.6 mm, 5 μm)
ACN:1% acetic acid (20:80, v/v)
Ac ce pt e
Poultry muscle, eggs
Extraction with acidic ACN
SPE on Nexus Abselut
Livers
Milk
MSPD with diatomaceous earth, silica gel or neutral alumina
Deproteinization with acidic ACN/water Polypropylene membrane protected micro-SPE on poly(methacrylic acidethylene glycol dimethacrylate)
Detection (LODs) DAD, 280 nm
23
(0.2 − 1.0 μg kg-1) UV, 270 nm
Chromolith Performance RP-18 (100×4.6 mm)
A: 0.05 mol L-1 acetate buffer (pH 3.4) B: MeOH, gradient
FL, 406 nm, 496 nm
Zorbax BonusRP (150×4.6 mm, 3.5 µm)
A: 2% acetic acid in Н2О B: ACN, gradient
FL, 401 nm, 495 nm
Belta ODS (150×3.9 mm, 5 μm)
Ref.
26 34
(0.1 − 0.5 μg L-1)
d
Pork, liver, chicken
Salting-out assisted extraction with ACN coupled with backextraction with water/ACN/dichlorom ethane SPE on magnetic molecular imprinted polymer
an
Swine muscle
Mobile phase
Analytical column
M
Matrix
cr
Table 6 Examples of HPLC–UV, HPLC–FL and HPLC–AD methods for the detection of SAs.
27
(2 − 17 μg kg-1) 30
(1.33 − 2.47 μg kg-1) MeOH : 1% acetic UV, acid (14:86, v:v) 260 nm
57
(0.38 − 0.62 μg L-1)
Page 67 of 76
Acidic deproteinization NovaPak C18 (150×3.9 mm, 5 Extraction with ethyl μm) acetate Centrifugation Restricted access media (RAM) octylbovine serum albumin column
Monolith-based stir bar Kromasil C18 sorptive extraction (250×4.6 mm, 5 μm)
DLLME and QuEChERS
C18 Ascentis™ (10cm×4.6cm, 3 μm)
A: 2% acetic acid in Н2О(pH 2.5) B: ACN, gradient
Centrifugation
Fish, shrimp
Extraction with 1% acetic acid in water. SPE on groupselective molecular imprinted polymer
Shrimp
Extraction with McIlvaine’s buffer. SPE on Oasis HLB cartridge
Honey
Sugaring-out assisted
AD, 1.25B
62
(15.0; 25.0 μg L-1) UV, 268 nm
64
(1.3 − 7.9 μg L-1) FL 405 nm, 495 nm
71
(0.6 − 2.7 μg L-1) UV, 268 nm
Venusil XBP C18 (250×4.6 mm, 5 μm)
А: acetic acid : Н2О (1:99, v/v) B: ACN, gradient
UV, 270 nm
Chromolith® Performance RP-18e (100×4.6 mm)
0.1M KH2PO4 (pH 3) : ACN:EtOH (80 : 15 : 5, v/v/v)
AD, 1.2B
Cosmosil 5C18AR-II (250×4.6
A: 2% acetic acid
FL, 405 nm,
Ac ce pt e
Restricted accessmolecular imprinted material
58
(–)
А: 0.1 mol L-1 phosphate buffer (pH 6.0)/МеОН (95:5, v/v) B: 0.1 mol L-1 phosphate buffer (pH 7.0)/ МеОН (83:17, v/v) C: 0.1 mol L-1 phosphate buffer (pH 8.0)/ МеОН (94:6, v/v)
Luna C18 (250×4.6 mm, 5 μm)
d
Milk
M
an
Milk
ACN:Н2О (35:75, v/v)
us
Milk
Luna octyl silica 0.05 mol L-1 (150×4.6 mm, KH2PO4 (pH 5) : 10 μm) ACN (82:18, v/v)
UV, 280 nm
ip t
Milk
А: NaAc (5mМ) B: ACN C: МеОН, gradient
cr
Milk
72
(0.8 μg L-1)
104
(8.4 − 10.9 μg kg-1) 105
(1.2 − 3.4 μg L-1) 114
Page 68 of 76
mm, 5 μm)
LLE
B: ACN, gradient
495 nm (0.6 − 0.9 μg kg-1)
Honey
Varian OmniSpher C18 (250×4.6 mm, 5 μm)
A: 25 mmol L-1 KH2PO4 in Н2О (pH 5) B: МеОН C: ACN, gradient
FL, 420 nm, 480 nm
C8 Inertsil (250×4.6 mm, 5 μm)
Ac ce pt e
d
Extraction with ACN. SPE on Oasis HLB, Bond Elut C18, Bond Elut Plexa, and Bond Elut Plexa PCX
Poultry feed
Feeds
Animal feeds
FL, 403 nm, 492 nm
A: 0.01 mol L-1 acetic acid in Н2О – NaAc buffer (pH 4.7) B: ACN, gradient
UV, 268nm
135
(5.0 − 18.0 μg L-1)
МеОН : Н2О : acetic acid (30:70:0.1, v/v/v)
UV, 270nm
Extraction with chloroform/acetone (50:50; v/v)
Luna C18 (250×4.6 mm, 5 μm)
А: 0.02 mol L-1 NH4Ac (pH 4.5) B: MeOH : ACN (50:50, v/v), gradient
DAD, 270 nm
LiChrospher 100 RP-18 (250×4 mm, 5 μm); Kinetex C18 (150×4.6 mm, 2.6 μm)
A: 0.01 mol L-1 formic acid − HCOONa (pH 3.4) B: ACN, gradient
FL, 405 nm, 485 nm
C18 column (70×4.6 mm, 5
МеОН : Н2О (55:45, v/v) (pH
DAD, 250 or 400
Environmental SPE on Bond Elutwater ENV, polystyrene-
129
(1.3 − 5.0 μg kg-1)
Shimadzu VPODS C18 (150×4.6 mm, 5 μm)
Extraction with AcEt/H2O (99:1, v/v)
117
(1.0 − 15.0 μg kg-1)
SPE on core-shell magnetic molecular imprinted polymers (Fe3O4@MIPs)
SPE on Strata SCX cartridge
115
(0.11 − 0.27 μg L-1)
ip t
A: 0.02 mol L-1 Ascentis RPAmide (250×4.6 NaAc (pH4.5) mm, 5 μm) B: ACN, gradient
Extraction with MeOH.
Animal feeds
UV, 260 nm
us
SPE on Oasis HLB, Strata-XL
МеОН:Н2О:NH4 Ac (15:75:1, v/v/v)
an
Honey
Belta ODS (150×3.9 mm, 5 μm)
cr
Salting-out LLE
M
Honey
142
(14.6 μg L-1 144
(390 − 640 μg kg-1) 145
(0.1 − 5.7 μg L-1) 161
Page 69 of 76
μm)
divinylbenzene
3.2)
nm (0.02 − 0.03 μg L-1)
Luna C18 (150×3.0 mm, 5 μm)
Environmental DSPE using magnetic water or non magnetic MWCNTs
Hypersil Gold A: 0.3% formic C18 (100×2.1 acid in Н2О mm and 1.9 μm) B: ACN, gradient
(3 μg L-1)
cr
us
DAD, 260 or 280 nm
Zorbax StableBond C18 (150×4.6 mm, 1.8 μm)
0.2% acetic acid:ACN (80:20, v/v)
DAD, 272 nm
Microwave-assisted extraction with nonionic surfactant Triton X-114
Zorbax SB C18 column (250×4.6 mm, 5 μm)
A: 1.0 % acetic acid in Н2О B: МеОН, gradient
UV, 270 nm
Extraction with acidic ACN.
Inertsil ODS-3 (250×4 mm, 5 μm)
A: 0.05 mol L-1 acetate buffer (pH 3.4) B: МеОН, gradient
FL, 406 nm, 496 nm
an
UV, 265 nm
d
SPE on Nexus Abselut
164
(0.008 − 0.032 μg L-1)
А: 0.1% formic acid in Н2О B: ACN, gradient
TC-C18 (150×4.6 mm, 5 μm)
Ac ce pt e
Biological fluids
163
UV, 269 nm
Environmental SPE on Oasis HLB water
Soil samples
AD, 1.2B
ACN : phosphate buffer solution (20 mmol L-1, pH 4.9) (25:75, v/v)
Environmental Ionic liquid-based water single-drop liquidphase microextraction
Inertsil ODS-4 (150×4.6 mm, 5 μm)
M
Environmental Magnetic SPE on water Fe3O4@SiO2/graphene
ACN : 2% acetic acid in Н2О (20:80, pH 3.2).
ip t
Environmental SPE on water hypercrosslinked polystyrene, Strata-X, Strata SDB-L, carbon nanomaterial Taunit or Diasorb-100C16T cartriges
166
(0.09 − 0.16 μg L-1) 168
(0.5 − 1.0 μg L-1) 159
(1 − 10 μg L-1) 179
(3.2 − 5.7 μg kg-1) 190
(0.1 − 0.3 μg L-1)
Page 70 of 76
LODs
Ref.
1.5 – 22.3 μg kg-1
54
cr
ip t
Table 7 Examples of immunoassays for the detection of SAs. Matrix Assay format Solid Immunogen and antibody support Edible Indirect 96-well 2-[[(4-aminophenyl)sulfonyl]animal competitive Maxisorp amino]-4-methyl)-5-pyrimidinetissues enzyme-linked microtitre carboxylic acid, 6-(4-aminoben(chicken) immunosorbent plates zensulfanylamino)pyridine-3assay (ELISA) carboxylic acid and (4-(4-aminobenzensulfonylamino)benzoic acid linked to bovine serum albumin (BSA); monoclonal antibodies (4E5) Fish Indirect Polystyrene Synthesized haptens against competitive 96-well sulfonamides and the ELISA microtiter commercial hapten N4plates phthalylsulfathiazole linked to BSA and OVA; peroxidaselabeled goat anti-rabbit immunoglobulins Honey Enzyme Costar N-sulfonyl-4-aminobutyric acid immunoassay 9018 linked to ovalbumin (OVA); (EIA) microplate rabbit polyclonal antibodies Feed ELISA Nunc 5-[4-aminophenylsulfonamide]Maxisorp 5-oxopentanoic acid linked to Microtiter OVA; female white New polystyrene Zealand rabbits antibodies plates Milk ELISA According to the RIDASCREEN ELISA test kits for sulfonamide (R3004) and sulfamethazine (R3001) Chicken Generic ELISA Polystyrene 6-(4-aminophenylsulfonamido)muscle microplate hexanoic acid, 4-(4-(4-aminophenylsulfonamido)phenylsulfonamido)benzoic acid and 4-(4(4-aminophenylsulfonamido)phenyl)butanoic acid linked to BSA; New Zealand white rabbits polyclonal antibodies Milk Hybrid The opaque Hapten-OVA conjugates; antiimmunosorbent white sulfonamide and anti-quinolone assay polystyrene broad-specificity monoclonal (fluorescence- microtiter antibodies linked plates and immunosorbent ELISA assay (FLISA) microtiter and ELISA) plates Milk DualMicrotiter 4-(4-(4-aminophenylsulfon-
106
0.05 μg L-1
122
40 –200 μg kg-1
141
3.5 – 10 μg L-1
196
~ 0.1 μg L-
198
Ac ce pt e
d
M
an
us
0.6 – 1 μg L-1
1
0.17 μg L-1
199
5.8 μg L-1
200
Page 71 of 76
Nitrocellul ose membrane (vivid 170)
Milk
4-aminobenzoic acid film grafted on a disposable electrode
201
0.12 – 8.41 μg L-1
202
Ac ce pt e
d
M
an
Integrated amperometric immunosensor based on direct competitive immunoassay
0.10 – 2.13 μg L-1
cr
Milk and Lateral flow Swine immunoassay Urine (LFA)
amido)phenyl)butanoic acid linked to BSA; monoclonal and polyclonal antibodies Hapten conjugate N1-[4(carboxymethyl)-2-thiazolyl] sulfanilamide linked to OVA; goat anti-rabbit antibody conjugated to colloidal gold particles Horseshoe crab hemocyanin linked to 5-(6-(4-aminophenylsulfonyl)pyridine-3-yl)-2methylpentanoic acid; female white New Zealand rabbits polyclonal antibody
ip t
plates
us
colorimetric ELISA
Page 72 of 76
O
O H2N
S
NH
NH2
H2N
S
NH2
O
S
N
O
Sulfadiazine (SDZ)
Sulfathiazole (STZ)
O
NH2 N
O S
NH2
N
H3C
O
CH3
H3C
N
NH O
S
Sulfamethazine (SMZ)
NH
NH
O
O
H3C
NH2
Sulfadoxine (SDO) NH2
S
NH2 N
O
Cl O
N
N
OH
N
S NH
d
O
Ac ce pt e
O
Sulfadimethoxine (SDM)
S N
OH
Sulfasalazine (SSZ)
H3C
H3C
O
N
O
M
O
N
O
N
N
Sulfamethoxypyridazine (SMP)
H3C
NH S
an
N
O O
H3C
S N
O
NH2
O H3C
NH
O
Sulfachlorpyridazine (SCP)
N
NH2
H2N
O O
N
H3C
S
NH
NH2
S NH
O
O
Sulfisoxazole (SSA)
O
NH
S O
O
Sulfamethoxazole (SMX) N
NH
CH3
O
O
O
NH2
O
O
O
S
Sulfamethizole (SMT)
us
NH2 N
NH
NH
Sulfamerazine (SMR)
CH3
O
cr
Sulfapyridine (SPY)
N S
O
N
N
H3C
ip t
NH S
N
NH
O
Sulfanilamide (SAM)
S
O
N
Sulfacetamide (SAA) CH3
CH3 NH2
S
O O NH
N
O
S
O
N
N NH2
Sulfaquinoxaline (SQX)
S H3C
N
NH
S
N
O
O
Sulfadimidine (SDD)
NH2
Sulfametrole (SML)
Fig. 1. Structures of the most commonly used sulfonamides.
Page 73 of 76
N
% 14
3000
12
2500
10 2000
8 6 1000
4
cr
500
2 0
us
20 11
Year
an
20 09
20 07
20 05
20 03
20 01
19 99
19 97
19 95
0 19 93
ip t
1500
Ac ce pt e
d
M
Fig. 2. The annual production of publications with titles, abstracts or keywords containing the term “sulfonamide” (■ histogram) and the percentage of these articles containing the term “sulfonamide” in the title (-♦- line).The data were derived from Scopus (on December 2013).
Page 74 of 76
Other 19%
Milk 23%
cr
ip t
Eggs 8%
us
Honey 10% Fish 11%
Meat 16%
d
M
an
Chicken 13%
Ac ce pt e
Fig. 3. Types of food samples that have usually been analysed for sulfonamides over the past 5 years.The data were derived from Scopus (on December 2013).
Page 75 of 76
Biosensors 3%
Fluorimetry 3%
ip t
Spectrophotometry, Colorimetry 9%
HPLC-MS(/MS) 38%
us
cr
Immunoassays 10%
an
Electrophoresis 15%
Ac ce pt e
d
M
HPLC-other 22%
Fig. 4. Analytical methods that have usually been applied to the detection of sulfonamides over the past 5 years.The data were derived from Scopus (on December 2013).
Page 76 of 76
