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Trends in Analytical Chemistry, Vol. 43, 2013

Advances in solventmicroextraction techniques

John M. Kokosa
Since its inception in 1995, solvent-microextraction (SME) techniques for sample preparation have grown increasingly popular due to their simplicity, low cost, and adaptability to a wide variety of sample types and analytes. SME methods are used alone or as nal clean-up and concentration techniques in preparing environmental, clinical, forensic, personal-care, pharmaceutical and food-product samples. There are two broad categories of SME: exposed-solvent and membrane-protected solvent techniques. The principal exposeddrop techniques include single-drop microextraction (SDME), headspace single-drop microextraction (HS-SDME), liquid-liquid microextraction (LLME), liquid-liquid-liquid microextraction (LLLME) and dispersive liquid-liquid microextraction (DLLME). The principal membrane-protected modes are hollow-ber-protected 2-phase microextraction [HF(2)ME] and hollow-ber-protected 3-phase microextraction [HF(3)ME]. In recent years, interest in SME has increasingly turned to renements of these modes for use in practical sample preparations. This has involved innovations (e.g., ionic liquids, ultrasonic-assisted emulsication, automation, and low-density solvents for DLLME). In this review, we explore these and other SME innovations appearing in the literature in the period from mid-2010 to mid2012. 2012 Published by Elsevier Ltd.
Keywords: Dispersive liquid-liquid microextraction (DLLME); Exposed solvent; Headspace single-drop microextraction (HS-SDME); Hollow-fiberprotected 2-phase microextraction [HF(2)ME]; Hollow fiber-protected 3-phase microextraction [HF(3)ME]; Liquid-liquid-liquid microextraction (LLLME); Liquid-liquid microextraction (LLME); Membrane-protected solvent; Single-drop microextraction (SDME); Solvent microextraction (SME)

1. Introduction
John M. Kokosa* MDRC Consulting, Mott Community College, Flint, MI 48503, USA

Tel.: +1 (810) 222 8082; Fax: +1 (810) 762 0466; E-mail: jmkokosa@yahoo.com

A practical denition of solvent microextraction (SME) is a technique of sample preparation by extraction and concentration of liquid, gaseous and solid samples with solvent volumes of 100 lL or less. SME is used for the extraction, purication and concentration of volatile, non-volatile, polar, non-polar, ionic and metallic analytes from environmental, forensic, clinical and agricultural samples. SME can be used alone or as a nal clean-up technique as part of a general sample-preparation method with other techniques [e.g., solidphase extraction (SPE) or dispersive solidphase extraction (d-SPE)]. SME should always be considered as complimentary, rather than exclusive of other sample-preparation techniques. There are many variations of SME, though they all fall into two rather broad categories: exposed solvent and membrane-protected solvent. The term liquid-phase microextraction (LPME) is also frequently

used to describe this process and, while just as an appropriate descriptive term as SME, LPME is associated by many with the membrane-protective modes of SME, rather than as a general term. A rather frustrating fact of academic research is that each experimentalist tends to vary a general method and then apply a new name, along with a new acronym, to their new variation. Thus, SME literature contains a confusing array of more than 100 acronyms and more keep appearing each year. This makes it difcult to search literature, to say the least. A listing of the more important variations of SME is available [1], and additional acronyms are dened in references [216]. I avoid the term LPME in this review, except in general terms, and, where possible, I prefer the terminology used in three references [1,6,7]. As an additional aid, Table 1 contains a list of the most commonly used basic SME acronyms, which are found in this review. The history, the advantages and the deciencies of SME are well documented

0165-9936/$ - see front matter 2012 Published by Elsevier Ltd. doi:http://dx.doi.org/10.1016/j.trac.2012.09.020

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Table 1. Definitions of common solvent microextraction (SME) acronyms used in this review Acronym SME LPME SDME HS-SDME LLME/DSDME LLLME DLLME HFME HF(2)ME HF(3)ME EME UAE Denition Solvent microextraction Liquid-phase microextraction Single-drop microextraction Headspace-single-drop microextraction Liquid-liquid microextraction/directly suspended droplet microextraction Liquid-liquid-liquid microextraction Dispersive liquid-liquid microextraction Hollow-ber-protected microextraction Hollow-ber-protected 2-phase microextraction Hollow-ber-protected 3-phase microextraction Electromembrane extraction Ultrasound-assisted extraction

Table 2. General solvent microextraction (SME) reviews and references Ref. SME theory and practice text Review of sample-preparation techniques Review of new approaches using SME for pollutants Review of SME in food analysis Review of SME for trace metals Review of exposed solvent SME Review of single-drop SME Review of DLLME Review of DLLME using low density solvents Paper on kinetic theory of HFME and EME Review on ionic liquids for metals determination Paper on environmental impact of ionic liquids Review on derivatization reactions for SME Review on chemometric optimization of SME Paper on automation of SDME Paper on automation of HFME Modes/Subjects All modes/applications/experimental procedures All modes All modes All modes All modes SDME/HS-SDME/LLME/LLLME/DLLME/theory SDME/HS-SDME/LLME/LLLME DLLME DLLME HFME/EME theory SDME/DLLME/HFME Ionic liquids toxicity Derivatization/ion-pair/complexes/phase transfer Designs/model adequacy/applications SDME/HS-SDME HFME Ref. [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16]

and are not detailed here. Since its inception in 1995, well over 1000 research and application papers have appeared in the eld, with more than 100 now being added each year. There have also been more than three dozen excellent review papers and an extensive book published covering the subject in the last dozen years. With the goal in mind to cover recent advances in SME techniques, I present in Table 2 a selection of 16 of the most pertinent review references. While this list omits many important reviews and general resource papers, the reader who is currently using or plans to use SME is encouraged to start with these references and then branch off into specic SME modes, as needed. This review focuses on recent developments and trends in SME over the two-year period mid-2010 to mid-2012. During this period, more than 200 papers devoted to SME appeared. Given the restrictions of this review, most of these papers cannot be discussed, so I cover only a few illustrative papers on important trends and innovations. As discussed above, SME techniques fall into two broad categories: exposed solvent and membrane-pro-

tected solvent. The exposed-solvent techniques include single-drop microextraction (SDME), headspace singledrop microextraction (HS-SDME), liquid-liquid microextraction (LLME, also referred to as directly-suspended droplet microextraction, DSDME), liquid-liquid-liquid microextraction (LLLME) and dispersive liquid-liquid microextraction (DLLME). The protected SME modes include hollow-ber-protected 2-phase microextraction [HF(2)ME] and hollow-ber-protected 3-phase microextraction [HF(3)ME]. HF(2)ME is often referred to in the literature as LPME or hollow-ber LPME, while HF(3)ME is often referred to as again LPME or 3-phase LPME. Unfortunately, some authors also refer to all other SME techniques as LPME, a confusing situation. Each of the SME modes has many minor or major variations, resulting in the profusion of acronym names in the literature. For example, if DLLME is conducted with ultrasound-assisted solvent emulsication and if a solvent with a density lower than water is used, the resulting acronym might be: USAELDSMLLE. To illustrate using actual examples, when ultrasound is used to

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Figure 1. Frequency of papers published in the period mid-2010 to mid-2012 for the major solvent microextraction (SME) modes: dispersive liquid-liquid microextraction (DLLME), hollow-ber-protected microextraction (HFME), single-drop microextraction/headspace-single-drop microextraction (SDME/HS-SDME) and liquid-liquid microextraction/liquid-liquid-liquid microextraction (LLME/LLLME).

Table 3. Single-drop microextraction (SDME) and headspace-single-drop microextraction (HS-SDME) applicationsa Reference subject SDME, using solvent bubbles to increase extraction efciency SDME, non-polar ionic liquids (ILs) HS-SDME, sampling for residual solvents in solid drug products HS-SDME, ultrasound-assisted extraction (UAE) SDME, combination of solid support-SME with silica-coated steel wire SDME, carrier-mediated ion-pair extracts coupled to CE SDME, In-syringe dynamic automation
a

Extraction solvent/analytes/instrumentation CHCl3/triazine pesticides-fruit juices/GC-FID ILs/PAHs/HPLC DMSO/powdered drug/GC-FID Heptadecane/essential oil components/GC-MS Propyl benzoate/pesticides in river water/GC-NPD 1-Octanol/amino acids/CE 1-Octanol/pesticides-on-column derivatization/GC-MS

Ref. [17] [18] [19] [20] [21] [22] [23]

DMSO, Dimethyl sulfoxide.

emulsify the extracting solvent (or solvent plus an emulsifying agent), the method has been referred to as ultrasound-assisted dispersive liquid-liquid microextraction (UA-DLLME), or ultrasound-assisted emulsication microextraction (with either UAME or USAEME acronyms having been used) or even sonication-assisted emulsication microextraction (SAEME). Proliferation of such acronyms is clearly confusing and not helpful until they have been widely accepted in the literature. While acronyms for specic SME variations can be useful, they are used in this review only when necessary, and with recurring denitions, to avoid confusion to the reader. Fig. 1 graphically represents the recent relative interest in the four major general SME modes: SDME/HS-SDME, LLME/LLLME, DLLME, and HFME. The references in Table 2 detail each of the SME modes, along with their applications, advantages and deciencies. Table 2 also contains useful references for ionic liquids (ILs), derivatization reactions used in SME, chemometric-optimization approaches for SME and automation methodology for SME. Tables 38 include papers for some of the recent interesting, practical, and innovative developments in SME. Essentially, all of the SME modes were developed within a dozen years of the rst application of the technique in 1995, and a vast majority of the literature was

from academic laboratories exploring new SME modes and their renement. Unlike many other sample-preparation techniques, SME has not yet been adopted by any of the major analytical suppliers and has thus mostly remained of academic research interest, until recently. During the last four to ve years, SME literature has increasingly turned to renements of each SME mode to allow their use for practical sample preparation. However, innovations are still occurring rapidly. Some of the more important areas of innovation interests include the use of: (1) ionic liquids (ILs); (2) chemometrics to optimize SME methods; (3) solvents less dense than water in DLLME; (4) electromembrane HF(3)ME extraction (EME) of ionized species; (5) ultrasound-assisted emulsication for DLLME; and, (6) SME procedures for practical on-line sample analyses. The following papers were selected not only to spotlight these and other innovative approaches to SME, but to serve as practical starting points for the development of sample-preparation procedures by regulatory, industrial, clinical, forensic and agricultural analytical laboratories. Many of the papers included also illustrate the use of chemometrics to optimize SME procedures.

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Table 4. Liquid-liquid microextraction (LLME) and liquid-liquid-liquid microextraction (LLLME) applicationsa Reference subject Directly suspended droplet/LLME screening for PAHs LLLME/LLME-SDME back extraction into HCl solution Solidied drop LLME LLME with molecularly imprinted-polymer ber SME Microuidic LLME device with phase separator Dynamic LLME with solvent drop and bubble in vertical narrow bore tube
a

Extraction solvent/analytes/instrumentation Toluene/PAHs in water/l-volume uorospectrometry 1-Octanol-HCl/alkaloids/CE 1-Dodecanol/DDTC metal complex/ICP-MS Toluene/chloroacetanilide herbicides/HPLC Toluene, hexane/amphetamine-pesticides/GC-MS 1-Hexanol-hexane/Pesticides in grape juice/GC-FID

Ref. [24] [25] [26] [27] [28] [29]

DDTC, Sodium diethyldithiocarbamate trihydrate.

Table 5. Dispersive liquid-liquid microextraction (DLLME) applications/extraction solvents with density greater than watera Reference subject Vortex-surfactant-assisted DLLME Vortex-assisted DLLME Vortex-assisted/ionic liquid DLLME Air-assisted in-syringe dispersion DLLME In situ IL formation DLLME/derivatization/thermal desorption Microwave-assisted in situ IL formation DLLME In situ IL formation DLLME SPE followed by solvent-assisted DLLME MIP d-SPE followed by DLLME SFE-DLLME SFE-DLLME Solvent-dispersion DLLME of vegetable oils
a

Extraction solvent/analytes/instrumentation Chlorobenzene-surfactant/pesticides/GC-FPD IL/cadmium in water-apples-rice/AAS IL/clozapine in urine and serum/CE Tetrachloroethane/phthalates/GC-FID IL/chlorophenols/thermal desorption-GC-MS IL/microwave extracts of fruit/HPLC IL/Cr(III), Cr(IV) in water/AAS Chlorobenzene-acetone/pesticides/GC-FPD TCE-acetone-acetic acid/Sudan dyes in egg yolk/HPLC Chlorobenzene-ACN/PAHs in marine sediments/GC CCl4-MeOH/nitrobenzenes in soil/GC MeOH-hexane-base/vegetable oils/phenolic acids/CE

Ref. [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41]

TCE, Trichloroethylene; MeOH, Methanol; SFE, Supercritical uid extraction; ACN, Acetonitrile.

Table 6. Dispersive liquid-liquid microextraction (DLLME) applications/extraction solvents with density lower than watera Reference subject Solvent-dispersion DLLME with capillary tube collection Solvent dispersion solidied drop DLLME Microwave-assisted solidied drop DLLME Solvent-dispersion DLLME with a narrow neck centrifuge vial Surfactant-assisted ion-pair DLLME with syringe collection Vortex-assisted DLLME with pipette tip in neck of volumetric ask Ultrasound-assisted DLLME in modied centrifuge vial Ultrasound-assisted DLLME in inverted centrifuge tube for collection Solvent-assisted DLLME in plastic disposable pipette Solvent-assisted DLLME solvent de-emulsied in plastic pipette Solvent-assisted DLLME solvent de-emulsied in syringe Solvent-assisted DLLME, co-solvent with density higher than water Vortex-assisted DLLME of edible oils with water-coated Fe3O4 particles
a

Extraction solvent/analytes/instrumentation 1-Octanol-acetone/preservatives in foods/GC-FID 1-Undecanol-ethanol/Cr, Co, Ni, Pb ions/AAS 1-Dodecanol-MeOH/herbicides in cereals/HPLC 1-Octanol-ACN/quercetin in honey/HPLC 1-Octanol-surfactant/acidic-basic aromatics/HPLC Toluene/pesticides in water/GC-lECD Toluene/Se(IV) complex in water/GC-FID Cylohexane-Tween-80/PAHs in water/HPLC Tributylphosphate/phenols/HPLC Hexane-acetone/PAHs/GC-MS Toluene-MeOH/fungicides/LC-MS Amyl acetate-CCl4-MeOH/Cu ion-complex/UV-Vis Water-Fe3O4 particles/3-chloropropanediol/GC-MS

Ref. [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54]

ACN, Acetonitrile; MeOH, Methanol.

Finally, a few precautionary words are necessary concerning the use of ILs. ILs have gained increasing popularity in SME due to their remarkable physical and solvent properties, as well as supposedly being less toxic than halogenated or organic solvents, and thus green chemicals. ILs do indeed have remarkable physical and solvent properties, making them very useful for SME, but the statement that they are less hazardous or green chemicals may be completely false. A cursory

examination of the materials safety data sheets (MSDSs) for ILs shows that they are not benign chemicals. They also show environmental persistence and are susceptible to bio-uptake and concentration, and their toxicology and environmental degradation are not well studied [12]. However, the relatively tiny amounts of solvent used in SME procedures allow not only ILs, but chlorinated solvents to be handled safely and disposed in a responsible manner. 5

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Table 7. Automated DLLMEa Reference subject Automation of DLLME, solvent lower density than water Automation of DLLME, solvent greater density than water Automation of DLLME, solvent lower density than water
a

Extraction solvent/analytes/instrumentation 1-Dodecanol-MeOH/Ag(I)/SI, AAS Amyl acetate-CCl4-ACN/SCN ion/SI, VIS 1-Octanol-ACN/phenol, B[a]P/multi-syringe, UV

Ref. [55] [56] [57]

SI, Sequential injection; ACN, Acetonitrile; B[a]P, Benzo[a]pyrene.

Table 8. Hollow-fiber 2-phase microextraction [HF(2)ME] and hollow fiber 3-phase microextraction [HF(3)ME] applications Reference subject HF(2)ME attached to pipette tip Microwave-assisted temperature-controlled headspace HF(2)ME HF(2)ME solvent bar with derivatization HF(2)ME solvent in sample absorbed by ber HF(3)ME 1200 lm id attached to pipette tip HF(3)ME with water soluble IL for acidic-neutral-basic analytes HF(3)ME with solvent in sample-lumen containing pH 5 buffer HF(3)ME with immiscible organic solvents in ber wall and lumen HF(3)ME solvent bar with IL in ber wall-base in lumen HF(3)ME 10 V electromembrane extraction-S6/2 1800 lm id ber HF(3)ME 50 V electromembrane-ultrasonic-DLLME-disposable pipette Extraction solvent/analytes/instrumentation Toluene/40 pollutants-fruit juice, plasma/GC-MS 1-Octanol/hexachlorocyclohexanes/GC-ECD 1-Octanol/pharmaceuticals in drain water/GC-MS Toluene-ethyl acetate/pesticides-orange juice/LC-MS 2-Octanone-HCl/fungicides in orange juice/CE 1-Octanol-IL/PAHs in river water/HPLC 1-Octanol-1-pentanol/sulfonamides in honey/LC-MS Dodecane-MeOH/drugs, urine-plasma/GC-MS/HPLC IL-base/phenols in seawater/HPLC 1-Octanol-base/acidic drugs in wastewater/HPLC 1-Octanol-base/chlorophenols in drainwater/GC-MS Ref. [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68]

2. Single-drop microextraction (SDME) and headspace single-drop microextraction (HS-SDME) SDME was the rst SME method developed and has some major advantages, as well as some signicant disadvantages. Its major advantages are its simplicity, the lack of carryover from one analysis to another (since the solvent is new for each analysis) and the fact that the method can be completely automated. All that is really needed is an inexpensive GC syringe, a little high-purity water-insoluble solvent, a magnetic stirrer, and between 30 lL and 40 mL of aqueous sample. The method consists of exposing a 0.33.0 lL drop of solvent at the tip of the syringe needle in the sample, withdrawing the solvent after the analytes have been extracted, and injecting it into an instrument for analysis. Typical extractions involve the use of 14 mL of aqueous solution, 12 lL of solvent and extraction times ranging from 530 min. The method is basically liquid-liquid extraction in miniature. HS-SDME has the advantage over static HS methods in that the extraction-chromatogram prole often closely resembles that of the chromatogram of the pure analytes. The major disadvantages of both techniques are the susceptibility of the drop to dislodge during the sampling process, a limitation in the size of the drop that can be generated, and the volatility of the extracting solvent. Like most extraction techniques, SDME and HS-SDME are equilibrium processes and normally the extractions are not taken to equilibrium, in order to shorten extraction time. This is not normally a

problem, however. The following papers (Table 3) address some of these issues. 2.1. Solutions for issues of SDME and HS-SDME drop instability, drop size and drop volatility Williams et al. [17] have turned a common problem with SDME into an advantage. Volatile extraction solvents (e.g., CHCl3) often grow a vapor bubble during the extraction process, leading to inconsistent results. Instead of trying to prevent bubble formation, they deliberately introduced air, along with the solvent drop, leading to a larger solvent surface area than would be possible otherwise. The bubble also tends to support high-density solvents (e.g., CHCl3) which tend to dislodge due to their weight. Another approach to the drop size and dislodgement problem is illustrated in a paper by Yao et al. [18], in which they use a water-insoluble IL as the extracting solvent. ILs have high viscosities and very low volatilities, allowing drop sizes of 3 lL and elevated extraction temperatures. To increase the size of the drop even more, they attached a segment of PEEK tubing to the needle tip to allow a drop size up to 10 lL. Due to their low volatility, ILs are not often used with gas chromatography (GC), but are quite compatible with high-performance liquid chromatography (HPLC), which was used in this case for PAH analysis. Residual solvents in pharmaceuticals and food products are often determined by static HS extraction from an aqueous or dimethyl sulfoxide (DMSO) solution. Yu et al.

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[19] used HS-SDME to extract polar residual solvents directly from powdered pharmaceuticals using a 2 lL drop of DMSO, followed by GC with ame-ionization detection (GC-FID). DMSO is a high boiling, viscous solvent, but, unlike ILs, it is compatible with GC. Wei et al. [20] approached HS-SDME from another direction. They extracted essential components from plant oil by using ultrasonic energy to nebulize a water slurry of the powdered plant sample, followed by passing a stream of heated nitrogen over the volatilized components, which carried them to a drop of heptadecane at the tip of a syringe. The extracts were then analyzed by gas chromatography-mass spectrometry (GC-MS). Finally, in an innovative process, Saraji and Farajmand [21] adsorbed the extraction solvent (propyl benzoate) on the surfaces of the pores of microporous silica, which had been deposited on a stainless-steel wire. The silica-coated wire is easily prepared using standard sodalime glass, and is quite durable and temperature stable. While the volume of solvent is less than normally used with SDME, the resulting surface area of the solvent is much larger, resulting in rapid, efcient extraction. After extraction of pesticides present in river water, the wire acted as a syringe needle for injection into a GC port. 2.2. In-line coupling of SDME to capillary electrophoresis (CE) Choi et al. [22] developed a technique for extracting a buffered solution of amino acids into a drop of 1-octanol extraction solvent at the tip of a capillary tube, followed by withdrawal of the drop into the tubing and injection directly into a CE system for analysis. This is a good example of many recent SME research programs: to automate and directly interface SME methods to analytical instrumentation. 2.3. Automated SDME SDME and HS-SDME can be fully automated using a computer-programmable autosampler, such as a CTC Combi PAL using patented software [1]. In a recent paper by Lee and Lee [23], carbamate pesticides were extracted from canal-water samples using dynamic, insyringe extraction with 1-octanol, followed by injection into a GC port for analyte derivatization and analysis. Dynamic, in-syringe extraction involves pulling sample solution into a syringe and pushing it out of the syringe repeatedly (1030 times). The process continually exposes new solvent surface in the syringe to the sample, thus decreasing sampling time. However, in order to be reproducible, the syringe-plunger movement must be precisely controlled, necessitating computer control of the process. While other SDME and HS-SDME techniques can be accomplished manually with very good reproducibility and precision, automation is a real necessity if the techniques are to be carried out with many samples, as is normally the case in a commercial laboratory.

3. Liquid-liquid microextraction (LLME) and liquid-liquid-liquid microextraction (LLLME) LLME and LLLME, like SDME and HS-SDME, are very simple techniques for extracting analytes from water, requiring a magnetic stirrer, a vial and an immiscible solvent, less dense than water. In addition, it may be feasible in many cases to automate completely the extraction process. In the traditional LLME technique, 10100 ll of a solvent (e.g., 1-octanol) is added to the center of a vortex of an aqueous sample being stirred. The direct interface of solvent and water leads to rapid extraction and concentration of analytes into the organic solvent, which is then removed with a capillary tube or syringe and injected into a GC for analysis. LLLME is similar, except that, while the analytes are being extracted into the organic solvent, they are then back-extracted into an aqueous drop suspended in turn into the organic solvent, usually at the tip of a syringe needle. Typically, this technique is used to extract acidic or polar analytes from the water into a nal acceptor solution that is acidic (for basic analytes) or basic (for acidic analytes). As with SDME or HS-SDME, the nal acceptor solution may also contain derivatizing agents. As is also true with SDME, particulates in the sample cannot be tolerated by these exposed-solvent modes, and membrane-protected modes have often replaced LLME and LLLME. However, the following papers (Table 4) illustrate how these techniques can still be quite useful. 3.1. LLME for rapid screening of PAHs in water Pena-Pereira et al. [24] used a standard LLME approach to extract PAHs from 5 mL of water using 35 lL of toluene in only 5 min. In a twist to the normal technique using GC-MS to analyze the extract, they used 2 lL of the extract in a portable, cuvetteless, microvolume spectrophotometer for total PAH determination. This provided a simple, rapid method for eld screening of PAHs in environmental waters. 3.2. LLLME of alkaloids for CE analysis Gao et al. [25] used LLLME to extract and to concentrate alkaloid samples in urine. Their approach illustrated the classic LLLME approach. They extracted 3.5 mL of sample into 60 lL of 1-octanol and then back extracted the alkaloids into a 1-lL drop of 20 mM HCl suspended from the needle of a syringe. The acidic extract was then placed into a microvial for CE analysis. 3.3. LLME of chelated trace heavy-metal ions using a oating solidied drop One technique available to simplify the process of withdrawing the extracting solvent from the water sample following extraction involves using a room-temperature melting solvent. Guo et al. [26] extracted Co, Pd, Cd, Pb

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and Bi ions from 10-mL volumes of water samples by rst adding a chelating agent and then extracting into 30 lL of a 1-dodecanol/p-xylene solvent mixture for 20 min. The vial was chilled in ice, the solidied 1dodecanol removed and placed into a vial, wherein it melted at room temperature and was analyzed by electrothermal inductively-coupled mass spectroscopy (ETVICP-MS). 3.4. LLME with molecularly-imprinted polymer (MIP)coated solid-phase microextraction (SPME) Hu et al. used LLME to overcome a water-incompatibility problem for MIPs. By rst extracting 10 mL of river and farm-water samples containing chloroacetanilide herbicides into 100 lL of toluene, and then inserting the MIP ber into the toluene. In one step, a highly selective, concentrated extract was obtained. The MIP ber was then placed into an SPME-HPLC injector and the extracts analyzed by HPLC. 3.5. LLME using a microuidic device directly interfaced to GC Miniaturization and complete automation of LLME is illustrated in a paper by Peroni et al. [28], who developed a device in which water and solvent are continually owing, and aqueous sample added in plugs. The solvent and sample mix in the device and extraction occurs. As the sample and solvent plug exit the device, the nonpolar toluene or hexane solvent is separated from the water through a non-polar-phase capillary tube attached perpendicularly to the ow line and collected for GC analysis. The method was used for analysis of amphetamine in urine, and volatile aromatics and organochlorine pesticides in water. 3.6. Dynamic LLME using a single drop in a narrowbore tube An innovative application of LLME has been reported by Farajzadeh et al. [29]. Rather than using a stirred solution with a oating organic drop, they used a vertical narrow tube (120 cm 5 mm) with a septum on the bottom. The tube was lled with sample and 30 lL of solvent (hexane/1-hexanol, 50:50) and 50 lL of air added with a syringe through the septum. As the bubble and solvent moved up the tube, extraction took place.

roextraction methods, DLLME has additional advantages (e.g., extraction is almost instantaneous, often with nearly 100% analyte recoveries). Traditional DLLME involved dissolving 20100 lL of a water-insoluble extraction solvent with a density higher than water (e.g., tetrachloroethylene or carbon tetrachloride) in 0.1 2 mL of a water-soluble solvent [e.g., methanol (MeOH), acetone or acetonitrile (ACN)]. The solution was then rapidly injected with a syringe into 410 mL of the aqueous sample in a centrifuge tube and a stable emulsion formed. The emulsion was then centrifuged and the extraction solvent removed from the tube with a syringe and analyzed by GC. The entire extraction process generally required only 510 min. The disadvantages of this technique are that it is most useful for non-polar analytes, it generally requires a halogenated solvent, the water-soluble co-solvent increases extraction-solvent solubility in water, centrifugation is required (so the process cannot be fully automated) and the solvent ends up at the bottom of the centrifuge tube. The following experimental modications (Table 5) overcome many of these disadvantages. Attempts at fully automating DLLME are discussed in Section 6. 4.1. Vortex-assisted DLLME In a paper by Yang et al. [30], a vortex mixer was used to emulsify 30 lL of chlorobenzene in 5 mL of a sample of diluted honey containing organophosphorus pesticides (OPPs). The sample also contained a dilute solution of Triton X-114 as an emulsier aid. The sample was then centrifuged to recover the chlorobenzene extract, which was analyzed by GC with a ame-photometric detector (GC-FPD). Chansaz et al. [31] also used vortex-assisted emulsication, but with an IL, rather than a chlorinated solvent. To 7 mL of sample containing Cd+2 was added an ethanol solution containing 60 lL of IL, and the mixture vortexed and centrifuged, as usual. The sample was removed and the IL diluted with ethanol, and the resulting solution analyzed by ame atomic absorption spectrometry (FAAS). Breadmore [32] extracted 30 lL200 lL of urine samples containing clozapine in micro-centrifuge vials with 520 lL of IL and vortexing. The emulsion was then directly analyzed by capillary electrophoresis (CE). This technique was performed with multiple samples, and could conceivably be fully automated. 4.2. In-syringe air-assisted emulsication Farajzadeh and Mogaddam [33] emulsied a mixture of 15 lL of 1,1,2,2-tetrachloroethane (1,1,2,2-TCE) and 5 mL of water sample containing phthalates by rapidly drawing the mixture into and out of a 10-mL glass syringe eight times through the syringe needle. The emulsion was centrifuged and the solvent analyzed by GC-FID.

4. Dispersive liquid-liquid microextraction (DLLME) using extraction solvents with densities greater than water As can be seen in Fig. 1, DLLME has, in the past few years, dominated SME research publications. In part, this has been because it is one of the newest SME modes and, in part, due to the development of suitable ILs for use in the technique. However, unlike almost all other mic8
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4.3. In situ formation of an ionic liquid (IL) emulsion Galan-Cano et al. [34] analyzed chlorophenol-containing solutions by rst derivatizing the phenols with acetic anhydride and then adding 10 mL of the solution to a centrifuge tube, along with 50 mg of 1-methyl-3-octyimidazolium chloride. To this solution was added 50 mg of KPF6, and the resulting IL emulsion centrifuged. The IL was then heated at 300C in a helium stream to transfer the phenol-acetate extracts to a GC port for analysis by GC-MS. When the extracted analytes are sufciently volatile and thermally stable, as in this case, this is an excellent way to allow the use of ILs with GC. The ILs themselves are far too non-volatile to be directly injected onto a GC column. Xiao and Zhang [35] used a similar method for the analysis of terpenoid ingredients in Chinese fruits. They extracted the analytes from a powdered sample by subjecting a water slurry, containing a water-soluble IL, to microwave heating, followed by addition of NH4PF6 to form a water-insoluble IL emulsion. After centrifugation, the extract was then analyzed by HPLC. In a third example, Lopez-Garcia et al. [36] used a similar in situ approach IL formation to extract combined Cr(III) and Cr(IV) complexes from water samples with an enrichment factor or 300 and a detection level of 0.05 lg/L using electrothermal atomic absorption spectroscopy. 4.4. Mixed-mode extractions, including DLLME DLLME has been used as a nal extraction-concentration method, in conjunction with other methods that use larger extraction volumes. In one example, Samadi et al. [37] extracted OPPs from water samples by rst subjecting 100 mL of sample to C-18 SPE and elution into 1 mL of acetone. A 12-lL portion of chlorobenzene was added to the acetone and the solution injected into 5 mL of water to form an emulsion. The sample was centrifuged and the extract analyzed by GC-FPD. In a second example, Yan et al. [38] rst used a dispersive solid-phase extraction method [d-SPE, commonly referred to as Quick, Easy, Cheap, Effective, Rugged, Safe (QuEChERS)] using molecularly-imprinted polymer microspheres (MIMs) for extraction of Sudan dyes from 100 mg of egg yolk. The 3-mL acetone-acetic acid extract was vacuum concentrated to 1 mL, mixed with 100 lL of tetrachloroethylene and injected into 5 mL of water to form an emulsion. The centrifuged sediment was evaporated, dissolved in methanol and analyzed by HPLC. Supercritical uid extraction (SFE) is an especially useful technique for extractions from solids (e.g., soil, and agricultural and processed food products). Disadvantages of the technique are: (1) the co-extraction of unwanted materials, necessitating additional clean-up steps; and, (2) the need to concentrate the collecting solvent.

Combining SFE with DLLME can attack these two problems. Rezaee et al. [39] extracted PAHs from marine-sediment samples using CO2-SFE, with 1 mL ACN as the collecting solvent. Chlorobenzene (16 lL) was added to the ACN and the solution injected into 5.0 mL of water. The resulting emulsion was broken by centrifugation and 2.0 lL of the chlorobenzene analyzed by GC. Jowkarderis and Raoe [40] used a similar SFE-DLLME combined method to extract nitrotoluenes from soil samples, using methanol as the collecting solvent and carbon tetrachloride as the extracting solvent for DLLME, which was then analyzed by GC. 4.5. DLLME of vegetable oils Typically, organic solvent is used to extract aqueous solutions. However, in an example by Bakar et al. [41], vegetable oils containing phenolic acids were extracted into a basic aqueous solution and then analyzed by CE. Thus, to 20 g of oil was added a solution of 300 lL MeOH/sodium hydroxide in 2 mL of hexane dispersion solvent. This process was repeated three times. The centrifuged extracts were then directly introduced into the CE instrument.

5. Dispersive liquid-liquid microextraction (DLLME) using extraction solvents with densities less than water DLLME techniques using solvents less dense than water were developed originally to enable the use of nonchlorinated solvents and thus to expand the range of solvents that could be used. The methods assisting emulsication are mostly the same as for solvents more dense than water (i.e. vortex, solvent, microwave and ultrasound). Ultrasound-assisted emulsication has become increasingly popular, since it easily forms ne emulsions. In addition, unlike solvent-assistance, UA does not dilute the sample or cause the extraction solvent to become more soluble in the solution. De-emulsication is typically done by centrifugation, though, in a few cases, this is accomplished by adding more emulsifying solvent (acetone, MeOH or ACN). However, this technique also tends to increase extraction solvent solubility, and has not been widely used. Most innovations for DLLME using solvents less dense than water have involved developing devices or methods to allow removal of the extracting solvent. The following papers (Table 6) illustrate these innovations. 5.1. Techniques for collecting liquid-extraction solvents The simplest techniques for collecting liquids involve simply removing a portion of the liquid with a capillary or syringe. Thus, Farazdeh et al. [42] used a glass capillary to collect a drop of 1-octanol from the centrifuged test tube after separation. The technique of using a
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room-temperature melting liquid for the extraction, as is used with LLME, is also quite effective for DLLME and is illustrated with two papers. Mirzai et al. [43] added a solution of 80 lL of 1-undecanol in 1.5 mL of ethanol to 50 mL of wastewater containing chelated Ni, Co, Pb and Cr ions. After centrifugation and cooling, the solidied solvent was removed and analyzed by graphite-furnace AAS (GF-AAS). Wang et al. [44] used a combination of microwave and solvent-assisted emulsication with 1-dodecanol to extract triazine herbicides from cereals. The solidied solvent was removed, allowed to melt, and then analyzed by HPLC. Most innovations for collecting the solvent involve specially-constructed devices or innovative ways to use available devices. Ranjbari et al. [45] used a modied centrifuge tube to carry out the extraction of quercetin from honey solutions. The tube had a narrowed neck at the top to aid in allowing the 1-octanol to be collected. Moradi et al. [46] have also used a modied centrifuge tube to simplify collection of the solvent. Their design uses a tube with a narrowed neck tted with a septum to allow addition of the solution of 1-octanol and an emulsifying agent. The tube also has an added second narrow-bore port to allow the collection of the less dense solvent. A similar separation scheme using the same device, but with ultrasound emulsication of toluene, was used by Naja et al. [47] to extract selenium in environmental waters. Jia et al. [48] used a modication of the original technique of performing the extraction in a volumetric ask. They extracted pesticides in water using 20 mL of water and 30 lL of toluene in a 25 mL volumetric ask, followed by vortex-assisted emulsication. The ask was centrifuged, an inverted plastic pipette tip placed in the ask opening, and water added to force the toluene into the tip for collection. Cheng et al. [49] used an interesting modied procedure with a standard centrifuge tube for the extraction of PAHs. Thus, 20 lL of cyclohexane containing a small amount of Tween-80 emulsier was added to 5 mL of sample in a 5-mL centrifuge tube. The mixture was emulsied with the aid of ultrasonication and the tube capped with a septum. The tube was then centrifuged upside down and the cyclohexane removed from the tip of the upside down tube. In another innovative procedure, Hu et al. [50] used tributylphosphate, rather than an organic solvent, to extract phenols from water, in a 5-mL disposable polyethylene pipette. After centrifugation, the pipette was simply squeezed to force the tributylphosphate extract into the narrow pipette capillary for easy collection with a syringe. Guo and Lee [51] used the same device to extract PAHs from environmental waters with hexane. These 10
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authors also used acetone as the emulsication aid and for solvent de-emulsication. Xia et al. [52] performed DLLME in an inverted glass 5 mL syringe using the solvent de-emulsication technique to extract fungicides from tap, rain and lake water. The separated solvent (20 lL of toluene) was forced into a clear plastics pipette tip attached to the syringe and collected. Finally, Skrlikova et al. [53] used an interesting trick to modify the density of a solvent by adding a solvent with a density higher than water. The combined solvent mix is thus denser than water and can be centrifuged to the bottom of a tube for collection. Thus, a 1:1:3 mixture of amyl acetate (the extracting solvent)/carbon tetrachloride and methanol (the disperser solvent) was added to 5 mL of water containing copper ion and a chelating agent. After centrifuging the emulsion, the solvent was removed and analyzed by UV-Vis. 5.2. DLLME of edible oils using water coated onto Fe3O4 magnetic nanoparticles (NPs) This last technique is very simple but unique enough to be placed in a separate category. Zhao et al. [54] coated magnetic NPs of Fe3O4 with water and added these to samples of edible oil to extract 3-chloropropane-1,2-diol (a potential carcinogen). Thus, to 20 mg of NPs were added 30 lL of water and 10 g of oil. After vortexing, the NPs were attracted to the bottom of the vial with a magnet, the oil removed, the NPs washed with hexane and the diol desorbed with 1 mL ethyl acetate. The extract was concentrated, dried, subjected to silane derivatization and the derivatized diol analyzed by GC-MS.

6. Automated DLLME DLLME use is rapidly becoming the most widely used SME procedure, due to its simplicity and its ability to extract analytes from water rapidly. However, a major disadvantage is the inability to automate DLLME fully when using centrifugation to break the emulsion. In the past three years, at least half-a-dozen papers have appeared addressing this issue. Three research groups have approached the problem from different directions and have achieved results (Table 7), which, while not perfect, show that a solution to this impediment is feasible. The instrumental set-ups used in the following three examples are complicated enough that the reader is encouraged to review these papers directly for full details, rather than repeating them here. Aristidis et al. [55] used a commercial ow-injection analysis system coupled to a ame atomic absorption spectrometer (FAAS) and sequence-injection system to handle samples, solvents and injections. They extracted chelated Ag ion using a continuously owing system by injecting 2% 1-dodecanol in methanol into the stream.

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The emulsion thus formed then owed through a micro-column packed with PEEK turnings to retain the 1-dodecanol. The solvent was then ushed from the column with 600 lL of methyl isobutyl ketone and directly analyzed by FAAS. Andruch et al. [56] also used a commercial sequenceinjection system for the analysis of thiocyanate ion in saliva, in which the emulsion was formed in a 1.5-mL conical test tube. To 680 lL of thiocyanate sample containing a complexing agent was added 300 lL of a mixture of 75 lL of amyl acetate (the extracting solvent), 75 lL CCl4 (the density modier) and 150 lL of ACN (the dispersion solvent). The cloudy mix was allowed to separate on its own and 90 lL of the separated solvents at the bottom of the tube was transferred to a microvolume cell for visible spectroscopy analysis. Maya et al. [57] used an apparatus consisting of three 5-mL syringes, a monolithic column and a 100-cm liquid waveguide capillary cell for UV analysis of phenol and benzo[a]pyrene. The extraction took place in one of the 5-mL syringes, by rapidly injecting 750 lL of a solution containing 56 lL of 1-octanol into 4.25 mL of sample. The cloudy mix rapidly separated and the 1-octanol rose to the top of the inverted syringe. The extract solution was then passed through the monolithic column and into the capillary cell for UV analysis. While all three of these procedures worked, they obviously have some drawbacks, especially if they were to be used with UHPLC or GC instrumentation. It is unclear from the papers whether the extracts are sufciently water-free (and thus possibly salt-free) and/or sensitive enough for capillary GC and UHPLC analyses. The rst procedure uses relatively large amounts of solvent to elute the extracting solvent, though the concentrating effect is 186-fold. The second and third procedures have relatively low concentrating effects (1020 fold), possibly due in part to real emulsions not being formed during the extraction process. This can be seen by the rapid separation of the solvent layers, though this is the price to pay for avoiding centrifugation or a separation column. However, these procedures do work quite well for the analyses of concern, and clearly illustrate that DLLME can be fully automated. One phase-separation technique that has yet not been tried and that may hold some promise with automation is solvent de-emulsication [51,52].

the lumen of the ber. Unlike SDME, the extracting solvent cannot be dislodged and lost. In addition, the ber protects the solvent from solid-matrix effects, unlike SDME and LLME, and the ber can contain fairly large amounts of solvent. The most commonly used ber is Accural Q3/2, manufactured by Membrana, Wuppertal, Germany. Q3/2 has an internal lumen diameter of 600 lm, a wall thickness of 200 lm and a pore size of 0.2 lm, and about 70% porosity. This ber therefore contains 2.8 lL solvent/cm in the lumen and an additional 3.5 lL/cm solvent in the ber wall. (2) The second HFME mode is HF(3)ME, which is used in a fashion similar to LLLME to extract polar and ionizable analytes (e.g., acids, phenols, amines and amino acids). Typically, a water-insoluble, non-polar solvent saturates the wall of the ber, while the lumen contains acid or base, for irreversible extraction of basic or acidic analytes, respectively. The major deciency of HFME is the time required for extraction, typically 2090 min. (3) One solution to this is the third HFME mode electromembrane extraction (EME) which is simply HF(3)ME with electrode wires placed inside and outside the ber. A direct current potential (1050 V) can result in rapid (510 min.) and complete extraction of ionizable analytes. The following papers (Table 8) represent the current trends in the use of HFME. 7.1. HF(2)ME of pollutants from fruit juices with the ber attached to a micropipette tip Classic HF(2)ME attaches the ber to a 22-gage or 23gage syringe needle, which holds the ber while extraction takes place. Instead, Manso et al. [58] attached the ber to a plastic 20 lL micropipette tip, trimming the tip so that it just tted snugly inside the ber. This technique provided a guide for syringe-needle insertion into the ber, while holding the ber securely during the extraction. This would also more easily allow the use of an autosampler for the extraction [16]. 7.2. Microwave-assisted, ber-cooled headspace HF(2)ME Tsai et al. [59] used HF(2)ME in HS mode by volatilizing hexachlorcyclohexane isomers in 10 mL of water with microwaves. The volatiles were extracted into 1-octanol contained in the lumen and pores of a 1.5 cm section of Q3/2 ber, which was located within a distillation condenser tube. 7.3. Solvent-bar HF(2)ME Guo and Lee [60] used a solvent bar to extract pharmaceutically-active compounds from drain water. A 11

7. Hollow-ber-protected microextraction (HFME) HFME, often referred to as liquid-phase microextraction (LPME), was developed by Rassmussen and PetersenBejergaard shortly after SDME [1,10]. HFME is used in three basic formats. (1) The rst, and simplest, is HF(2)ME, in which a porous polypropylene hollow ber contains extraction solvent within the pores of the ber and within

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solvent bar is simply a ber containing solvent and closed at both ends. The ber segment is then added to the sample and agitated with a magnetic stir bar. Upon completion of the extraction, one end of the bar is cut off and the solvent removed for analysis. A derivatizing reagent was also added to the solvent during the extraction to aid GC analysis. 7.4. HF(2)ME with solvent in the sample and no solvent in the ber In this modication of normal HF(2)ME, Bedendo et al. [61] added solvent (400 lL of toluene/ethyl acetate) directly to 9 mL of fresh orange-juice sample and a 1.5-cm piece of ber attached to a stem, which was in turn held by the vial septum. During the course of the extraction, analytes were rst extracted into the organic solvent, which in turn was absorbed into the pores of the ber. The ber was then extracted with methanol/acetone to recover pesticides present in the juice. 7.5. HF(3)ME extraction of fungicides from orange juice Barahona et al. [62] used a Q3/2 ber with a 1200lm internal diameter and a 200-lm wall thickness. This larger diameter ber holds more solvent, and is also compatible with a larger diameter 200-lL plastic pipette tip, which was used as a guide for a 22-gage HPLC syringe needle. The walls of the ber were saturated with 2-octanone and the lumen lled with dilute HCl, to extract the fungicides irreversibly, while the orange-juice sample was made basic. Following extraction, the aqueous acceptor solution in the lumen was analyzed by liquid chromatography-mass spectroscopy (LC-MS). 7.6. HF(3)ME using a water-soluble ionic liquid in the ber lumen Liu et al. [63] modied the standard HF(3)ME procedure by using a water-soluble IL in the lumen of the ber and 1-octanol in the ber wall to extract acidic, basic and neutral compounds in river water. No acid or base was added to the lumen, only to the sample solution. The IL extract was then directly analyzed by HPLC. 7.7. HF(3)ME with solvent in the sample in addition to solvent in the ber and acceptor solution in the lumen This procedure by Bedendo et al. [64] is very similar in concept to the HF(2)ME procedure used by the same research group [61]. Sulfonamides in honey were analyzed by adding 300 lL of a mixture of 1-octanol and 1pentanol to an aqueous acidic solution of honey, which was extracted using an 8-cm section of ber lled with basic acceptor solution. No solvent was initially in the wall of the ber. After extraction, the acceptor solution was analyzed by LC-MS.

7.8. HF(3)ME using two immiscible organic solvents in the ber wall and ber lumen Ghambarian et al. [65] successfully extracted tricyclic antidepressant drugs in urine and plasma using an 8-cm segment of ber with the wall saturated with dodecane and the lumen lled with methanol acceptor. This technique allowed the acceptor solution to be analyzed directly by either HPLC or GC. 7.9. HF(3)ME solvent bar using water-insoluble ionic liquid in the ber wall and aqueous acceptor in the lumen Guo and Lee [66] used a three-phase solvent bar for extraction of phenols in seawater. The phenols present in acidied seawater and the aqueous acceptor phase was basic to ionize the phenols. The extracts were removed from the solvent bar and analyzed directly by HPLC. 7.10. HF(3)ME electromembrane extraction (EME) The following two papers represent the capabilities of EME. Payan et al. [67] used a 2.4 cm piece of Accurel S6/2 polypropylene ber, which has an internal diameter of 1800 lm, a wall thickness of 450 lm and a pore size of 0.2 lm. The larger diameter ber had to be large enough to insert the electrode wire. The remaining electrode was placed in the wastewater sample, which contained nonsteroidal anti-inammatory drugs (NSAIDs). Both sample and acceptor solutions were basic. The ber wall was saturated with 1-octanol. The analytes were extracted into the acceptor phase using a 10 V potential in only 10 min. Finally, Guo and Lee [68] performed EME to extract chlorophenols from drainwater samples using a 3 cm 0.5 cm envelope constructed from polypropylene Accurel Q3/2 sheet (170 lm thickness, 0.2 lm pore size). The sample (100 mL) was acidied, the walls of the envelope saturated with 1-octanol and 1 mL of basic acceptor used. The electrodes were inserted and 50 V applied for 10 min. Since this EME method uses a relatively large volume of acceptor, the extracts were acidied, transferred to a 3-mL polyethylene disposable pipette and extracted into 30 lL of 1-octanol using ultrasound-assisted DLLME, using a disposable pipette methodology similar to those in references [50] and [51]. The 1-octanol extracts were then in-port derivatized and analyzed by GC-MS.

8. Conclusions SME methods are increasingly accepted as useful samplepreparation techniques, due to their simplicity, low cost, adaptability to a wide variety of sample types and analytes, and exceptional ability to purify and to concentrate samples for all major instrumentation analytical

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techniques. Recent innovations and trends in SME include the use of solvents less dense than water for DLLME, the use of IL-extraction solvents and chemometric optimization of methods. In recent years, increasing effort has also been placed on innovating SME to allow for on-line and automated procedures. SME therefore has a promising future in analytical methodology. References
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