# Magnetic Solid Phase Extraction Applied to Food Analysis

Authors: Israel S. Ibarra; Jose A. Rodriguez; Carlos A. Galán-Vidal; Alberto Cepeda; Jose M. Miranda
Journal: Journal of Chemistry
 (2015)

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## Abstract

Magnetic solid phase extraction has been used as pretreatment technique for the analysis of several compounds because of its advantages when it is compared with classic methods. This methodology is based on the use of magnetic solids as adsorbents for preconcentration of different analytes from complex matrices. Magnetic solid phase extraction minimizes the use of additional steps such as precipitation, centrifugation, and filtration which decreases the manipulation of the sample. In this review, we describe the main procedures used for synthesis, characterization, and application of this pretreatment technique which were applied in food analysis.


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## Body

## 1. Introduction

Analysis of residues of organic compounds in food matrices usually results in a difficult process. The analytical procedure consists of the following main steps: sampling, sample conservation, storage, sample pretreatment, and analysis. The critical stage during food analysis is the sample pretreatment, which can promote loss of analytes or contamination of sample. A successful extraction depends on the complexity of the analytical matrix and the concentration of the analytes in the sample.In food samples, the presence of carbohydrates, proteins, and other additives makes the analysis of residues during extraction and clean-up of the samples difficult. Several methods have been developed in the search of new techniques in the pretreatment in food samples such as QuEChERS [1–4], supercritical fluid extraction (SFE) [5], pressurized fluid extraction (PFE) [6], microwave-assisted extraction (MAE) [7, 8], matrix solid-phase dispersion (MSPD) [9–11], solid-phase extraction (SPE) [12–18], and solid-phase microextraction (SPME) [19, 20]. All these separation techniques have been applied to preparation of different food samples (e.g., fruits, juices, vegetables, milk, grain, and meat). Most of these procedures are expensive and sometimes labor-intensive due to the complexity of the analytical matrix and usually involve sample homogenization with the use of different solvents.Magnetic solid phase extraction (MSPE) is a technique that has received considerable attention in the analysis of residues in food samples. MSPE is based on the extraction of different compound from the sample using solids with magnetic properties. This technique can be visualized as a magnetic separation commonly used to separate magnetic phases from nonmagnetic phases [21]. The simplicity of this technique influences the development and application of separation techniques involving the use of magnetic fields.This technique consists in the synthesis of particles with magnetic properties (generally magnetite Fe3O4) followed by a coating of the magnetic phase with diverse organic compounds. The modified solids are applied as adsorbents during isolation, separation, and preconcentration of the analytes [22–24]. The MSPE is based on the dispersion of a magnetic adsorbent in solution. The magnetic adsorbents with the analytes adsorbed on the surface can be isolated and eluted with the addition of appropriate solvents. The procedure does not need additional steps such as centrifugation, precipitation, or filtration of the sample.MSPE technique has been employed for these recognized benefits, such as simplicity, efficiency, cost, and high selectivity. This technique employs the application of external magnetic field in the isolation of the magnetic particles in the separation and analysis of different types of compounds with the main objective of separate analytes of large volume without additional steps that could cause loss of analyte [25–27], since its discovery has received considerable attention in the development of several applications in the separation of diverse analytes.The synthesis by coprecipitation is the method which is more applied to the synthesis of the magnetic phase. Magnetic solids can be coated with antibodies, specific receptors, encapsulating of magnetic particles with biological agents, polymers, and silica modified with different functional groups [28–30]. Additional effects of their physical and chemical characteristics must be taken into account during the design of MSPE based methodology.In the food area MSPE has been applied to isolation and selective preconcentration of proteins [31], metal ions [32–38], and organic compounds such as antibiotics, pesticides, dyes, phenolic compounds, and promoters growing that are present in several foodstuff samples [25, 39–44].A variety of analytical techniques has been applied in the determination of different types of residues in food samples using the combination of MSPE with capillary electrophoresis [25–27], gas chromatography [45–47], high performance liquid chromatography/mass spectrometry (HPLC/MS) [48–55], atomic absorption spectrometry (AAS), inductively coupled plasma optical emission spectrometry (ICP-OES) [36–38], high performance liquid chromatography (HPLC) [48, 56–64], and spectrofluorimetry [65].


## 2. Background and History

MSPE was introduced in 1999 by Šafaříková and Šafařík. It was considered as a new procedure for the preconcentration of target analytes from large volumes based on the use of magnetic adsorbents. Initially, the MSPE was employed in experiments with copper phthalocyanine dye attached to silanized magnetite and magnetic charcoal as adsorbents in the separation of safranin O and crystal violet, with an enrichment of up to 460-fold [22].The MSPE procedure is shown in Figure1. Initially the magnetic adsorbent is conditioned with organic solvent in an ultrasonic bath (Figure 1(a)). Then, the adsorbent is magnetically isolated and washed, and the supernatant is discarded (Figure 1(b)). Consequently, an adequate aliquot is taken of sample solution and is mixed with the preactivated magnetic adsorbent under sonication for a few minutes (Figure 1(c)); subsequently an external magnetic field is applied to isolate the adsorbent with the adsorbed analytes on the surface of the magnetic particles (Figure 1(d)). The liquid phase is decanted, and the solid phase is washed with buffer solution and water (Figure 1(e)). The analytes are eluted by dispersion of the adsorbent with organic solvent. After the elution the solution is evaporated to dryness, and the residue is reconstituted with low volumes of solvent. Finally, the solution is filtered and analyzed by different techniques (Figure 1(f)) [66, 67].Figure 1
Schematic procedure for the isolation of several analytes from food samples using MSPE: (a) conditioning of magnetic adsorbent, (b) magnetic isolation, wash, and decantation, (c) extraction of the analytes, (d) magnetic isolation of the adsorbent with the adsorbed analytes, (e) decantation and wash of the magnetic adsorbent, and (f) elution of the analytes (liquid solid extraction).A relevant aspect of magnetic adsorbents is their synthesis, due to their composition, compatibility, and suitability for several applications which depends on the characteristics of the solid phase.The advantages of the MSPE technique have promoted its application for analysis of water samples as it has been reviewed recently by Ambashta and Sillanpää [68]. The compounds analyzed include pesticides, phenolic compounds, herbicides, dyes, and heavy metals. Regarding the application of this sample preparation technique during the analysis of complex matrices such as food samples there is less information because of the high interactions between the sample components (proteins, carbohydrates, and lipids) and the analytes.


## 3. Magnetic Adsorbents: Synthesis and Characterization

In recent years, the synthesis of magnetic adsorbents in MSPE has received considerable attention by its several applications in biology, biochemistry, and analytical and environmental chemistry. Recently, MSPE has been applied to food area during control and analysis of residues of organic compounds in food samples. The problems caused by the presence of these residues in human health have promoted the synthesis of new magnetic adsorbents for MSPE as preconcentration method in the analytical cycle [69–72].The synthesis of the adsorbents and the application in MSPE consist in that adsorbent acquired magnetic properties which in most of cases are through incorporation of magnetite (Fe3O4) [21]. The synthesis is most used in the preparation of magnetic adsorbents according to the literature; authors employ the synthesis based on the coprecipitation of iron ions in alkaline media forming a dark precipitate, which consists of magnetite.Once the magnetite is synthesized, it is covered with diverse materials such as silica, alumina, metal oxides, and organic polymers/nonpolymers, and then they are applied as sorbents to MSPE. The most applied coating consisted in silica modified, and the phase was obtained via sol-gel process in which once the magnetite is obtained this is coated with silica obtained by the reaction of an alkoxy silane in alkaline solution. This method provides the controlled growth of the particles with spherical morphology and obtains uniform size [73–75].The preconcentration and isolation process by MSPE depend on functional group. This process ensures the interaction with the analyte and the functional group on the surface of the magnetic adsorbent. These interactions involve ionic, dipole-dipole, dipole-induced dipole, hydrogen bonding, and dispersion forces. Some authors reported that hydrophobic and Van der Waals interactions are presented in reversed phase systems while hydrogen bonding, dipole-dipole, andπ-π interactions exist in normal-phase separations. These interactions are related to the functional group employed for coating the magnetic particles. The functional groups mainly employed in MSPE in the silica phase are amine, thiol, carboxylic acid, alkyl, and aryl [25, 26, 46, 53, 56, 71].The selection of the adsorbent is a critical parameter to obtain the best results in the preconcentration processes. Additionally, some factors must be taken into account, for example, the polarity of the analytes, the nature, and the complexity of the analytical matrix. Figure2 shows a representation of possible functional compounds used to promote different interactions.Figure 2
Magnetic nanoparticles of silica-coated Fe3O4 modified with different functional groups and their processes of interaction.The characterization of magnetic adsorbents is a fundamental part that contributed to establishing a relation between the adsorption capacities and their morphology through their physical and specific characteristics of each magnetic adsorbent, uniformity, specific surface area, functionality, pore volume, and pore size.The techniques employed in characterization of magnetic adsorbents are transmission electron microscopy (TEM), scanning electron microscopy (SEM), and powder X-ray diffraction (XRD) [23]. TEM is based on detecting differences in electron density and allows observation of the size and shape of the magnetic particles, while SEM is used for the characterization of the morphology of the magnetic adsorbent [71]. Other techniques in the characterization of these particles are realized by Brunauer-Emmett-Teller (BET); this technique allows determining the surface area through the adsorption of N2 and morphology of porous of the adsorbent [20, 35, 65]. The use of X-ray diffraction (XRD) is basic to verify the presence of magnetite or other iron phases present in the adsorbent. Another important factor is the amount of iron present, which is usually measured by atomic absorption spectroscopy (AAS) or inductively coupled plasma (ICP) spectrometry [75].


## 4. Application of Magnetic Particles in Food Samples

In recent years, the food area has seen the need to provide food for human consumption of high quality in order to protect the health of consumers. In particular it is important to mention the negative effects due to the presence of residues of several compounds in food samples. International organizations have established maximum residue limits (MRLs) in different food matrices. The European Commission (EC) and the Food and Drug Administration (FDA) have been integrated to ensure the safety of animal and plant foods for human consumption [71, 72].Several research groups have proposed the use of different MSPE procedures in order to achieve the MRLs established. The high concentration ratio offered by MSPE techniques is a consequence of the large sample volumes during extraction and low volumes for elution. This characteristic in combination with their simplicity, adaptability, and easy handling has been attractive for many areas.The analysis of residues in food samples involves many inorganic and organic species; these come from several sources such as irrigation water, packing additives, use of pesticides, and antibiotics. The importance of the analysis of residues is related to the problems that they can cause on human health, such as development of anti-microbial resistance, allergies, gastrointestinal disorders, and in some cases the development of diseases carcinogen. The compounds commonly analyzed include growth promoters (hormones), antibiotics, dyes, metal ions, pesticides, and water. In the tables, the application of MSPE in different groups was proposed according to the food matrix used. Tables1 and 2 show the application of MSPE in food of animal origin and derivatives. The analysis of vegetal samples is presented in Tables 3 and 4. Other food samples (soft drinks, tea leave, and coffee) are collected in Tables 5 and 6.Table 1
Experimental MSPE conditions used for analysis of milk samples.
Analyte
Amount of liquid sample
Magnetic material coating
Eluent volume
Eluent
Technique
Limit of detection
Recovery
References
Sulfonamides(a)
10.0 mL
Fe3O4/silica/poly(methacrylic acid-co-ethylene glycol dimethacrylate)
1.0 mL
Acetone with 5% ammonia (v/v)
LC-MS/MS
0.5–49.5 ng/L
87.6–115.6%
[50]
Fluoroquinolones(a)
2.0 mL
Fe3O4-ethylene glycol, ethylene diamine, ammonium acetate
1.0 mL
MeOH (7.0% ammonium)
HPLC-UV
1.8–3.2 ng/g
94.0–124.4%
[56]
Estrogens(b)
10.0 mL
MMIP(Fe3O4@SiO2)-ethylene glycol dimethacrylate
7.0 mL
Acetic acid/methanol (0.5 mol/L)
HPLC-UV
1.5–5.5 ng/g
77.3–95.2%
[55]
Endocrine disruptors(b)
3.0 mL
Fe3O4@SiO2@C18
2.3 mL
n-Hexane
GC-MS
0.1–0.3µg/L
81.0–107.0%
[45]
Melamine(c)
20.0 mL
MMIP melamine-methacrylic acid-ethylene glycol dimethacrylate-Fe3O4
0.5 mL × 6
Methanol-acetic acid
LC-MS/MS
2.6 ng/mL
88.0–95.8%
[51]
Aflatoxin M1(d)
10.0 mL
Hydrophobic oleic acidmodified Fe3O4 nanoparticles
3.0 mL
Acetonitrile
Spectrofluorimetry
13.0 ng/L
91.3–99.5%
[65]
Lead(e)
100.0 mL
CaFe2O4-3-aminopropyl-triethoxysilane-phthalic anhydride
3.0 mL
Nitric acid 1.0 mol/L
AAS
0.78µg/L
98.2%
[33]
Lead and cadmium(e)
50.0 mL
1-(2-Pyridylazo)-2-naphthol-modified Fe3O4/TiO2
1.0 mL
Nitric acid 1.59 mol/L
AAS
1.21 mg/L Pb(II)0.21 mg/L Cd(II)
96.9–101.6% Pb(II)96.5–100.7% Cd(II)
[36]
(a)Antibiotics, (b)hormones, (c)packing additives, (d)mycotoxins, and (e)Metal ions.
MMIP: magnetic molecularly imprinted polymer.Table 2
Experimental MSPE conditions used for analysis of tissue samples.
Analyte
Amount of liquid sample
Magnetic material coating
Eluent volume
Eluent
Technique
Limit of detection
Recovery
References
Sulfonamides(a)
5.0 mL
Fe3O4@SiO2-(methacrylic acid-ethylene glycol dimethacrylate-azobisisobutyronitrile and sulfamethazine)
—
Methanol-acetic acid(9 : 1, v/v)
HPLC
2 mg/kg
63.3–76.5% (duck)68.7–74.7% (chicken)
[64]
Tetracyclines(a)
20.0 mL
MMIP-Fe3O4-oxytetracycline
3.0 mL × 3
Methanol-0.5% acetic acid
HPLC-MS/MS
Less than 0.2 ng/g
72.8–96.5%
[53]
Benzimidazole(a)
10.0 mL
Magnetite/silica/poly(methacrylic acid-co-ethyleneglycol dimethacrylate)
1.0 mL
Acetonitrile-trifluoroacetic acid(100 : 0.5, v/v)
CZE
1.05–10.42 ng/g (muscle)1.06–12.61 ng/g (liver)
81.1–105.4%
[27]
Polycyclic aromaticshydrocarbons(b) (grilled meat samples)
≈15.0 mL
Multiwalled carbon nanotubes-magnetic nanoparticles
5.0 mL
Dichloromethane
GC-MS
0.035–0.100µg/Kg
81.3–96.7%
[49]
Lead(c)
15.0 mL
Lead imprinted polymer-vinyl-diphenylcarbazide@SiO2@Fe3O4@ ethylene glycol dimethylacrylate and azobisisobutyronitrile
2.0 mL
Hydrochloric acid 3 mol/L
AAS
1.3µg/L
95.0–115.0%
[34]
Zinc(c) (red meat)
300.0 mL
Zinc imprinted polymer-2-vinylpyridine-ethylene glycol dimethacrylate-Fe3O4
14.0 mL
Hydrochloric acid (12% v/v)
AAS
0.15 mg/L
95.0–99.0%
[38]
(a)Antibiotics, (b)aromatic compounds, and (c)Metal ions.
MMIP: magnetic molecularly imprinted polymer.Table 3
Experimental MSPE conditions used for analysis of fruits or vegetables samples.
Analyte
Amount of liquid sample
Magnetic material coating
Eluent volume
Eluent
Technique
Limit of detection
Recovery
References
Endogenous cytokinins(a) (plants)
10.0 mL
2-Acrylamido-2-methyl-1-propanesulfonic acid-co-ethylene glycol dimethacrylate(Fe3O4/SiO2/P(AMPS-co-EGDMA))
3.0 mL
Acetone with 5% ammonia (v/v)
HILIC-MS/MS
0.18–3.65 pg/mL
72.8–115.5%
[66]
Pesticide(b) (fruits and vegetables)
1.0 mL
(QuEChERS)-Fe3O4
—
—
GC-MS/MS
0.03–2.17µg/kg
71.5–111.7%
[47]
Linuron(b) (apple, lettuce)
40.0 mL
Fe3O4@SiO2@ionic liquids
4.0 mL
Ethanol
UV-Vis
0.04–20.00µg/mL
95–98.5%
[67]
Pyrethroid(b)
10.0 mL
Fe3O4@SiO2@C18
2.0 mL
Acetone
UF-HPLC
0.63–1.2 ng/g
76.0–99.5%
[62]
Lead(c) (tomato paste, parsley)
100.0 mL
CaFe2O4-3-aminopropyl-triethoxysilane-phthalic anhydride
3.0 mL
Nitric acid 1.0 mol/L
AAS
0.78µg/L
99.7% (tomato)91.3% (parsley)
[33]
Zinc(c) (parsley, basil)
300.0 mL
Zinc imprinted polymer-2-vinylpyridine-ethylene glycol dimethacrylate
14.0 mL
Hydrochloric acid (12% v/v)
AAS
0.15 mg/L
95–99%
[38]
(a)Hormones, (b)pesticides, and (c)Metal ions.Table 4
Experimental MSPE conditions used for analysis of cereal samples.
Analyte
Amount of liquid sample
Magnetic material coating
Eluent volume
Eluent
Technique
Limit of detection
Recovery
References
Ochratoxin A(a) (cereals products)
850.0µL
Aptamer for ochratoxin, immobilized onto magnetic nanospheres
2.5 mL
95% acetonitrile (1% acetic acid)
LC-Fl
0.3µg/kg
67.20–87.80%
[57]
Ochratoxin A(a) (rice, wheat, and corn)
50.0 mL
Fe3O4-3-(trimethoxysilyl)-1-propanethiol and modified by ethylene glycol bismercaptoacetate
2.0 mL
Thiourea
HPLC-FLD
0.03–2.6 ng/mL
84.0–96.0%
[59]
Copper(b) (rice)
≈32.0 mL
Fe3O4@Sio2@ poly(allylaminehydrochloride)-poly(ethylene-alt-maleic anhydride)
2.0 mL
Hydrochloric acid(1.0 mol/L)
AAS
0.23 ng/mL
94.4–114.1%
[35]
Silver, cadmium, copper, mercury, and lead(b)
100.0 mL
Ethylene glycolbismercaptoacetate modified 3-(trimethoxysilyl)-1-propanethiol@Fe3O4 nanoparticles
1.0 mL
Hydrochloric acid1 mol/L (5% thiourea)
ICP-OES, AAS
0.01–0.09 ng/mL
95.4–99.8%
[37]
Zinc(b)
50.0 mL
Zinc imprinted polymer-2-vinylpyridine-ethylene glycol dimethacrylate
14.0 mL
Hydrochloric acid (12% v/v)
AAS
0.15 mg/L
95.0–99.0%
[38]
(a)Mycotoxin and (b)Metal ions.Table 5
Experimental MSPE conditions used for analysis of drink samples.
Analyte
Amount of liquid sample
Magnetic material coating
Eluent volume
Eluent
Technique
Limit of detection
Recovery
References
Bisphenol A(a) (soft drinks)
3.0 mL
Tetradecanoate-coated magnetic nanoparticles
2.0 mL
Methanol
LC/MS/MS
7 ng/L
91–105%
[52]
Additives(a) (wine)
10.0 mL
Tetraethylenepentamine functionalizedFe3O4 magnetic polymer
HPLC
0.06–0.15 mg/L
80.1–97.1%
[58]
Ochratoxin A(b) (coffee)
850µL
Aptamer for ochratoxin, immobilized onto magnetic nanospheres
2.5 mL
95% acetonitrile (1% acetic acid)
LC-Fl
0.5µg/kg
68.8–81.0%
[59]
Phenolic acids(c) (fruit juice)
5.0 mL
Fe3O4@ magnesium-aluminum layered double hydroxide
75.0µL
Trifluoroacetic acid (8% v/v)
HPLC-UV-Vis
0.44–1.3µg/L
81.2–109%
[61]
Dicofol(d) (tea)
10.0 mL
Fe3O4-molecularly imprinted microspheres(mag-MIMs) chlorodiphenyltrichloroethane
4.0 mL
15% acetic acidDichloromethane
GC-ECD
0.05 ng/g
83.6–94.5%
[46]
Pyrethroids(d) (tea drinks)
150.0 mL
Polyaniline coated magnetic particles (Fe3O4/C/PANI microbowls)
3.0 mL
Methanol
UFLC-UV
0.025–0.032 ng/mL
72.1–118.4%
[60]
Organophosphorus pesticides(d) (tea drinks)
25.0 mL
Poly(ionic liquid) vinyltriethoxysilane-modified Fe3O4@SiO2
2.0 mL
Methanol
HPLC
0.01µg/L
81.4–112.6%
[47]
Synthetic pigments(e)
1.0 mL
Amino-functionalized low degrees of cross-linking magnetic polymer
—
—
UFLC-MS/MS
—
82.8–116.2%.
[48]
Silver, cadmium, copper, mercury, and lead(f) (tea leaves)
100.0 mL
Ethylene glycolbismercaptoacetate modified 3-(trimethoxysilyl)-1-propanethiolcoated Fe3O4 nanoparticles
1.0 mL
Hydrochloric acid1 mol/L (5% thiourea)
ICP-OES and AAS
0.01–0.09 ng/mL
95.4–99.8%
[37]
(a)Packing additives, (b)mycotoxin, (c)aromatic compounds, (d)pesticides, (e)dyes, and (f)Metal ions.Table 6
Experimental MSPE conditions used for analysis of food and water samples.
Analyte
Amount of liquid sample
Magnetic material coating
Eluent volume
Eluent
Technique
Limit of detection
Recovery
References
Chloramphenicol(a) (honey)
20.0 mL
MMIP(Fe3O4@SiO2)-chloramphenicol-oleic acid-ethylene glycol dimethacrylate
1.0 mL × 3
Methanol-1.0% acetic acid
LC-MS/MS
0.047 ng/g
84.3–90.9%
[54]
Fluoroquinolones(a) (honey)
10.0 mL
Fe3O4-one-dimensional polyaniline
1.0 mL
Acetone-1.0% formic acid
HPLC-FLD
0.4–1.4 ng/g
86.3–121.3%
[56]
Tetracycline(a) (eggs)
20.0 mL
MMIP-Fe3O4-oxytetracycline-methacrylic acid-styrene and divinylbenzene
3.0 mL × 3
Methanol-0.5% acetic acid
LC-MS/MS
Less than 0.2 ng/g
72.8–96.5%
[53]
Malachite green(b) (water and fish tissues)
100.0 mL
Melamine supported magnetic iron oxide nanoparticles (Fe3O4@Mel)
2.0 mL
Acetic acid 4 mol/L
UV-Vis
0.05 mg/mL
90.05–107.8% (water)87.5–103.7% (fish)
[43]
Malachite green(b) (fish tissues)
5.0 mL
MMIP(Fe3O4@SiO2)-ethylene glycol dimethacrylate
1.0 mL
Methanol/acetic acid (9 : 1,v/v)
Electrochemiluminescence(ECL)
7.3 ng/kg
77.1–101.2%
[42]
Lead(c) (water and fish)
100.0 mL
CaFe2O4-3-aminopropyltriethoxysilane-phthalic anhydride
3.0 mL
Nitric acid1.0 mol/L
AAS
0.78µg/L
100.0% (water)94.5% (fish)
[33]
Mercury(c) (fish)
100.0 mL
Mercury(II) imprinted polymer-N-(pyridin-2-ylmethyl)ethenamine (V-Pic)-Fe3O4
5.0 mL
Hydrochloric acid/EDTA 0.1 mol/L
ICP-OES
0.03 ng/mL
98.2–103.0%
[32]
Silver, cadmium, copper, mercury, and lead(c) (tune fish)
50.0 mL
Ethylene glycolbismercaptoacetate modified 3-(trimethoxysilyl)-1-propanethiol@Fe3O4 nanoparticles
1.0 mL
Hydrochloric acid1 mol/L (5% thiourea)
ICP-OES and AAS
0.01–0.09 ng/mL
95.4–99.8%
[37]
(a)Antibiotics, (b)dyes, and (c)Metal ions.
MMIP: magnetic molecularly imprinted polymer.


## 5. Conclusions

The MSPE technique based on the synthesized magnetic adsorbent (Fe3O4-SiO2-modified) has been shown to be an efficient strategy for the rapid preconcentration of residues in complex matrices (food samples). The methodology described is faster than classical preparation procedures, with a minimum sample manipulation, lower solvent consumption, and consequently lower cost. Additionally, this technique provides good results in terms of sensitivity and accuracy. When it is coupled with several analysis techniques, the MSPE method allows obtaining LODs according to the MRLs established by health instances.



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