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Dispersive liquid-liquid microextraction based binary extraction techniques prior to chromatographic analysis: A review
Accepted Manuscript Dispersive liquid-liquid microextraction based binary extraction techniques for chromatographic analysis: A review Muhammad Sajid, Khalid Alhooshani PII:
S0165-9936(18)30302-9
DOI:
10.1016/j.trac.2018.08.016
Reference:
TRAC 15226
To appear in:
Trends in Analytical Chemistry
Received Date: 11 July 2018 Revised Date:
20 August 2018
Accepted Date: 23 August 2018
Please cite this article as: M. Sajid, K. Alhooshani, Dispersive liquid-liquid microextraction based binary extraction techniques for chromatographic analysis: A review, Trends in Analytical Chemistry (2018), doi: 10.1016/j.trac.2018.08.016. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Dispersive liquid-liquid microextraction based binary extraction techniques for chromatographic analysis: A review
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Muhammad Sajid a,*, Khalid Alhooshani b
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a
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Center for Environment and Water, Research Institute, King Fahd University of Petroleum and Minerals, Dhahran 31261, Saudi Arabia. b
Department of Chemistry, King Fahd University of Petroleum and Minerals, Dhahran 31261, Saudi Arabia.
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*Corresponding author email: [email protected]; [email protected] Abstract
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The recent developments in the analytical sample preparation signpost a trend of combining dispersive liquid-liquid microextraction (DLLME) with other extraction techniques. The objectives of these binary techniques are inclined toward achieving an improvement in separation, cleanup, detection limits, enrichment factors, and coping with complex matrices. DLLME has been combined with both conventional and micro- or miniaturized methods. It has been either followed by or following another extraction in the combination. This review aims to highlight and share the progress in this area with the analytical community. The objectives and merits of each combination are critically appraised. At the end, a brief description is provided on accomplishments, limitations, and future directions
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Keywords
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DLLME; Combined extraction methods; Analytical sample preparation; Microextraction; Preconcentration; Chromatographic analysis; Samples with complex matrix
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1. Introduction
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Despite all the key developments in analytical instrumentation, sample preparation is still considered as a bottleneck in the quantitative chemical analysis. The area of sample preparation is driven by the requirement of trace-level analysis, instrument incompatible sample matrices, and recent regulatory obligations [1]. The sample preparation is performed with the aim of getting improved separations, clean up, enrichment factors (EFs), and bringing the analytes into an instrument compatible medium. Both the conventional as well as micro- extractions are used for sample preparation and possess their own advantages and pitfalls. Conventional extraction techniques are exhaustive in nature and provide an efficient extraction and clean up while micro- extractions are based on equilibrium and directed toward miniaturization of extraction devices, reduction in the use of chemicals, and to explore the possibilities of automation with analytical instrumentation. Micro- extractions are also recognized for their better extraction performance, enhanced sensitivity and selectivity, and many other analytical figures of merit [2].
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DLLME has been introduced by Assadi and co-workers in 2006 [3] and it immediately attained the attention of the researchers. DLLME is based on a ternary solvent system, in
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(i) (ii) (iii)
(iv)
The injection of extraction and disperser solvents into the sample. The formation of a cloudy solution/emulsion due to the cosolvency of the disperser solvent with two other solvents. The establishment of extraction equilibrium in a short time based on the extensive surface contact between the droplets of the extraction solvent and the sample. Centrifugation to obtain the sedimented extraction phase, which is enriched with analytes.
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which a disperser solvent is injected along with the extraction solvent into the aqueous sample. As clear from the name, the role of the disperser solvent is to disperse the extraction solvent within the aqueous sample solution to achieve better extraction. Briefly, a typical DLLME procedure consists of the following processes
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Over the period of time, DLLME has gone through an extensive evolution with regards to special extraction devices, achievement of dispersion through the aid of different processes such as microwave, ultrasound, vortex, manual shaking, agitation, magnetic stirring etc., a search of less-toxic solvents, and attaining de-emulsification without centrifugation [4]. The major advantages of DLLME are the requirement of the negligible amount of extraction solvent, rapid extraction, and high EFs due to the high phase ratio of donor to acceptor phase. Moreover, it is simple, quick, efficient, and meets most of the Green Analytical Chemistry aspects. These aspects include reduction of the solvent volume, search and application of green solvents, energy effectiveness, and less waste generation [5]. Nevertheless, this technique also possesses certain limitations, which primarily result from the requirements related to the extraction and disperser solvents, toxic nature of the commonly used halogenated solvents, and special design of the extraction devices.
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To address some of the limitations of DLLME and deal with the certain scenario of sample preparation, DLLME has been combined with other macro- and microextractions. A combination of DLLME with other techniques has been proposed as a feasible way to birth a novel extraction method that can draw synergistic advantages of the individual methods while introducing its own unique merits. In addition, this is a way to reduce the disadvantages of individual techniques and solve the problems related to special sample preparation scenarios. At this stage, DLLME based combined methods represent a developing area of research in the field of sample preparation.
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Many review articles have been published in the area of DLLME covering different aspects from its evolution to applications [4,6–10]. Although some of these and other earlier articles [11] and our recent article discussed in brief the combination of DLLME with other techniques [12] but there is no specific article, which covered DLLME based binary extraction techniques with an adequate detail. Secondly, an update is required to cover recent advancements. Hence, this article aims to review DLLME based combined methods and evaluate their role in enhancing the efficiency of the entire analytical process from extraction to the determination. This review will provide an overview of the objectives of such methods, the limitations of individual methods that can be overcome by combination, and the scenarios where such methods can be a good choice. The
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applications of these methods in environmental, food, and biological analysis are discussed in sufficient detail.
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DLLME based binary extraction methods can be broadly classified into following three categories and each category will be discussed separately in the coming sections Conventional or macro- extractions followed by DLLME miniaturized or micro- extractions followed by DLLME DLLME followed by miniaturized or micro- extractions. A schematic of classification is given in Fig 1.
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The major milestones achieved in DLLME based combined extraction techniques, to best of our knowledge, are listed in Fig 2. The dates selected are based on when paper was published online.
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Figure 1. Classification of DLLME based binary extraction methods
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DLLME based combined extraction approach
Ref.
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Solid phase extraction followed by DLLME
[13]
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[15]
DLLME coupled with dispersive micro solid-phase extraction
[16] [17]
Ultrasound assisted extraction followed by DLLME
[18]
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Supercritical fluid extraction followed by DLLME
Stir bar sorptive extraction followed by DLLME
[19]
Microwave assisted extraction followed by DLLME
[20]
Matrix solid phase dispersion followed by DLLME
[21]
Subcritical water extraction followed by DLLME
[22]
Pressurized liquid extraction followed by DLLME
[23]
Electro membrane extraction followed by UAEME
[24]
Electro membrane extraction followed by DLLME
[25]
DLLME followed by single drop microextraction
[26]
Micro-solid-phase extraction followed by DLLME
[27]
Magnetic solid phase extraction followed by DLLME
[28]
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Dispersive solid-phase extraction followed by DLLME
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Acetonitrile based extraction followed by DLLME
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Counter current salting-out homogenous liquid–liquid extraction followed by DLLME Simultaneous hollow fiber supported liquid membrane and DLLME
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Dual DLLME
[31]
Tandem DLLME
[32]
DLLME followed by solid phase microextraction
[33]
[30]
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Microextraction in packed syringe followed by DLLME
[34]
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2. Conventional or macro- extraction techniques followed by DLLME
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Figure 2: Historical timeline of DLLME based combined methods
In this section, conventional extraction techniques such as solid phase extraction (SPE), supercritical fluid extraction (SFE), microwave assisted extraction (MAE), ultrasoundassisted extraction (UAE), subcritical water extraction (SWE) combined with DLLME have been discussed. 2.1.Solid phase extraction combined with DLLME
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This combination can be used to accomplish certain goals related to large volume and complex natured liquid samples. SPE provides both concentration and cleanup of the analytes. In some cases, SPE requires a very large volume of elution solvents, which decrease EFs. In those cases, DLLME can provide enrichment of analytes as it utilizes very small volume of extraction solvent (in microliter range). The main advantages derived from SPE coupled DLLME are effective cleanup and high EFs.
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DLLME cannot offer appropriate cleanup when extracting samples characterized by complex matrix composition. A sample pretreatment is always desired. For example, DLLME was reported to be an unsuitable method for the extraction of fungicides from wine samples, particularly red wines, since matrix components may precipitate in the settled drop of extraction solvent, preventing its chromatographic analysis. Secondly, with complex matrices changes in the volume of the sedimented phase and extraction performance are potential problems [35]. Thirdly, DLLME provides EFs mostly in the range of 50–1000, which are still lower in many cases of ultra-trace analysis [36].
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Apart from better sample clean up, the combination of DLLME with SPE presents some valuable advantages. First, analytes recovered from the SPE are rapidly concentrated in a smaller volume of solvent without the requirement of an evaporative concentration step. This combination results in very high EFs (up to 50,000 reported). The reason for such high EFs can be attributed to
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Retention of analytes from large volume samples onto a small amount of SPE adsorbent. Elution of analytes from SPE adsorbent using a minimum volume of desorption solvent. Further preconcentration using DLLME.
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The values of EFs may vary depending upon the initial sample volume, nature of the sorbent and volume of elution solvent in SPE, and volume of extraction solvent in DLLME.
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Second, the selectivity of the sample preparation process is improved by using both techniques in tandem. The use of SPE and DLLME can extend its applicability to complex liquid and biological matrices.
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The applications of SPE-DLLME are mostly related to large volume aqueous samples related to the environment. SPE-DLLME combination was first reported in 2007 for the extraction of chlorophenols in water samples [13]. Later, this combination was used for extraction of organophosphorus pesticides (OPPs) in aqueous samples. The extract obtained from SPE was treated as disperser solvent for DLLME, which provides a greener aspect in terms of solvent consumption. EFs as high as 50,000 and LODs as low as pg/L were obtained. These results were not attainable using either of the methods alone [37]. This combination has been widely used for extraction of variety of analytes in environmental samples, the key parameters of such methods are listed in Table S1.
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This combination has also shown some exciting applications in food analysis. For example, it was used for the extraction of eight pyrethroids in cereal samples prior to their analysis by GC-MS. LOQs with SPE-DLLME almost 10 times higher than SPE alone except for few analytes [38]. This combination is also used for extraction of different analytes in food samples such as wine, porcine tissues, smoked bacon, pistachios, honey, and dietary supplements. The analytical figures of merits of these methods are listed in Table S1.
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This combination is also used for extraction of different analytes in urine and plasma samples [39–41].
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As far as the limitations of SPE-DLLME are concerned, to achieve higher EFs it generally requires large volume liquid samples that are not always available particularly in case of biological fluids. Moreover, solid samples need to be pretreated before SPEDLLME, as they are required in liquid form. Depending on the nature of the solid samples, they may require the steps like grinding, homogenizing, extracting, defatting before DLLME-SPE. These steps may contribute in the loss of analytes.
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Basically, the need of this all arises from the gross architecture of the solid samples such as fruits, meat, vegetables, soil or mud. The objective is to decrease the particle size of the sample in a way that its maximum area can be subjected to extraction. This needs mincing or dicing of the sample. Then it is subjected to homogenization in presence of water or organic solvents. Based on the requirement, samples can be dried by various ways such as freeze drying, drying by dry-ice, or by placing in liquid nitrogen. The resulting material is easier to crush mechanically. Biological samples might require even stronger treatments such as addition of detergents. The finely divided powder then can be extracted by directly mixing with the solvents or by packing in a column and passing the solvents over it. The extraction may need repeated cycles of using fresh solvents, centrifuging, pooling the supernatants to get higher recoveries. The complications such as formation of emulsion with the extraction solvent may arise [42]. Apart from the mincing of solid samples, other extractions such as ultrasound assisted extraction has also been applied before SPE-DLLME [43].
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Generally, large volumes of the solvents are required in conventional SPE that is not recommended by the recent movements in Green Analytical Chemistry. It should be noted that in most of the SPE-DLLME procedures described above, SPE utilizes nearly 500 mg of the sorbent, and analytes are usually eluted by 1.0 or 2.0 mL of the eluent. The
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same analyte-concentrated is employed as disperser solvent in the subsequent DLLME. The eluent of SPE, in some reports, have been evaporated to dryness and then reconstituted in another solvent for upcoming DLLME procedure [38]. The evaporation of toxic solvents may have impact on the workers and the environment.
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The analytical features of the above mentioned SPE-DLLME combined procedures are provided in Table 1. 2.2.Supercritical fluid extraction combined with DLLME
The first work on the combination of supercritical fluid extraction (SFE) and DLLME was reported in 2010 for the extraction of PAHs in marine sediments [17]. In the SFEDLLME procedure, the collecting solvent of SFE is employed as a disperser solvent in following DLLME. After completion of SFE, the suitable volume of extraction solvent is added to the collecting solvent of SFE and this mixture is rapidly injected into aqueous sample followed by the routine steps of DLLME. This combination offers several advantages in comparison with Soxhlet extraction and SFE alone. Compared to Soxhlet extraction, it utilizes lower volume of extraction solvent as well as extraction time is shorter. Moreover, it results in a clean extract. For example, for extraction of PAHs from soil samples, SFE requires few mL of the collecting organic solvents while the volume needed for soxhlet is five hundred milliliters. SFE completes in less than an hour while soxhlet takes 24 hours.
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Like conventional SFE procedures, SFE-DLLME does not involve vaporization of large quantities of toxic organic solvents, which is time-consuming and of environmental concern. DLLME in this combination provides high EFs. This combination extends the application of DLLME to solid samples. SFE-DLLME provided LODs of 0.2 mg/kg for extraction of PAHs in marine sediments [17]. This method was also applied for the extraction of OPPs in soil and marine sediments and the resulting LODs were in the range of 0.001 – 0.009 mg/kg [44]. Some other applications of SFE-DLLME in environmental analysis are listed in Table S2. The only limitations that can be imagined for SFE-DLLME relates to multistep manual procedure. Errors or deviations in any individual step may affect the reproducibility of the procedure.
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Microwave-assisted extraction (MAE) employs microwave radiation that can penetrate and produce heat within the solid matrix in presence of the polar solvents. The performance of MAE is derived by many extraction parameters including the solvent type, irradiation time, temperature, and volume of the solvent in comparison to amount of the solid. Due to assistance of microwave irradiation, the solvent consumption and subsequent waste generation is minimized. MAE is preferable choice of analyte extraction from the solid samples coming from environmental, food, and biological origins such as sediments, meat, biota, etc. MAE extracts can be further enriched by DLLME to achieve higher EFs and detection sensitivities.
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The first extraction method describing MAE combined with DLLME for extraction of fungicides in apple pulp and peel was published online at the end of 2010 [20]. The 7
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second report was published at the start of the 2011 where N-nitrosamines were extracted in meat samples. Apart from the good extraction recoveries, the method’s excellent performance was demonstrated by the quantitation of the analytes that was accomplished using aqueous calibration. This shows that matrix effect was significantly reduced. High EFs (220 and 342) and low LODs were attributed to DLLME [45]. The same combination was utilized for extraction of polyaromatic hydrocarbons (PAHs) in smoked fish. This method also provided good EFs and LODs [46]. The applications of MAEDLLME were extended to different food matrices. MAE-DLLME was used for the extraction of polyamine in turkey breast meat samples. After MAE, analytes were derivatized in MAE aqueous extract which was later utilized for DLLME [47]. In another work, pharmaceutical antimicrobials were extracted from the fish sample using the combination of MAE with solid phase purification and DLLME. MAE was used to digest/extract the solid sample in acetonitrile. The extract was passed through an alumina column for purification. The effluent was evaporated to dryness and reconstituted in 200 µL of acetonitrile which was then employed in DLLME. This method provided extremely low LODs ranging from 4.54 – 101.3 pg/kg [48]. The other applications of this combination in food and environmental analysis are listed in Table S2.
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MAE can be followed by simultaneous DLLME and derivatization when analytes of interest are to be converted into suitable derivatives before analysis. In such cases, MAE extract, extraction solvent, and derivatizing reagents are mixed and rapidly injected into another solution (usually aqueous). This results in formation of a cloudy solution from which extraction solvent is separated by centrifugation. Haloanisoles and halophenols in cork stoppers and oak barrel sawdust were extracted into methanol by MAE. The same methanolic extract was used as a disperser solvent in following DLLME. The methanolic extract, derivatizing reagent, and extraction solvent were mixed and rapidly injected into an aqueous potassium carbonate solution and a cloudy solution was formed [49]. The simultaneous derivatization and microextraction are desired features in the green derivatization process [50].
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2.4.Ultrasound-assisted extraction combined with DLLME
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Being the vibrational source of energy, ultrasound is flexible and adjustable for a different type of samples and therefore ultrasound-assisted extraction (UAE) has many beneficial features for extraction of analytes in the solid matrix. UAE is relatively fast and enhances extraction rate significantly. Basically, it provides adequate amount of energy to disrupt the interior architectures of the solid samples. It also enhances the contact surface between the solid sample and solvent medium, which improves mass transfer from sample to extracting phase. After the efficient release of the analytes from the solid samples, UAE can also be integrated with DLLME. The objective is to enrich the target species into a small volume leading to better cleanup as well as sensitivity.
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This combination has been mostly used for extraction of pollutants, volatiles, and flavors in food samples. The first combined method based on UAE and DLLME was developed for OPP residues in tomato samples and the final determination was made by gas chromatography-flame photometric detection (GC–FPD). In this method, UAE part was
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performed by using very small volume of acetone (5 mL). The need for steps like additional clean up and evaporation was omitted. Further enrichment of analytes was performed by DLLME [18]. UAE-DLLME was also used for identification of volatile compounds in tea and quantification of caffeine. This method was green in nature because very small quantities of samples, as well as extraction solvents, were required (sample 0.1 g, methanol 1.0 mL, and 27 µL chloroform). In addition, dispersion solvent was avoided in DLLME as emulsification was achieved through the ultrasound [51]. The same combination has been used for extraction of analytes from food samples, the detail of which listed in Table S2.
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The green aspect of UAE-DLLME combination is demonstrated by the fact that extraction solvent of UAE can also be used as a disperser solvent of subsequent DLLME. This reduces overall solvent consumption. The acetonitrile used for UAE of ochratoxin A and citrinin in fruit samples was employed as disperser solvent in the following DLLME [52]. The other applications in food analysis include determination of volatile components in saffron [53].
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The second application area of this combination is directed toward extraction of pollutants from environmental solid samples such as soil and marine sediments. The example of this category is elution of PCBs from marine sediments using UAE. UAE extract was evaporated and reconstituted in 1 mL of extraction solvent which was further subjected to DLLME. Reasonably low LODs ranging from 0.021 to 0.057 ng/g were obtained [54]. Chemometric assisted ultrasound leaching-solid phase extraction followed by dispersive-solidification liquid-liquid microextraction was used for determination of OPPs in soil samples [55]. UAE-DLLME was also used for extraction of nitrophenols in the soil samples combined with microvial insert large volume injection GC-MS [56].
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The third area of application is related to extraction of analytes from complex biological samples. For example, phthalate metabolites were extracted from the nail samples. Extracted analytes were determined by UPLC-MS/MS and LODs were in the range of 2 – 14 ng/g [57].
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2.5.Accelerated solvent extraction combined with DLLME
Accelerated solvent extraction (ASE) is another advancement in sample preparation which is based on the extraction of analytes from the solids into a solvent under high temperature and pressure conditions. It allows accomplishing efficient extraction in relatively shorter periods of time. The use of high temperature leads to better extraction through improved analyte solubility, increased diffusion rates, decreased solvent viscosities, and reduced solvent-matrix interactions. Similarly, high pressure makes analytes to boil at higher temperatures than their boiling points leading to the accelerated extraction process. There are several opportunities to combine ASE with microextractions. For example, ASE can be used for extraction from complex matrices such as soil, food, etc., and then further enhancement can be done by combining with microextraction.
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ASE was combined with DLLME for extraction of phenols from the soils. The analytes were first extracted from soil using ASE. Water was used as an extraction solvent. The extract was then used for DLLME. Prior to DLLME analytes were derivatized. ASE converted soil in liquid extract suitable for coupling with DLLME as solid samples cannot be directly extracted with DLLME. LODs were in the range of 0.06 – 1.83 ng/g [58]. ASE which is also known as pressurized liquid extraction (PLE) was used in combination with derivatization-UA-DLLME for extraction of carbohydrates in tobacco samples [59] and with DLLME for extraction of vitamin E in cosmetic products [60].
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2.6.Subcritical water extraction combined with DLLME
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Subcritical water extraction (SWE) is performed at temperatures between 100 and 374°C and pressure high enough to maintain the liquid state. Water has exceptional properties of disproportionately high boiling point for its mass, a high dielectric constant as well as high polarity. As the temperature increases, there is a noticeable and systematic reduction in permittivity, an upsurge in the diffusion rate and a decrease in the viscosity and surface tension. As a result, more polar analytes with high solubility in water at ambient conditions are extracted from the solid samples most efficiently at lower temperatures, whereas moderately polar and non-polar analytes require a less polar medium induced by elevated temperatures.
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SWE has many advantages compared to conventional organic solvent extractions. Subcritical water at high temperature may possess a permittivity very comparable to representative organic solvent, and this characteristic makes it conceivable to use water to selectively extract polar, mid-polar, and nonpolar substances simply by varying its temperature and pressure. SWE is anticipated as an alternative greener extraction method.
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However, when analytes are extracted from the solid samples using SWE, dilution can occur while transferring the analytes from solid to water. A lot of impurities can also coextract. Thus, certain strategies are required to concentrate and purify the analytes from the extract. The combination with DLLME presents one solution to this problem.
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SWE was integrated with DLLME and derivatization for extraction and enrichment of 13 endocrine disrupting chemicals in the sediment samples before their analysis by GC-MS. This study took advantage of the subcritical water and using water-miscible organic solvents both as an organic modifier for SWE and disperser solvent for DLLME. LODs were in the range of 0.006 to 0.639 ng/g [61]. This approach was previously used for extraction of hydroxylated-PAHs in sediment samples [22]. The analytical figures of merit of conventional extractions combined with DLLME are summarized in Table 2.
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3. DLLME combined with other miniaturized or microextraction techniques
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In this section, the combination of mini- or micro-scaled extraction techniques with DLLME is discussed. Techniques like dispersive and magnetic SPE, QuEChERS, and matrix solid phase dispersion are also included here, although one may argue regarding
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their scale of extraction. In that case, if such techniques do not perfectly fit to definition of microextraction, then they are at least mini-scaled compared to classical approaches. 3.1. Dispersive/magnetic solid phase extraction followed by DLLME
DSPE-DLLME can be performed either using single or double step procedure. The principal objectives of this combination are to achieve purification of the analytes, minimize the matrix effects and enrich the analytes in lesser volume of final extract. The function of the DSPE is the cleaning up of initial solvent extract. DSPE can also be assisted by ultrasound.
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DSPE-DLLME combination was introduced in 2009 for the extraction of sulfonylurea herbicides in the soil prior to their determination by HPLC-DAD. The soil samples were extracted in acetone and cleanup was performed by the C18 sorbent. The acetone extract was further subjected to DLLME and EFs of 102 – 216 were obtained [15].
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Single step DSPE-DLLME allows many processes to perform simultaneously. Sorbent based extraction, solvent extraction, and if required derivatization can be carried out in one step. Basically, this is the reason that ultra-high EFs can be achieved. The example of this kind is extraction and enrichment of aliphatic amines from atmospheric fine particles. EFs were in the range of 307 – 382 [62]. In the two step DSPE-DLLME, both techniques are performed separately. The objective of DSPE is to provide better clean up by employing a suitable adsorbent. This method was used for extraction of benzoylurea insecticides in soil and sewage sludge[63]. The other applications of DSPE-DLLME in food and environmental analysis are listed in Table S3.
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Probably the first method where MSPE was followed by DLLME was reported in 2013. Magnetic graphene was used for extraction of five chloroacetanilide herbicides in water samples and green tea samples. MSPE extract was further subjected to DLLME. The EFs were in between 3399 and 4002 [28]. Similarly, nano polypyrrole based MSPE combined with DLLME was used for extraction of megestrol acetate and levonorgestrel in biological samples prior to their quantitation by HPLC-UV. This method provided very high EFs (3680 – 3750) and ultra-low LODs (0.03 ng/mL) [64]. The affinity of the functional materials combined/coated over magnetic substrate can further enhance the EFs. MSPE employing octadecyl modified magnetic silica nanoparticles was utilized for extraction of phthalates in water. The average values of EFs for all the analytes were near 20000 resulting in a very low LODs (ng/L) [65].
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3.2.Quick, Easy, Cheap, Effective, Rugged, and Safe Method followed by DLLME
Quick, Easy, Cheap, Effective, Rugged, and Safe Method (QuEChERS) was originally introduced for extraction using acetonitrile as extraction solvent (with a mixture of inorganic salts) followed by a sorbent based dispersive cleanup [66]. This method has widespread applications for treating samples of complex composition. Excellent cleanup can be attained from QuEChERS, although, EFs are not that high. However, its coupling with DLLME is an inexpensive way to resolve this problem by further concentrating the analytes into extremely low volumes of extraction solvent consequently improving detection limits. The loss of analytes due to evaporative concentration can be avoided. 11
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This method provides a fast way to extract a large number of samples per working day, which favors its application in routine analysis.
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QuEChERS-DLLME based sample preparation has been widely used for analysis of pesticides in variety of food samples. Although authors did not use term QuEChERS, probably the first report on such combination was published in 2007 where OPPs in watermelon and cucumber were extracted by acetonitrile based extraction(solvent extraction) followed by DLLME [14]. Later a similar approach was used for extraction of multi pesticide residues in maize samples before their quantitation by GC-MS. In addition to excellent EFs, DLLME exhibited superb cleanup of polar matrix species, which resulted in enhanced sensitivity of single quadruple MS. EF was ten times higher than QuEChERS alone. [67]. Complex food samples cannot be extracted with DLLME alone, a supporting technique is required for cleanup. QuEChERS integrated with DLLME based on solidification of floating organic droplet (SFOD) was used for extraction of OCPs in fish. [68]. The schematic of this combination is shown in Fig 3.
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Generally, the acetonitrile extract obtained after QuEChERS is used as a dispersive solvent for DLLME. This again minimizes the use of organic solvents. Other applications in food analysis include extraction of pesticide residues in different food samples. The detail of the analytical figure of merits of these methods listed in Table S3.
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Fig 3. The combination of QuEChERS-DLLME (SFOD). Reproduced with permission from Ref [68]. Copyright (2016) Elsevier B.V.
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This combination has also been used for extraction of bisphenol A (BPA) and bisphenol B (BPB) in canned seafood samples. Besides the good EFs, the final DLLME extractive step was used for the simultaneous acetylation of the compounds for their gas chromatographic analysis [69]. The same combination was proposed for simultaneous 12
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extraction, concentration and derivatization of BPA and BPB in canned vegetables and fruits prior to GC–MS analysis. Method LODs were 0.3 and 0.6 µg/kg for BPA and BPB respectively [70]. Ionic liquids are reported as green alternatives to halogenated extraction solvents in DLLME. IL ([C6mim][Tf2N]) based DLLME was used for enrichment of BPA from acetonitrile extract [71].
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Apart from the applications in food analysis, this combination is also used for extraction of analytes in environmental samples, for example, co-occurrence of musk fragrances and UV-filters in both seafood and macroalgae collected in different European hotspots was investigated using the combination of QuEChERS-DLLME [72].
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Matrix solid phase dispersion (MSPD) technique was first introduced in 1989 for the extraction of drug residues from bovine tissue [73]. Since then, it has proved to be an efficient, versatile technique for extraction of several classes of analytes, from a wide variety of samples. Although MSPD was initially developed for extracting solid samples by disrupting/dispersing their architecture, it has also been applied to viscous and other liquid samples. The wide applicability of MSPD is due to its simplicity (it does not require any instrumentation or specific equipment), flexibility, and ruggedness compared to other extraction methods. The mild extraction conditions preserve analytes from degradation and denaturation. The selection of the solid support and elution solvent determine the efficiency and the selectivity of the process [42]. Generally, MSPD consumes low volumes of organic solvents, especially in its miniaturized form. It has great potential to be coupled with microextraction methods.
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Molecularly imprinted polymer (MIP) based MSPD was combined with DLLME for extraction of Sudan dyes in egg yolk. The MIP was blended with egg yolk and the eluent of MSPD was used as disperser solvent of DLLME. The EFs are in the range of 55 – 59 and method showed great potential for complex matrices [21].
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MSPD was combined with magnetic ionic liquid-based DLLME for extraction of triazine herbicides in oilseeds. Ionic liquids (ILs) are famous organic molten salts with low melting points formed from the combinations of organic cations and various anions. ILs display unique physicochemical properties, such as high chemical and thermal stabilities, negligible vapor pressures, wide ranges of viscosities, and lower toxicity than some organic solvents. Due to this, ILs are a good choice for DLLME. Magnetic ionic liquids (MILs) combine the properties of ILs with good phase separation of magnetic materials. However, most MILs are miscible with water or polar solvents due to the existence of protonated cations and the hydrophilic tetrachloro- or tetrabromoferrate (Ⅲ) anions, which bound their applications in aqueous solutions. On the contrary, MILs are generally immiscible with hydrophobic solvents. Thus, they were used for extraction in n-hexane. MSPD-DLLME provided LODs in the range of 1.20 – 2.72 ng/g [74]. The schematic of this combination is shown in Fig 4. Magnetic matrix solid phase dispersion (MMSPD) and DLLME were also combined and the obtained LODs were lower than any of the individual techniques [75]. Some other applications of MSPD and DLLME in food and environmental analysis are listed in Table S3.
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3.4.Dual and tandem DLLME
Dual DLLME in its original form was developed for extraction of analytes from oil samples. It comprised of reverse phase DLLME and standard DLLME. In the reverse phase DLLME, instead of toxic organic solvents, greener alternatives like surfactants were used as dispersants. As surfactants can damage the capillary column, second DLLME was performed to decrease their concentration, remove any other interferences, and increase the analytes in final extract [31]. In this way, dual DLLME is a combination of forward and backward DLLMEs. Forward DLLME is used to extract the analytes while backward DLLME is used to decrease the interferences and further enrich the analytes by back extraction. The schematic of the dual DLLME is shown in Fig 5.
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Fig 4. Schematic of MSPD-DLLME. Copied with permission from Ref [74]. Copyright (2015) Elsevier B.V.
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Figure 5. The proposed dDLLME method. (A) The n-hexane and extraction solution (containing TX-100) were injected into the oil sample; (B) a cloudy solution was obtained; (C) the supernatant was transferred to another tube; (D) water and ethyl acetate were added to the resulting supernatant; (E) a turbid solution was obtained; (F) the organic phase was mixed with internal standard, for GC–MS analysis [31].
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The process of derivatization is unavoidable for some analytes to enhance their sensitivity and detectability toward the detection system. In such cases, first DLLME is used to cleanup and enrich the analytes from the complex matrix. The analytes in the extract are then subjected to derivatization. The second DLLME is used to remove excess reagents and preconcentrate the derivatized analytes. The example of dual DLLME (DDLME) with in between derivatization includes extraction (PPD and PPT) in rat plasma [76].
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Simple DLLME is efficient with clean aqueous samples but many interferences can coelute while working with complex matrices. This also complicates the resulting chromatograms. Hence, a tandem DLLME was developed to solve this problem. For the extraction of basic drugs from wastewater and human plasma samples, two versions of DLLME, ultrasound assisted emulsification microextraction (UAEME) and air-agitated liquid-liquid microextraction (AALLME) were combined. In UAEME, basic drugs were extracted into organic solvent by adjusting the pH of the sample near alkaline region. In AALLME, basic drugs were back extracted into an acidic acceptor phase. The interferences co-eluted in the first DLLME, can be avoided by the back extraction step of second DLLME [32]. The other examples of tandem DLLME include extraction of pharmaceutical drugs in human plasma and pharmaceutical wastewater [77,78], and water [32,79].
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In short, both dual and tandem DLLME is performed by carrying out two DLLME procedures sequentially. They are suitable for liquid samples. Main advantages are
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Second DLLME can reduce the interferences that can co-elute with first DLLME. Analytes are extracted back into the extraction solvent of second DLLME.
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The situation where derivatization is performed with or after first DLLME, second DLLME can be used to remove excess derivatizing reagents, solvents, and catalysts. If not removed, these all can cause severe interferences in separation and detection of analytes.
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3.5.Salting out assisted homogenous liquid-liquid extraction combined with DLLME
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Homogeneous liquid-liquid extraction (HLLE) is based on a phase separation phenomenon in a homogeneous solution with a very small final volume. As HLLE has initially a homogeneous solution because there is no interface between the water and water-miscible organic solvent or between the water and water-immiscible solvent. Phase separation is achieved through salting-out phenomenon. This method is preferable due to its simplicity, rapidly achievable partition equilibrium, and enrichment of analytes in the extract. In addition, the water-soluble organic solvents used by this extraction technique are relatively environment friendly. SHLLE has also been performed in a narrow-bore tube for extraction of phthalate esters in real water samples. The phase separation was obtained using salting-out effect, and analytes were extracted into the fine droplets of extraction solvent that was collected on the surface of aqueous phase [80].
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Another version of SHLLE (where extraction solvent moves up and collected as upper layer) named counter current salting-out homogenous liquid-liquid extraction (CCSHLLE) followed by DLLME was introduced to attain high extraction recovery and EFs. In this method, firstly analytes are extracted into fine droplets of a mixture of 1,2dibromoethane and acetonitrile during CCSHLLE from the relatively high volume of aqueous sample. It does not require all sample pass through the narrow bore tube filled with NaCl making extraction more facile. Further enrichment is achieved by subjecting the final organic extract to DLLME. This combination has been used to determine some pesticide residues in well water, river water, and apple, sour cherry, and grape juices. EFs were in the range of 3480–3800 and LODs were 0.1 – 5 µg/L [29]. This combination has also been used for determination of pesticides in fruit juices [81]. CCSHLLE-DLMESFO was used for extraction of amphetamines in urine samples. This combination provides high EFs, and suitable for complex matrices without any pretreatment or dilution [82]. HLLE-DLLME was also used for extraction of PAHs in water samples and EFs in the range of 616 – 752 were obtained [83].
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3.6.Stir-bar sorptive extraction followed by DLLME
SBSE is a sample preparation technique that involves the extraction and enrichment of organic compounds from a liquid sample. In SBSE, the sorbent is coated on a magnetic stir bar which is stirred in the sample solution for an optimum time. After the extraction, the analytes can be introduced into the analytical system by thermal or liquid desorption. The key difference between SPME and SBSE is the much larger volume of sorbent used in the latter, which provides higher recoveries and higher sample capacity. SBSE can be combined with DLLME to achieve higher EFs and lower detection limits.
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The first application of SBSE-DLLME was reported probably in 2010 for extraction of pesticides in aqueous samples prior to their determination by GC-FID and GC-MS. EFs were in the range of 282–1792 [19].
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SBSE was combined with DLLME-SFO for extraction of PAHs in water samples followed by HPLC-UV analysis. This resulted in low LODs (0.0067 – 0.010 µg/L) and high EFs (1630 – 2637) [84].
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3.7. Micro-solid phase extraction followed by DLLME
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Micro-solid phase extraction (µ-SPE) is a miniaturized format of conventional SPE. It involves packing of few mg of the inside of a porous polymer membrane bag (µ-SPE device) packed through heat sealing [2]. µ-SPE can be directly immersed in samples of complex matrix composition as the sorbent is suitably protected inside the membrane. It significantly reduces the amount of sorbent and desorption solvents [85,86]. Such µ-SPE devices can be reused for 20 to 30 extraction/desorption cycles without substantial carryover effects as well as signs of tears and wears due to mechanical stress [87]. In other versions, µ-SPE is also performed by keeping few mg of the sorbent inside two frits and packing in a micro-cartridge [88]. In both cases, much-decreased volumes of the solvents are required. Interestingly, µ-SPE can be combined with other extractions.
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Vortex-assisted µ-SPE (VA-µ-SPE) followed by low-density solvent based DLLME (LDS-DLLME) was used for trace level determination of phthalate esters in environmental water samples. The analytes were first extracted by VA-µ-SPE and then desorbed in acetonitrile with the aid of sonication. Acetonitrile extract served as disperser solvent in subsequent LDS-DLLME. 4 mg of MWCNTs were used as a sorbent in VA-µSPE, while 30µL of n-hexane was used as an extraction solvent in DLLME. The LODs were as low as 0.006 µg/L [27].
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Apart from the above listed combinations, EME [24,25], HF supported liquid membrane [30], microextraction in packed syringe (MEPS) [34] have also been combined with DLLME.
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The key features of DLLME based methods combined with other extraction techniques are provided in Table 3.
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4. DLLME followed by other extractions 4.1.DLLME combined with SDME
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Low density solvent based DLLME was followed by SDME for extraction of chlorophenols in environmental water samples prior to their determination by HPLC-UV. A layered of LDS was formed over the aqueous layer after centrifugation. This layer was then brought into contact with a drop of acceptor phase and SDME was performed. The EFs were in the range of 67 – 309 [26].
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DLLME based on low-density solvent demulsification was also combined with SDME. It would be more appropriate to describe the procedure for understanding the objectives of 17
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the combination. A mixture of an extraction solvent and disperser solvent was rapidly injected into the aqueous sample to form a cloudy solution. Then a demulsifier solvent (acetonitrile) was injected. The emulsion became clear and the organic phase accumulated at the top of the aqueous phase. Then, a drop of acceptor solution was introduced into the upper layer and SDME was performed for the back-extraction. This combination does not require any electric equipment (centrifuge, stirrer or ultrasonic cleaner) because this prevents the centrifugation in DLLME and the stirring involved in SDME and LLLME. This combination was successfully used for extraction of sulfonamides in environmental waters prior to their analysis by HPLC. The LODs were in the range of 0.22 to 1.92 µg/L [89]. 4.2. DLLME with dispersive micro solid phase extraction
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DLLME and dispersive microsolid-phase extraction (D-µ-SPE) was developed for the fast extraction of PAHs in environmental samples. The new technique gives the flexibility to use any organic solvent immiscible with water (high or low density) as an extraction solvent in DLLME. It also eliminates the need for special apparatus, such as conical-bottom test tubes, and tedious procedural steps of centrifugation, refrigeration of the solvent, and then thawing it, associated with classical DLLME. In the first step, organic solvent is injected and vortexed in sample solution to extract the analytes. In the second step, a derivatized magnetic sorbent is used to capture the analyte containing solvent droplets. The magnetic sorbent is derivatized to interact with the organic solvent instead of the analytes. Brief procedure is given below.
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The first step involved the rapid injection of 20 µL of 1-octanol into 20 mL sample solution vial for DLLME. Then, the vial was sealed and swirled on a vortex agitator 3200 rpm for 120 s. After that, 10 mg of the derivatized magnetic nanoparticles were quickly added to the vial to target the extractant droplets instead of PAHs. The vortex was turned on for another 60 s. The external magnet was used at the bottom of the vial to isolate the nanoparticles and sample solution was discarded. With the magnet still in place, an aliquot of water (0.5 mL) was added to the vial to rinse the residue. After that magnet was removed, and 1-octanol as well as the PAHs from the nanoparticles, were desorbed in 100 µL acetonitrile by sonication for 4 min. Finally, the magnet was again used to separate the adsorbent, and the supernatant was collected for analysis. This method provided EFs ranging from 110- to 186-fold. The limits of detection were in the range of 11.7−61.4 pg/mL [16].
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4.3. DLLME followed by magnetic solid phase extraction
A two-step extraction technique combining IL-DLLME with magnetic solid-phase extraction (MSPE) was developed for the preconcentration and separation of aflatoxins in animal feedstuffs prior to their analysis by HPLC with fluorescence detection. An ionic liquid 1-octyl-3-methylimidazolium hexafluorophosphate was employed as an extraction solvent in DLLME, and hydrophobic pelargonic acid modified Fe3O4 MNPs were used to retrieve the aflatoxins-containing ionic liquid. The objective of using MNPs was to target the ionic liquid rather than the aflatoxins. Because of the rapid mass transfer related to DLLME and magnetic solid phase steps, fast extraction can be attained. The detection 18
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limits were 0.632, 0.087, 0.422 and 0.146 ng/mL for aflatoxins B1, B2, G1, and G2, respectively. IL-DLLME-MSPE provided superior results than direct MSPE [90]. DLLME followed by magnetic nanoparticles based D-µ-SPE for extraction of PCBs in juices [91]. 4.4.DLLME followed by SPME
In SPME, analytes are extracted by a sorbent coated on a fiber. Depending on the vapor pressure of the analytes, SPME can be performed in the headspace or direct immersion mode. SPME has many advantages such as simplicity, solvent-free nature, high EFs, applicable to wide range of matrices, in vivo sampling and offline or online coupling with analytical instruments. The nature of the fiber coating plays an important role for the extraction of polar, semi-polar and non-polar compounds. Therefore, the choice of sorbent phase can provide selectivity in this method. However, the disadvantages of SPME include limited available polar-sorbent coatings for the extraction of polar analytes, the damage of fiber coating by an organic solvent, and acidic or basic solution. In addition, the partitioning of the analyte among the sample, headspace and fiber coating can affect the extraction efficiency. Complex matrices may affect the active adsorption/absorption sites on SPME coating.
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DLLME offers many advantages such as low consumption of solvents, short extraction times, and flexibility to use low or high-density solvents, better cleanup and easy operation. Besides the advantages, DLLME has some limitations related to the matrix effect and the use of toxic solvents, very little volume injection to the detection system out of total DLLME extract that may reduce sensitivity especially at ultra-trace levels in the complex matrices. DLLME with SPE and µ-SPE as sorbent-based extraction techniques have been discussed with advantages of high EFs and high clean up capability. However, the limitations of these combinations are the use of large sample and solvent volumes.
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The combination of DLLME and SPME was proposed to take benefit of the advantages of two methods while overcoming their abovelimitations. In this combination, DLLME was performed first and its extract was transferred to another vial with septum where the extract including solvent and analytes were subjected to total vaporization. SPME was performed in the headspace. However, this approach has limitations related to nonvolatile analytes and stripping of SPME coating [33]. The GC analysis of the whole organic extract obtained by DLLME can also be accomplished by the placing it in a microvial insert thermal desorption, an approach that uses a thermal desorption injector [56,92].
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5. Green aspects of DLLME based binary extraction techniques
Recent developments in sample preparation techniques are aimed to introduce green character in extraction procedures. There are several ways which contribute greenness in an extraction procedure: (i) (ii) (iii)
Eliminating or minimizing the use of solvent Replacing the conventional sorbents and solvents with the green alternatives Reducing the scale of extraction from macro to micro and nano. 19
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Use of the green energy media such as microwave and ultrasound instead of conventional heating.
DLLME is a modern solution to classical LLE, it is a solvent minimized microextraction technique that offers an efficient extraction of target compounds in variety of sample media. However, it cannot handle solid or complex matrixed samples directly. Thus, its combination with other conventional or micro- extraction techniques has been suggested a viable way to solve the potential limitations of DLLME while maintaining its advantages of better sensitivity and high EFs.
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DLLME based binary extractions involve the combination of two extraction techniques which ultimately increases the overall number of steps. This aspect is not favored by GAC. However, based on the literature survey, still there is a room to make the binary procedures green in a way that an agreement can be reached between method’s performance and greenness. For example, the solvents for binary procedures can be selected in a way that extract of first technique can be used as disperser solvent of the DLLME. This will reduce overall consumption of the solvents. In DLLME, dispersion can be achieved using alternative ways such as use of dispersing solids, air, multiple withdrawing and injecting by a syringe, etc. In case derivatization is required, DLLME and derivatization can be performed simultaneously. The derivatization solvent can be selected to act as disperser solvent as well. Apart from all the claims of greenness in any extraction procedure, it would be scarce to declare any method green without taking into account the volumes of the solvents and reagents used, health and safety hazards associated with them, energy requirements, and status and handling of the generated waste.
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When discussing the green aspects, it would be more appropriate to consider the whole analytical method from sample collection to final determination. During the sample preparation different steps are involved that may utilize the solvents, reagents, energy and produce a waste. Similarly, the analytical instruments may utilize some solvents and energy and produce some waste. It is therefore difficult to claim, or present one method as green analytical method only based on the amount of the solvent. It is therefore necessary to have some scale to evaluate the greenness of an analytical methods.
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Over the years, number of tools have been developed to evaluate the green nature of the analytical processes accounting the different parameters. The first tool that was introduced in this regard was NEMI labelling [93]. It is based on a circle that consists of four partitions. Each partition is labelled green if the certain requirements are filled. The first partition is related to reagents employed, it is represented as PBT (Persistent, bioaccumualtive, toxic). This partition will only be considered green if none of the solvents or reagents in analytical procedure belong to PBT category. The second partition is related to nature of the waste generated during the analytical procedure. This partition will be labelled as green if none of the chemicals employed in an analytical procedure belong to U, P, D, or F hazardous waste category. The third partition belongs to the corrosive nature of the chemicals. If the pH is in the range of 2 – 12, the corrosive
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partition is filled green. The fourth partition is related to amount of the waste, if it is less than 50 g, the partition will be filled with green color. The advantage of NEMI labelling is one can guess the nature of analytical procedure by just having a look on the pictogram. However, it provides only qualitative information scale. Some improvements in the NEMI procedure were suggested by de la Guardia and Armenta [94]. They suggested to use red, yellow, and green colors in each partition of NEMI pictogram representing non-environment friendly, moderate environment-friendly, and benign environment friendly respectively. Based on this three-degree scale, NEMI seems more quantitative.
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The third tool in this connection is Analytical Eco-Scale [95]. This is based on assigning the penalty points to the reagents, waste, energy, their amount with regards to health and safety hazards associated with them. This tool considers all the steps involved in an analytical procedure from sample collection to final determination. The penalty points are subtracted from 100 to get the total score of the analytical Eco-Scale. The closer the score to 100 the greener the procedure is. This method provides even improved and quantitative information on the greenness of an analytical procedure. Although, Eco-Scale compares different parameters and steps in the analytical process, it still does not provide comprehensive information about the evaluated protocols. It is not conclusive about the nature and structure of hazardous chemicals.
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With the passage of time, new tools are being introduced for assessing the greenness of an analytical procedure which can reveal more information about the nature of the procedure. The most recent tool in this regard has been introduced by Plotka-Wasylka, named as green analytical procedure index (GAPI) [96].
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In GAPI, a specific symbol with five pentagrams can be used to assess and enumerate the environmental impact involved in each step of an analytical procedure, mainly from green through yellow to red portraying low, medium to high impact, respectively. It assesses the nature of entire analytical procedure based on values assigned to the reagents and their volume, energy and its amount, waste and its amount plus handling. It also considers whether the sample preparation/extraction is required or not and its scale such as nano-, micro-, and macro- extraction. A simple look at the resulting diagram will give a comparative idea of greenness among different methods. Compared to NEMI, more parameters can be glanced in a single view using GAPI. The GAPI has been employed to access the greenness of some selected DLLME based binary extraction methods (Fig 6).
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6. Conclusion and future recommendations
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Figure 6. Evaluation of greenness of some methods based on GAPI (a) SFC-DLLME [44] (b) UAE-DLLME [18] (c) T-DLLME [77]
The concept of combined DLLME based methods has been introduced to deal with special sample preparation scenarios or to eliminate the drawbacks associated with individual techniques. DLLME has been combined both with conventional and microextractions. DLLME is either performed after or before the other extraction. The combinations where DLLME is performed after the other extractions are aimed to provide a clean extract for DLLME application that can further enrich the analytes. In most of the applications, the role of DLLME based combined methods is centered on achieving one or more of the following objectives (i) (ii) (iii) (iv)
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Dealing with the samples originating from complex matrix composition To obtain higher cleanups To get higher EFs that will enhance the sensitivity of analysis To make trace or ultra-trace level analysis possible
SPE-DLLME is the best choice to deal with complex samples particularly when one has the liberty of sample size. Ultra-high EFs up to 50,000 and ultra-low LODs down to ppq level have been reported. However, the requirement of the large volume of samples is a limitation. Dual or tandem DLLME can be a good choice to deal with complex or low volume liquid samples. Both sample cleanup and EFs can be achieved. QuEChERs or DSPE followed by DLLME is another solution for getting cleanup as well as preconcentration. Despite all the advantages of DLLME based combined methods, they may be time-consuming, as one has to perform two methods separately and look for optimum conditions for both. As such methods are performed in steps, a poor precision may result because an additional step may introduce potential errors. Moreover, working at ultra-trace concentrations may result in poor repeatability.
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Apart from the above said limitations, two major drawbacks associated with DLLME based combined extraction methods are
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Difficulties associated with automation of the both combined techniques, as in majority of the cases, they are performed separately and manually. 22
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Online coupling with the analytical instruments
These two problems should be well thought out to further the research in this area. The automation and online coupling will reduce the manual labor as well as chances of error. This is true that a lot has been done concerning the automation of DLLME with chromatographic instruments [97], the automation opportunities of DLLME based combined methods still need to be studied/investigated in the future.
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Acknowledgements
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The authors gratefully acknowledge the support of King Fahd University of Petroleum and Minerals. Muhammad Sajid would like to thank and acknowledge Center for Environment and Water (CEW), Research Institute, King Fahd University of Petroleum and Minerals, Saudi Arabia.
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The authors certify that they have no conflict of interest in the subject matter or materials
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discussed in this manuscript.
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M. Sajid, C. Basheer, M. Daud, A. Alsharaa, Evaluation of layered double hydroxide/graphene hybrid as a sorbent in membrane-protected stir-bar supported micro-solid-phase extraction for determination of organochlorine pesticides in urine samples, J. Chromatogr. A. 1489 (2017). doi:10.1016/j.chroma.2017.01.089.
1157 1158 1159 1160
[86]
M. Sajid, C. Basheer, K. Narasimhan, M. Choolani, H.K. Lee, Application of microwave-assisted micro-solid-phase extraction for determination of parabens in human ovarian cancer tissues, J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 1000 (2015) 192–198. doi:10.1016/j.jchromb.2015.07.020.
1161 1162 1163 1164
[87]
M. Sajid, C. Basheer, A. Alsharaa, K. Narasimhan, A. Buhmeida, M. Al Qahtani, et al., Development of natural sorbent based micro-solid-phase extraction for determination of phthalate esters in milk samples, Anal. Chim. Acta. 924 (2016) 35–44. doi:10.1016/j.aca.2016.04.016.
1165 1166 1167 1168
[88]
H. Bagheri, M. Zare, H. Piri-Moghadam, A. Es-haghi, A combined micro-solid phase-single drop microextraction approach for trace enrichment of volatile organic compounds, Anal. Methods. 7 (2015) 6514–6519. doi:10.1039/C5AY01077B.
1169 1170 1171 1172 1173
[89]
X. Li, Q. Li, A. Xue, H. Chen, S. Li, Dispersive liquid–liquid microextraction coupled with single-drop microextraction for the fast determination of sulfonamides in environmental water samples by high performance liquid chromatography-ultraviolet detection, Anal. Methods. 8 (2016) 517–525. doi:10.1039/C5AY02619A.
1174 1175 1176 1177 1178
[90]
J. Zhao, Y. Zhu, Y. Jiao, J. Ning, Y. Yang, Ionic-liquid-based dispersive liquidliquid microextraction combined with magnetic solid-phase extraction for the determination of aflatoxins B1, B2, G1, and G2 in animal feeds by highperformance liquid chromatography with fluorescence detection, J. Sep. Sci. 39 (2016) 3789–3797. doi:10.1002/jssc.201600671.
1179 1180 1181
[91]
R.A. Pérez, B. Albero, J.L. Tadeo, C. Sánchez-Brunete, Oleate functionalized magnetic nanoparticles as sorbent for the analysis of polychlorinated biphenyls in juices, Microchim. Acta. 183 (2016) 157–165. doi:10.1007/s00604-015-1617-2.
1182 1183 1184 1185
[92]
J.I. Cacho, N. Campillo, P. Viñas, M. Hernández-Córdoba, In situ ionic liquid dispersive liquid-liquid microextraction coupled to gas chromatography-mass spectrometry for the determination of organophosphorus pesticides, J. Chromatogr. A. (2017). doi:10.1016/J.CHROMA.2017.12.059.
1186 1187
[93]
L.H. Keith, L.U. Gron, J.L. Young, Green Analytical Methodologies, Chem. Rev. 107 (2007) 2695–2708. doi:10.1021/cr068359e.
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M. de la (Miguel de la) Guardia, S. (Sergio) Armenta, Green analytical chemistry : theory and practice, Elsevier, 2011.
1190 1191 1192
[95]
A. Gałuszka, Z.M. Migaszewski, P. Konieczka, J. Namieśnik, Analytical EcoScale for assessing the greenness of analytical procedures, TrAC Trends Anal. Chem. 37 (2012) 61–72. doi:10.1016/J.TRAC.2012.03.013.
1193 1194 1195
[96]
J. Płotka-Wasylka, A new tool for the evaluation of the analytical procedure: Green Analytical Procedure Index, Talanta. 181 (2018) 204–209. doi:10.1016/J.TALANTA.2018.01.013.
1196 1197 1198
[97]
L. Guo, H.K. Lee, Automated Dispersive Liquid–Liquid Microextraction–Gas Chromatography–Mass Spectrometry, Anal. Chem. 86 (2014) 3743–3749. doi:10.1021/ac404088c.
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Table 1. Key features of the methods combining SPE and DLLME
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1201
NC
Matrix
SPE sorbent
SPEDLLME
Fungicides
7
Wine
SPEDLLME
PBDEs
7
Water
RP-OASIS Acetone HLB (60 mg) LC-C18 n-hexane column (1 g)
SPEDLLME
Chloropheno ls
19
Water
SPEDLLME
OPPs
6
Water
SPEDLLME
Pyrethroids
8
SPEDLLME SPE-
aflatoxins
4
Acetone
TE D
Functionaliz ed styrenedivinylbenze ne polymer (PPL) (100 mg) RP C-18 stationary phase (500 mg) Cleanert florisil (1000 mg/6 mL)
SPE eluent
DLLME extraction solvent 1,1,1trichloroeth ane 1,1,2,2tetrachloroe thance chlorobenz ene
Instrument
EFs
GC-ECD GC-MS
156 254
GC-ECD
6838 – 4.2 – 7.9 9405
GC-ECD
CCl4
GC-MS
4390 – 1.1 – 6.4 0.0005 – 0.1 [13] 17870 (with IS) and 2.5 – 9.7 (without IS). 20000 – 8.6 – (38 – 230) × [37] 50000 10.4 10-6
SC
Analytes
M AN U
Method
AC C
1202
EP
Acetone
Benzodiazepi 3
Cereals
Pistachi os Human
C18 (3 mL)
nⅢ Chlorobenz hexane/acet ene one (v/v, 8:2) Methanol CHCl3
HPLC-FD
Ethanol
HPLC-UV
DCM
GC-MS
18.1 25.7
RSDs (%) –
LODs (ppb ppb) ppb
1 – 15
– 3.6 10.9
Ref.
[35]
0.04 – 0.16
– 0.2 – 4.0
7.4 – 0.02 – 0.04 12.5 3.2 – 8.8 0.07 – 0.7
34
[36]
[38]
[43] [39]
nes
SPEDLLME
Amphetamin es
4
SPEDLLME
Carbamazepi ne
1
urine and plasma Urine and plasma
Carbon disulfide
6.1 13.5
– 0.1 – 0.5
1206 1207 1208
M AN U
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EP
1205
HPLC
AC C
1204
CHCl3
HPLC-UV
[40]
170 4.2 (aq), 0.4 (aq), 0.8 [41] (aq), 7.8 (urine) and 132 (urine), 1.7 (plasma) (urine), 9.6 105 (plasma) (plasma ) *extraction solvents indicate only the extraction solvents of DLLME. Any conditioning, washing, reconstituting, derivatization or disperser solvents are not mentioned here. NC, number of compounds; ACN, acetonitrile; CCl4, Carbon tetrachloride; DCM, dichloromethane; CHCl3, chloroform; 1203
Urine and plasma
Fe3O4 Methanol nanoparticle s was coated by sodium dodecyl sulfate C18 ACN
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DLLME
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Table 2. Key features of the methods combining some conventional extraction techniques and DLLME Matrix
Solvent for 1st technique ACN (CS)
SFEDLLME SFEDLLME
PAHs
10
OPPs
7
MAEDLLME MAEDLLME MAEDLLME MAE-SPPDLLME
Nnitrosamines PAHs
9
Marine sediments Soil and ACN marine sediments Meat NaOH
16
Polyamines
3
Smoked fish Meat
Antimicrobial pharmaceutica ls MAEHaloanisoles DLLMEand Derivatizatio halophenols n
6
Fish
8
Cork Methanol stoppers and oak barrel sawdust
UAEDLLME UAEDLLME
OPPs
13
Tomatoes
Acetone
Caffeine
42
Tea
Methanol
Extraction solvent of DLLME Chlorobenze ne CCl4
CCl4
EFs
RSDs (%)
LODs (ppb)
Ref.
GC-FID
88 – 286
1.3 – 10.3
200
[17]
GC-FID
67 – 144
3.1 – 7.5
1.0 – 9.0
[44]
GC-MS
220 342 244 373 190 305
Ethylene tetrachloride 1-octanol
GC-MS HPLC-UV
DCM
LC-MS/MS
CCl4
GC-ECD
Chlorobenze ne CHCl3
GC-FPD
EP
TE D
KOH:Ethano l (1:1) Perchloric acid ACN
Instrumen t
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NC
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Analytes
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Method
AC C
1210
GC-MS
4.0 42.6
– 5.9 – 10
0.12 – 0.56 – 2.8 – 9.0 0.11 – 0.43 – 6.72 – 0.24 – 7.30 0.42 1.7 – 3.6 (4.54 – 101.3) ×10-6 <11.2 0.032 – 0.092 (Cork stoppers) 0.016 – 0.046 (Oak barrels) <10 0.1 – 0.5
– 4.8
0.3
[45] [46] [47] [48]
[49]
[18] [51]
36
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28
Saffron
Methanol/A CN Acetone
CHCl3
GC-MS
7
OPPs
4
Nitrophenols
6
Marine sediments Soil samples Soil
Isooctane
GC-MS
Methanol
1-undecanol
Methanol
DCM
UAEDLLME ASEDLLME PLE-D-UADLLME
Phthalate metabolites Phenols
7
Nails
TFA:MeOH
4
Soil
Water
Carbohydrates
11
Tobacco
50:50 ethanol/wate r ACN
3.6 41.3 -
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Volatile components PCBs
GC-MS
6890– 8830
LVI-GCMS
TE D
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UAEDLLME UAEDLLME USL-SPEDSLLME UAEDLLME
AC C
EP
PLEVitamin E Cosmetics DLLME SWEEDCs 13 Sediments Water with DLLME10% acetone Derivatizatio n SWEOH-PAHs 8 Sediments Water with DLLME20% ACN Derivatizatio n Solvent for 1st technique refers to collecting solvent in case SFE.
Trichloroeth ylene chlorobenzen e CHCl3
CCl4 Chlorobenze ne
Chlorobenze ne
UPLCMS/MS GC-MS
-
GC-FID
Capillary LC-UV GC-MS
GC-MS
-
– 2.48 9.82 <7.6
– (6 – 123) ×103 0.021 – 0.057 4.06 – 8.9 0.012 – 0.2 12.2 – 0.4 – 0.8 18.5 (without IS) 4.2 – 11.1 (with IS) 8.8 – 17.1 2 – 14
[53] [54] [55] [56]
[57]
5.06 – 0.006 – [58] 9.17 1.83 2.1 – 6.6 60 – 900 [59]
<7.8
3 – 15
[60]
1.5 – 15
0.006 0.639
– [61]
2.81 11.07
– 0.0139 – [22] 0.2334
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Table 3. Key features of the miniaturized extraction techniques combined with DLLME methods
Sulfonylurea herbicides Aliphatic amines Benzoylurea insecticides Megestrol acetate and levonorgestrel Phthalates
4
2
OCPs
13
BPA and BPB
2
BPA
1
QuEChERSDLLME (SFOD) QuEChERSDLLME QuEChERSIL-DLLME MIP-MSPDDLLME MSPDDLLME MMSPDDLLME
Sudan dyes Triazine herbicides PCBs
8 2
RSDs (%)
Canned seafood Canned food
AC C
MSPEDLLME
10
Extraction solvent Instrument EFs of DLLME Soil Chlorobenzene HPLC102 – DAD 216 Atmospheric DCM GC-MS 307 – fine particles 382 Soil and sludge 1-undecanol HPLC-UV 104 – 118 Biological Dihexyl ether HPLC-UV 3680 samples – 3750 Water Tetrachloroethylene GC-FID 17749 – 21278 Fish 1-undecanol GC-ECD
SC
DSPEDLLME DSPEDLLME DSPE-VADLLME MSPEDLLME
Matrix
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NC
TE D
Analytes
EP
Combination
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Ref.
5.2 – 7.2
LODs (ppb) 0.5 – 1.2
<7.0
0.03 – 0.09
[62]
2.16 – 6.26
0.08 – 0.56
[63]
5.3 – 5.9
0.03
[64]
6.8 – 10.4
0.002 0.003
<15
0.65 – 1.58
[68]
<20
0.2 – 0.4
[69]
0.1
[71]
2.3 – 6.1
[21] [74]
C2Cl4
GC-MS
[C6mim][Tf2N]
HPLC-UV
98
<7.2
55 59
– 2.9 – 6.7
4
Egg yolk
Tetrachloroethylene
HPLC-UV
6
Oilseeds
[C4mim][FeCl4]
UFLC-UV
<7.7
1.20 – 2.72
5
Water
Chlorobenzene
GC-ECD
4.9 – 8.2
0.00005 0.0001
[15]
– [65]
– [75]
38
Psychotropic drugs
3
CCSHLLEDLLME
Pesticides
11
CCSHLLEDLLME CCSHLLEDLLME-SFO HLLEDLLME SBSEDLLME SBSEDLLME-SFO
Pesticides
7
Fruit juices
Amphetamines
2
Urine
PAHs
5
Water
Triazole pesticides PAHs
LDS-SD-
Sulfonamides
TDLLME
3
6
3
UHPLCMS/MS HPLC-UV
164 182 75 – <6.5 100
0.010 0.015 0.8 – 1.0
HPLC-UV
63 – 4.5 – 9.2 94 50 – <6.2 101
3 – 10
[79]
0.7 – 1.0
[32]
HPLC-UV
88 99
1.0 – 1.5
[78]
GC-FID
3480 3800 544 600 157 – 168 616 – 752 282 – 1792 1630 – 2637 6 – 91
2–7
0.1 - 5
[29]
2–6
2 – 12
[81]
<5
0.5 – 2
[82]
<6
0.08 – 0.20
[83]
<5.2
0.53 – 24.0 [19] (GC-FID) 0.0067 – [84] 0.010
RI PT
3
M AN U
TDLLME
Rat plasma
TE D
2
Pharmaceutical drugs TCAs
2
EP
DUADLLME- PPD and PPT MAD TDLLME Beta blockers
SC
TDLLME
Bromocyclohexane, Bromobenzene Human plasma 1,2-dichloroethane, and water pharmaceutical wastewater Aqueous CCl4, acidic aqueous matrices solution Wastewater 1,2-dichloroethane, and plasma acidic aqueous solution Pharmaceutical CCl4, acidic aqueous wastewater solution and human plasma Aqueous 1,2-dibromoethane
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1,1,2,2tetrachloroethane 1-undecanol
HPLC-UV
GC-FID HPLC-UV
1,1,2‐trichloroethane GC-FID
Aqueous samples Water
1,1,2,2‐ tetrachloroethane
Environmental
1-octanol
GC-FID, GC-MS HPLC-UV
HPLC-UV
– <9.3
2.17 – 6.92
<4.6
– [76] [77]
0.22 – 1.92
[89]
39
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DLLMESDME IL-DLLMEMSPE
waters Animal feed
1-octyl-3HPLC-FD methylimidazolium hexafluorophosphate DLLMEParathion and 2 Environmental 1,1,2,2GC-CDSPME diazinon waters and tetrachloroethane IMS fruit juices Dual-DLLME Phenylpropenes 6 Oils Triton X-100 in GC-MS ACN, Ethyl acetate NC: number of compounds; only DLLME extraction solvents are listed.
1214
1220 1221 1222 1223
0.007 0.020
– [33]
1.0 – 3.0
[31]
EP
1219
– [90]
AC C
1218
2965 <10 – 3150 3.2 – 2.61 – 4.33 37.1
0.087 0.632
TE D
1215
1217
– 3.2 – 6.4
M AN U
1213
1216
22 25
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4
SC
Aflatoxins
1224
40
ACCEPTED MANUSCRIPT
1225
List of abbreviations
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1226 1227
DLLME: Dispersive liquid-liquid microextraction
1229
SPE: Solid phase extraction
1230
EFs: Enrichment factors
1231
SFE: Supercritical fluid extraction
1232
MAE: Microwave assisted extraction
1233
UAE: Ultrasound-assisted extraction
1234
SWE: Subcritical water extraction
1235
OPPs: Organophosphorus pesticides
1236
PBDEs: Polybrominated diphenyl ethers
1237
OCPs: Organochlorine pesticides
1238
PPCPs: Pharmaceutical and personal care products
1239
PAHs: Polyaromatic hydrocarbons (PAHs)
1240
GC–FPD: Gas chromatography-flame photometric detection
1241
PLE: Pressurized liquid extraction
1242
DSPE: Dispersive solid phase extraction
1243
VA: Vortex assisted
1244
MSPE: Magnetic solid phase extraction
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SFO: Solidified floating organic drop
1246
GC-MS: Gas chromatography mass spectrometry
1247
GC-FID: Gas chromatography flame inonization detection
1248
GC-ECD: Gas chromatography electron capture detection
1249
HPLC: High performance liquid chromatography
1250
LC-MS/MS: Liquid chromatography tandem mass spectrometry
1251
QuEChERS: Quick, Easy, Cheap, Effective, Rugged, and Safe Method
1252
MSPD: Matrix solid phase dispersion
1253
MMSPD: Magnetic matrix solid phase dispersion
1254
DDLLME: Dual DLLME
1255
TDLLME: Tandem DLLME
1256
BPA: Bisphenol A
1257
BPB: Bisphenol B
1258
MAD: Microwave assisted derivatization
1259
ACN: Acetonitrile
1260
MIPs: Molecularly imprinted polymers
1261
ILs: Ionic liquids
1262
MILs: Magnetic ionic liquids
1263
TCA: Tricyclic antidepressant drugs
1264
LODs: limits of detection
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UA-DLLME: Ultrasound-assisted DLLME
1266
HLLE: Homogeneous liquid-liquid extraction
1267
SHLLE: Salting out assisted HLLE
1268
CCSHLLE: Counter current SHLLE
1269
SBSE: Stir bar sorptive extraction
1270
HF-LPME: Hollow fiber liquid phase microextraction
1271
SPME: Solid phase microcextraction
1272
µ-SPE: Micro-solid phase extraction
1273
SDME: Single drop microextraction
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Highlights •
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Sample preparation methods combining DLLME with other extraction techniques for chromatographic analysis are discussed. The objectives and merits of each combination are critically appraised. Applications of DLLME based combined extraction methods are provided.
S0165-9936(18)30302-9
DOI:
10.1016/j.trac.2018.08.016
Reference:
TRAC 15226
To appear in:
Trends in Analytical Chemistry
Received Date: 11 July 2018 Revised Date:
20 August 2018
Accepted Date: 23 August 2018
Please cite this article as: M. Sajid, K. Alhooshani, Dispersive liquid-liquid microextraction based binary extraction techniques for chromatographic analysis: A review, Trends in Analytical Chemistry (2018), doi: 10.1016/j.trac.2018.08.016. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Dispersive liquid-liquid microextraction based binary extraction techniques for chromatographic analysis: A review
1 2 3
Muhammad Sajid a,*, Khalid Alhooshani b
4 5
a
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Center for Environment and Water, Research Institute, King Fahd University of Petroleum and Minerals, Dhahran 31261, Saudi Arabia. b
Department of Chemistry, King Fahd University of Petroleum and Minerals, Dhahran 31261, Saudi Arabia.
8 9
*Corresponding author email: [email protected]; [email protected] Abstract
11 12 13 14 15 16 17 18 19 20
The recent developments in the analytical sample preparation signpost a trend of combining dispersive liquid-liquid microextraction (DLLME) with other extraction techniques. The objectives of these binary techniques are inclined toward achieving an improvement in separation, cleanup, detection limits, enrichment factors, and coping with complex matrices. DLLME has been combined with both conventional and micro- or miniaturized methods. It has been either followed by or following another extraction in the combination. This review aims to highlight and share the progress in this area with the analytical community. The objectives and merits of each combination are critically appraised. At the end, a brief description is provided on accomplishments, limitations, and future directions
21
Keywords
22 23
DLLME; Combined extraction methods; Analytical sample preparation; Microextraction; Preconcentration; Chromatographic analysis; Samples with complex matrix
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1. Introduction
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Despite all the key developments in analytical instrumentation, sample preparation is still considered as a bottleneck in the quantitative chemical analysis. The area of sample preparation is driven by the requirement of trace-level analysis, instrument incompatible sample matrices, and recent regulatory obligations [1]. The sample preparation is performed with the aim of getting improved separations, clean up, enrichment factors (EFs), and bringing the analytes into an instrument compatible medium. Both the conventional as well as micro- extractions are used for sample preparation and possess their own advantages and pitfalls. Conventional extraction techniques are exhaustive in nature and provide an efficient extraction and clean up while micro- extractions are based on equilibrium and directed toward miniaturization of extraction devices, reduction in the use of chemicals, and to explore the possibilities of automation with analytical instrumentation. Micro- extractions are also recognized for their better extraction performance, enhanced sensitivity and selectivity, and many other analytical figures of merit [2].
39 40
DLLME has been introduced by Assadi and co-workers in 2006 [3] and it immediately attained the attention of the researchers. DLLME is based on a ternary solvent system, in
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(i) (ii) (iii)
(iv)
The injection of extraction and disperser solvents into the sample. The formation of a cloudy solution/emulsion due to the cosolvency of the disperser solvent with two other solvents. The establishment of extraction equilibrium in a short time based on the extensive surface contact between the droplets of the extraction solvent and the sample. Centrifugation to obtain the sedimented extraction phase, which is enriched with analytes.
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45 46 47 48 49 50 51 52
which a disperser solvent is injected along with the extraction solvent into the aqueous sample. As clear from the name, the role of the disperser solvent is to disperse the extraction solvent within the aqueous sample solution to achieve better extraction. Briefly, a typical DLLME procedure consists of the following processes
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41 42 43 44
Over the period of time, DLLME has gone through an extensive evolution with regards to special extraction devices, achievement of dispersion through the aid of different processes such as microwave, ultrasound, vortex, manual shaking, agitation, magnetic stirring etc., a search of less-toxic solvents, and attaining de-emulsification without centrifugation [4]. The major advantages of DLLME are the requirement of the negligible amount of extraction solvent, rapid extraction, and high EFs due to the high phase ratio of donor to acceptor phase. Moreover, it is simple, quick, efficient, and meets most of the Green Analytical Chemistry aspects. These aspects include reduction of the solvent volume, search and application of green solvents, energy effectiveness, and less waste generation [5]. Nevertheless, this technique also possesses certain limitations, which primarily result from the requirements related to the extraction and disperser solvents, toxic nature of the commonly used halogenated solvents, and special design of the extraction devices.
66 67 68 69 70 71 72 73
To address some of the limitations of DLLME and deal with the certain scenario of sample preparation, DLLME has been combined with other macro- and microextractions. A combination of DLLME with other techniques has been proposed as a feasible way to birth a novel extraction method that can draw synergistic advantages of the individual methods while introducing its own unique merits. In addition, this is a way to reduce the disadvantages of individual techniques and solve the problems related to special sample preparation scenarios. At this stage, DLLME based combined methods represent a developing area of research in the field of sample preparation.
74 75 76 77 78 79 80 81 82 83
Many review articles have been published in the area of DLLME covering different aspects from its evolution to applications [4,6–10]. Although some of these and other earlier articles [11] and our recent article discussed in brief the combination of DLLME with other techniques [12] but there is no specific article, which covered DLLME based binary extraction techniques with an adequate detail. Secondly, an update is required to cover recent advancements. Hence, this article aims to review DLLME based combined methods and evaluate their role in enhancing the efficiency of the entire analytical process from extraction to the determination. This review will provide an overview of the objectives of such methods, the limitations of individual methods that can be overcome by combination, and the scenarios where such methods can be a good choice. The
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applications of these methods in environmental, food, and biological analysis are discussed in sufficient detail.
86 87
DLLME based binary extraction methods can be broadly classified into following three categories and each category will be discussed separately in the coming sections Conventional or macro- extractions followed by DLLME miniaturized or micro- extractions followed by DLLME DLLME followed by miniaturized or micro- extractions. A schematic of classification is given in Fig 1.
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(i) (ii) (iii)
The major milestones achieved in DLLME based combined extraction techniques, to best of our knowledge, are listed in Fig 2. The dates selected are based on when paper was published online.
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97 98 99 100 101 102 103 104 105
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Figure 1. Classification of DLLME based binary extraction methods
3
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106 107
DLLME based combined extraction approach
Ref.
2007
Solid phase extraction followed by DLLME
[13]
2012
[15]
DLLME coupled with dispersive micro solid-phase extraction
[16] [17]
Ultrasound assisted extraction followed by DLLME
[18]
SC
Supercritical fluid extraction followed by DLLME
Stir bar sorptive extraction followed by DLLME
[19]
Microwave assisted extraction followed by DLLME
[20]
Matrix solid phase dispersion followed by DLLME
[21]
Subcritical water extraction followed by DLLME
[22]
Pressurized liquid extraction followed by DLLME
[23]
Electro membrane extraction followed by UAEME
[24]
Electro membrane extraction followed by DLLME
[25]
DLLME followed by single drop microextraction
[26]
Micro-solid-phase extraction followed by DLLME
[27]
Magnetic solid phase extraction followed by DLLME
[28]
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2013
Dispersive solid-phase extraction followed by DLLME
M AN U
2011
[14]
TE D
2010
Acetonitrile based extraction followed by DLLME
EP
2009
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Year
2015
2016
Counter current salting-out homogenous liquid–liquid extraction followed by DLLME Simultaneous hollow fiber supported liquid membrane and DLLME
[29]
Dual DLLME
[31]
Tandem DLLME
[32]
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Microextraction in packed syringe followed by DLLME
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2. Conventional or macro- extraction techniques followed by DLLME
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Figure 2: Historical timeline of DLLME based combined methods
In this section, conventional extraction techniques such as solid phase extraction (SPE), supercritical fluid extraction (SFE), microwave assisted extraction (MAE), ultrasoundassisted extraction (UAE), subcritical water extraction (SWE) combined with DLLME have been discussed. 2.1.Solid phase extraction combined with DLLME
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This combination can be used to accomplish certain goals related to large volume and complex natured liquid samples. SPE provides both concentration and cleanup of the analytes. In some cases, SPE requires a very large volume of elution solvents, which decrease EFs. In those cases, DLLME can provide enrichment of analytes as it utilizes very small volume of extraction solvent (in microliter range). The main advantages derived from SPE coupled DLLME are effective cleanup and high EFs.
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DLLME cannot offer appropriate cleanup when extracting samples characterized by complex matrix composition. A sample pretreatment is always desired. For example, DLLME was reported to be an unsuitable method for the extraction of fungicides from wine samples, particularly red wines, since matrix components may precipitate in the settled drop of extraction solvent, preventing its chromatographic analysis. Secondly, with complex matrices changes in the volume of the sedimented phase and extraction performance are potential problems [35]. Thirdly, DLLME provides EFs mostly in the range of 50–1000, which are still lower in many cases of ultra-trace analysis [36].
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Apart from better sample clean up, the combination of DLLME with SPE presents some valuable advantages. First, analytes recovered from the SPE are rapidly concentrated in a smaller volume of solvent without the requirement of an evaporative concentration step. This combination results in very high EFs (up to 50,000 reported). The reason for such high EFs can be attributed to
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Retention of analytes from large volume samples onto a small amount of SPE adsorbent. Elution of analytes from SPE adsorbent using a minimum volume of desorption solvent. Further preconcentration using DLLME.
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The values of EFs may vary depending upon the initial sample volume, nature of the sorbent and volume of elution solvent in SPE, and volume of extraction solvent in DLLME.
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Second, the selectivity of the sample preparation process is improved by using both techniques in tandem. The use of SPE and DLLME can extend its applicability to complex liquid and biological matrices.
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The applications of SPE-DLLME are mostly related to large volume aqueous samples related to the environment. SPE-DLLME combination was first reported in 2007 for the extraction of chlorophenols in water samples [13]. Later, this combination was used for extraction of organophosphorus pesticides (OPPs) in aqueous samples. The extract obtained from SPE was treated as disperser solvent for DLLME, which provides a greener aspect in terms of solvent consumption. EFs as high as 50,000 and LODs as low as pg/L were obtained. These results were not attainable using either of the methods alone [37]. This combination has been widely used for extraction of variety of analytes in environmental samples, the key parameters of such methods are listed in Table S1.
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This combination has also shown some exciting applications in food analysis. For example, it was used for the extraction of eight pyrethroids in cereal samples prior to their analysis by GC-MS. LOQs with SPE-DLLME almost 10 times higher than SPE alone except for few analytes [38]. This combination is also used for extraction of different analytes in food samples such as wine, porcine tissues, smoked bacon, pistachios, honey, and dietary supplements. The analytical figures of merits of these methods are listed in Table S1.
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This combination is also used for extraction of different analytes in urine and plasma samples [39–41].
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As far as the limitations of SPE-DLLME are concerned, to achieve higher EFs it generally requires large volume liquid samples that are not always available particularly in case of biological fluids. Moreover, solid samples need to be pretreated before SPEDLLME, as they are required in liquid form. Depending on the nature of the solid samples, they may require the steps like grinding, homogenizing, extracting, defatting before DLLME-SPE. These steps may contribute in the loss of analytes.
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Basically, the need of this all arises from the gross architecture of the solid samples such as fruits, meat, vegetables, soil or mud. The objective is to decrease the particle size of the sample in a way that its maximum area can be subjected to extraction. This needs mincing or dicing of the sample. Then it is subjected to homogenization in presence of water or organic solvents. Based on the requirement, samples can be dried by various ways such as freeze drying, drying by dry-ice, or by placing in liquid nitrogen. The resulting material is easier to crush mechanically. Biological samples might require even stronger treatments such as addition of detergents. The finely divided powder then can be extracted by directly mixing with the solvents or by packing in a column and passing the solvents over it. The extraction may need repeated cycles of using fresh solvents, centrifuging, pooling the supernatants to get higher recoveries. The complications such as formation of emulsion with the extraction solvent may arise [42]. Apart from the mincing of solid samples, other extractions such as ultrasound assisted extraction has also been applied before SPE-DLLME [43].
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Generally, large volumes of the solvents are required in conventional SPE that is not recommended by the recent movements in Green Analytical Chemistry. It should be noted that in most of the SPE-DLLME procedures described above, SPE utilizes nearly 500 mg of the sorbent, and analytes are usually eluted by 1.0 or 2.0 mL of the eluent. The
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same analyte-concentrated is employed as disperser solvent in the subsequent DLLME. The eluent of SPE, in some reports, have been evaporated to dryness and then reconstituted in another solvent for upcoming DLLME procedure [38]. The evaporation of toxic solvents may have impact on the workers and the environment.
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The analytical features of the above mentioned SPE-DLLME combined procedures are provided in Table 1. 2.2.Supercritical fluid extraction combined with DLLME
The first work on the combination of supercritical fluid extraction (SFE) and DLLME was reported in 2010 for the extraction of PAHs in marine sediments [17]. In the SFEDLLME procedure, the collecting solvent of SFE is employed as a disperser solvent in following DLLME. After completion of SFE, the suitable volume of extraction solvent is added to the collecting solvent of SFE and this mixture is rapidly injected into aqueous sample followed by the routine steps of DLLME. This combination offers several advantages in comparison with Soxhlet extraction and SFE alone. Compared to Soxhlet extraction, it utilizes lower volume of extraction solvent as well as extraction time is shorter. Moreover, it results in a clean extract. For example, for extraction of PAHs from soil samples, SFE requires few mL of the collecting organic solvents while the volume needed for soxhlet is five hundred milliliters. SFE completes in less than an hour while soxhlet takes 24 hours.
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Like conventional SFE procedures, SFE-DLLME does not involve vaporization of large quantities of toxic organic solvents, which is time-consuming and of environmental concern. DLLME in this combination provides high EFs. This combination extends the application of DLLME to solid samples. SFE-DLLME provided LODs of 0.2 mg/kg for extraction of PAHs in marine sediments [17]. This method was also applied for the extraction of OPPs in soil and marine sediments and the resulting LODs were in the range of 0.001 – 0.009 mg/kg [44]. Some other applications of SFE-DLLME in environmental analysis are listed in Table S2. The only limitations that can be imagined for SFE-DLLME relates to multistep manual procedure. Errors or deviations in any individual step may affect the reproducibility of the procedure.
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Microwave-assisted extraction (MAE) employs microwave radiation that can penetrate and produce heat within the solid matrix in presence of the polar solvents. The performance of MAE is derived by many extraction parameters including the solvent type, irradiation time, temperature, and volume of the solvent in comparison to amount of the solid. Due to assistance of microwave irradiation, the solvent consumption and subsequent waste generation is minimized. MAE is preferable choice of analyte extraction from the solid samples coming from environmental, food, and biological origins such as sediments, meat, biota, etc. MAE extracts can be further enriched by DLLME to achieve higher EFs and detection sensitivities.
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The first extraction method describing MAE combined with DLLME for extraction of fungicides in apple pulp and peel was published online at the end of 2010 [20]. The 7
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second report was published at the start of the 2011 where N-nitrosamines were extracted in meat samples. Apart from the good extraction recoveries, the method’s excellent performance was demonstrated by the quantitation of the analytes that was accomplished using aqueous calibration. This shows that matrix effect was significantly reduced. High EFs (220 and 342) and low LODs were attributed to DLLME [45]. The same combination was utilized for extraction of polyaromatic hydrocarbons (PAHs) in smoked fish. This method also provided good EFs and LODs [46]. The applications of MAEDLLME were extended to different food matrices. MAE-DLLME was used for the extraction of polyamine in turkey breast meat samples. After MAE, analytes were derivatized in MAE aqueous extract which was later utilized for DLLME [47]. In another work, pharmaceutical antimicrobials were extracted from the fish sample using the combination of MAE with solid phase purification and DLLME. MAE was used to digest/extract the solid sample in acetonitrile. The extract was passed through an alumina column for purification. The effluent was evaporated to dryness and reconstituted in 200 µL of acetonitrile which was then employed in DLLME. This method provided extremely low LODs ranging from 4.54 – 101.3 pg/kg [48]. The other applications of this combination in food and environmental analysis are listed in Table S2.
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MAE can be followed by simultaneous DLLME and derivatization when analytes of interest are to be converted into suitable derivatives before analysis. In such cases, MAE extract, extraction solvent, and derivatizing reagents are mixed and rapidly injected into another solution (usually aqueous). This results in formation of a cloudy solution from which extraction solvent is separated by centrifugation. Haloanisoles and halophenols in cork stoppers and oak barrel sawdust were extracted into methanol by MAE. The same methanolic extract was used as a disperser solvent in following DLLME. The methanolic extract, derivatizing reagent, and extraction solvent were mixed and rapidly injected into an aqueous potassium carbonate solution and a cloudy solution was formed [49]. The simultaneous derivatization and microextraction are desired features in the green derivatization process [50].
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2.4.Ultrasound-assisted extraction combined with DLLME
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Being the vibrational source of energy, ultrasound is flexible and adjustable for a different type of samples and therefore ultrasound-assisted extraction (UAE) has many beneficial features for extraction of analytes in the solid matrix. UAE is relatively fast and enhances extraction rate significantly. Basically, it provides adequate amount of energy to disrupt the interior architectures of the solid samples. It also enhances the contact surface between the solid sample and solvent medium, which improves mass transfer from sample to extracting phase. After the efficient release of the analytes from the solid samples, UAE can also be integrated with DLLME. The objective is to enrich the target species into a small volume leading to better cleanup as well as sensitivity.
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This combination has been mostly used for extraction of pollutants, volatiles, and flavors in food samples. The first combined method based on UAE and DLLME was developed for OPP residues in tomato samples and the final determination was made by gas chromatography-flame photometric detection (GC–FPD). In this method, UAE part was
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performed by using very small volume of acetone (5 mL). The need for steps like additional clean up and evaporation was omitted. Further enrichment of analytes was performed by DLLME [18]. UAE-DLLME was also used for identification of volatile compounds in tea and quantification of caffeine. This method was green in nature because very small quantities of samples, as well as extraction solvents, were required (sample 0.1 g, methanol 1.0 mL, and 27 µL chloroform). In addition, dispersion solvent was avoided in DLLME as emulsification was achieved through the ultrasound [51]. The same combination has been used for extraction of analytes from food samples, the detail of which listed in Table S2.
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The green aspect of UAE-DLLME combination is demonstrated by the fact that extraction solvent of UAE can also be used as a disperser solvent of subsequent DLLME. This reduces overall solvent consumption. The acetonitrile used for UAE of ochratoxin A and citrinin in fruit samples was employed as disperser solvent in the following DLLME [52]. The other applications in food analysis include determination of volatile components in saffron [53].
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The second application area of this combination is directed toward extraction of pollutants from environmental solid samples such as soil and marine sediments. The example of this category is elution of PCBs from marine sediments using UAE. UAE extract was evaporated and reconstituted in 1 mL of extraction solvent which was further subjected to DLLME. Reasonably low LODs ranging from 0.021 to 0.057 ng/g were obtained [54]. Chemometric assisted ultrasound leaching-solid phase extraction followed by dispersive-solidification liquid-liquid microextraction was used for determination of OPPs in soil samples [55]. UAE-DLLME was also used for extraction of nitrophenols in the soil samples combined with microvial insert large volume injection GC-MS [56].
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The third area of application is related to extraction of analytes from complex biological samples. For example, phthalate metabolites were extracted from the nail samples. Extracted analytes were determined by UPLC-MS/MS and LODs were in the range of 2 – 14 ng/g [57].
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2.5.Accelerated solvent extraction combined with DLLME
Accelerated solvent extraction (ASE) is another advancement in sample preparation which is based on the extraction of analytes from the solids into a solvent under high temperature and pressure conditions. It allows accomplishing efficient extraction in relatively shorter periods of time. The use of high temperature leads to better extraction through improved analyte solubility, increased diffusion rates, decreased solvent viscosities, and reduced solvent-matrix interactions. Similarly, high pressure makes analytes to boil at higher temperatures than their boiling points leading to the accelerated extraction process. There are several opportunities to combine ASE with microextractions. For example, ASE can be used for extraction from complex matrices such as soil, food, etc., and then further enhancement can be done by combining with microextraction.
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ASE was combined with DLLME for extraction of phenols from the soils. The analytes were first extracted from soil using ASE. Water was used as an extraction solvent. The extract was then used for DLLME. Prior to DLLME analytes were derivatized. ASE converted soil in liquid extract suitable for coupling with DLLME as solid samples cannot be directly extracted with DLLME. LODs were in the range of 0.06 – 1.83 ng/g [58]. ASE which is also known as pressurized liquid extraction (PLE) was used in combination with derivatization-UA-DLLME for extraction of carbohydrates in tobacco samples [59] and with DLLME for extraction of vitamin E in cosmetic products [60].
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2.6.Subcritical water extraction combined with DLLME
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Subcritical water extraction (SWE) is performed at temperatures between 100 and 374°C and pressure high enough to maintain the liquid state. Water has exceptional properties of disproportionately high boiling point for its mass, a high dielectric constant as well as high polarity. As the temperature increases, there is a noticeable and systematic reduction in permittivity, an upsurge in the diffusion rate and a decrease in the viscosity and surface tension. As a result, more polar analytes with high solubility in water at ambient conditions are extracted from the solid samples most efficiently at lower temperatures, whereas moderately polar and non-polar analytes require a less polar medium induced by elevated temperatures.
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SWE has many advantages compared to conventional organic solvent extractions. Subcritical water at high temperature may possess a permittivity very comparable to representative organic solvent, and this characteristic makes it conceivable to use water to selectively extract polar, mid-polar, and nonpolar substances simply by varying its temperature and pressure. SWE is anticipated as an alternative greener extraction method.
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However, when analytes are extracted from the solid samples using SWE, dilution can occur while transferring the analytes from solid to water. A lot of impurities can also coextract. Thus, certain strategies are required to concentrate and purify the analytes from the extract. The combination with DLLME presents one solution to this problem.
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SWE was integrated with DLLME and derivatization for extraction and enrichment of 13 endocrine disrupting chemicals in the sediment samples before their analysis by GC-MS. This study took advantage of the subcritical water and using water-miscible organic solvents both as an organic modifier for SWE and disperser solvent for DLLME. LODs were in the range of 0.006 to 0.639 ng/g [61]. This approach was previously used for extraction of hydroxylated-PAHs in sediment samples [22]. The analytical figures of merit of conventional extractions combined with DLLME are summarized in Table 2.
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3. DLLME combined with other miniaturized or microextraction techniques
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In this section, the combination of mini- or micro-scaled extraction techniques with DLLME is discussed. Techniques like dispersive and magnetic SPE, QuEChERS, and matrix solid phase dispersion are also included here, although one may argue regarding
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their scale of extraction. In that case, if such techniques do not perfectly fit to definition of microextraction, then they are at least mini-scaled compared to classical approaches. 3.1. Dispersive/magnetic solid phase extraction followed by DLLME
DSPE-DLLME can be performed either using single or double step procedure. The principal objectives of this combination are to achieve purification of the analytes, minimize the matrix effects and enrich the analytes in lesser volume of final extract. The function of the DSPE is the cleaning up of initial solvent extract. DSPE can also be assisted by ultrasound.
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DSPE-DLLME combination was introduced in 2009 for the extraction of sulfonylurea herbicides in the soil prior to their determination by HPLC-DAD. The soil samples were extracted in acetone and cleanup was performed by the C18 sorbent. The acetone extract was further subjected to DLLME and EFs of 102 – 216 were obtained [15].
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Single step DSPE-DLLME allows many processes to perform simultaneously. Sorbent based extraction, solvent extraction, and if required derivatization can be carried out in one step. Basically, this is the reason that ultra-high EFs can be achieved. The example of this kind is extraction and enrichment of aliphatic amines from atmospheric fine particles. EFs were in the range of 307 – 382 [62]. In the two step DSPE-DLLME, both techniques are performed separately. The objective of DSPE is to provide better clean up by employing a suitable adsorbent. This method was used for extraction of benzoylurea insecticides in soil and sewage sludge[63]. The other applications of DSPE-DLLME in food and environmental analysis are listed in Table S3.
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Probably the first method where MSPE was followed by DLLME was reported in 2013. Magnetic graphene was used for extraction of five chloroacetanilide herbicides in water samples and green tea samples. MSPE extract was further subjected to DLLME. The EFs were in between 3399 and 4002 [28]. Similarly, nano polypyrrole based MSPE combined with DLLME was used for extraction of megestrol acetate and levonorgestrel in biological samples prior to their quantitation by HPLC-UV. This method provided very high EFs (3680 – 3750) and ultra-low LODs (0.03 ng/mL) [64]. The affinity of the functional materials combined/coated over magnetic substrate can further enhance the EFs. MSPE employing octadecyl modified magnetic silica nanoparticles was utilized for extraction of phthalates in water. The average values of EFs for all the analytes were near 20000 resulting in a very low LODs (ng/L) [65].
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3.2.Quick, Easy, Cheap, Effective, Rugged, and Safe Method followed by DLLME
Quick, Easy, Cheap, Effective, Rugged, and Safe Method (QuEChERS) was originally introduced for extraction using acetonitrile as extraction solvent (with a mixture of inorganic salts) followed by a sorbent based dispersive cleanup [66]. This method has widespread applications for treating samples of complex composition. Excellent cleanup can be attained from QuEChERS, although, EFs are not that high. However, its coupling with DLLME is an inexpensive way to resolve this problem by further concentrating the analytes into extremely low volumes of extraction solvent consequently improving detection limits. The loss of analytes due to evaporative concentration can be avoided. 11
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This method provides a fast way to extract a large number of samples per working day, which favors its application in routine analysis.
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QuEChERS-DLLME based sample preparation has been widely used for analysis of pesticides in variety of food samples. Although authors did not use term QuEChERS, probably the first report on such combination was published in 2007 where OPPs in watermelon and cucumber were extracted by acetonitrile based extraction(solvent extraction) followed by DLLME [14]. Later a similar approach was used for extraction of multi pesticide residues in maize samples before their quantitation by GC-MS. In addition to excellent EFs, DLLME exhibited superb cleanup of polar matrix species, which resulted in enhanced sensitivity of single quadruple MS. EF was ten times higher than QuEChERS alone. [67]. Complex food samples cannot be extracted with DLLME alone, a supporting technique is required for cleanup. QuEChERS integrated with DLLME based on solidification of floating organic droplet (SFOD) was used for extraction of OCPs in fish. [68]. The schematic of this combination is shown in Fig 3.
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Generally, the acetonitrile extract obtained after QuEChERS is used as a dispersive solvent for DLLME. This again minimizes the use of organic solvents. Other applications in food analysis include extraction of pesticide residues in different food samples. The detail of the analytical figure of merits of these methods listed in Table S3.
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Fig 3. The combination of QuEChERS-DLLME (SFOD). Reproduced with permission from Ref [68]. Copyright (2016) Elsevier B.V.
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This combination has also been used for extraction of bisphenol A (BPA) and bisphenol B (BPB) in canned seafood samples. Besides the good EFs, the final DLLME extractive step was used for the simultaneous acetylation of the compounds for their gas chromatographic analysis [69]. The same combination was proposed for simultaneous 12
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extraction, concentration and derivatization of BPA and BPB in canned vegetables and fruits prior to GC–MS analysis. Method LODs were 0.3 and 0.6 µg/kg for BPA and BPB respectively [70]. Ionic liquids are reported as green alternatives to halogenated extraction solvents in DLLME. IL ([C6mim][Tf2N]) based DLLME was used for enrichment of BPA from acetonitrile extract [71].
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Apart from the applications in food analysis, this combination is also used for extraction of analytes in environmental samples, for example, co-occurrence of musk fragrances and UV-filters in both seafood and macroalgae collected in different European hotspots was investigated using the combination of QuEChERS-DLLME [72].
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3.3.Matrix solid phase dispersion combined with DLLME
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Matrix solid phase dispersion (MSPD) technique was first introduced in 1989 for the extraction of drug residues from bovine tissue [73]. Since then, it has proved to be an efficient, versatile technique for extraction of several classes of analytes, from a wide variety of samples. Although MSPD was initially developed for extracting solid samples by disrupting/dispersing their architecture, it has also been applied to viscous and other liquid samples. The wide applicability of MSPD is due to its simplicity (it does not require any instrumentation or specific equipment), flexibility, and ruggedness compared to other extraction methods. The mild extraction conditions preserve analytes from degradation and denaturation. The selection of the solid support and elution solvent determine the efficiency and the selectivity of the process [42]. Generally, MSPD consumes low volumes of organic solvents, especially in its miniaturized form. It has great potential to be coupled with microextraction methods.
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Molecularly imprinted polymer (MIP) based MSPD was combined with DLLME for extraction of Sudan dyes in egg yolk. The MIP was blended with egg yolk and the eluent of MSPD was used as disperser solvent of DLLME. The EFs are in the range of 55 – 59 and method showed great potential for complex matrices [21].
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MSPD was combined with magnetic ionic liquid-based DLLME for extraction of triazine herbicides in oilseeds. Ionic liquids (ILs) are famous organic molten salts with low melting points formed from the combinations of organic cations and various anions. ILs display unique physicochemical properties, such as high chemical and thermal stabilities, negligible vapor pressures, wide ranges of viscosities, and lower toxicity than some organic solvents. Due to this, ILs are a good choice for DLLME. Magnetic ionic liquids (MILs) combine the properties of ILs with good phase separation of magnetic materials. However, most MILs are miscible with water or polar solvents due to the existence of protonated cations and the hydrophilic tetrachloro- or tetrabromoferrate (Ⅲ) anions, which bound their applications in aqueous solutions. On the contrary, MILs are generally immiscible with hydrophobic solvents. Thus, they were used for extraction in n-hexane. MSPD-DLLME provided LODs in the range of 1.20 – 2.72 ng/g [74]. The schematic of this combination is shown in Fig 4. Magnetic matrix solid phase dispersion (MMSPD) and DLLME were also combined and the obtained LODs were lower than any of the individual techniques [75]. Some other applications of MSPD and DLLME in food and environmental analysis are listed in Table S3.
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3.4.Dual and tandem DLLME
Dual DLLME in its original form was developed for extraction of analytes from oil samples. It comprised of reverse phase DLLME and standard DLLME. In the reverse phase DLLME, instead of toxic organic solvents, greener alternatives like surfactants were used as dispersants. As surfactants can damage the capillary column, second DLLME was performed to decrease their concentration, remove any other interferences, and increase the analytes in final extract [31]. In this way, dual DLLME is a combination of forward and backward DLLMEs. Forward DLLME is used to extract the analytes while backward DLLME is used to decrease the interferences and further enrich the analytes by back extraction. The schematic of the dual DLLME is shown in Fig 5.
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Fig 4. Schematic of MSPD-DLLME. Copied with permission from Ref [74]. Copyright (2015) Elsevier B.V.
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Figure 5. The proposed dDLLME method. (A) The n-hexane and extraction solution (containing TX-100) were injected into the oil sample; (B) a cloudy solution was obtained; (C) the supernatant was transferred to another tube; (D) water and ethyl acetate were added to the resulting supernatant; (E) a turbid solution was obtained; (F) the organic phase was mixed with internal standard, for GC–MS analysis [31].
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The process of derivatization is unavoidable for some analytes to enhance their sensitivity and detectability toward the detection system. In such cases, first DLLME is used to cleanup and enrich the analytes from the complex matrix. The analytes in the extract are then subjected to derivatization. The second DLLME is used to remove excess reagents and preconcentrate the derivatized analytes. The example of dual DLLME (DDLME) with in between derivatization includes extraction (PPD and PPT) in rat plasma [76].
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Simple DLLME is efficient with clean aqueous samples but many interferences can coelute while working with complex matrices. This also complicates the resulting chromatograms. Hence, a tandem DLLME was developed to solve this problem. For the extraction of basic drugs from wastewater and human plasma samples, two versions of DLLME, ultrasound assisted emulsification microextraction (UAEME) and air-agitated liquid-liquid microextraction (AALLME) were combined. In UAEME, basic drugs were extracted into organic solvent by adjusting the pH of the sample near alkaline region. In AALLME, basic drugs were back extracted into an acidic acceptor phase. The interferences co-eluted in the first DLLME, can be avoided by the back extraction step of second DLLME [32]. The other examples of tandem DLLME include extraction of pharmaceutical drugs in human plasma and pharmaceutical wastewater [77,78], and water [32,79].
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In short, both dual and tandem DLLME is performed by carrying out two DLLME procedures sequentially. They are suitable for liquid samples. Main advantages are
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Second DLLME can reduce the interferences that can co-elute with first DLLME. Analytes are extracted back into the extraction solvent of second DLLME.
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The situation where derivatization is performed with or after first DLLME, second DLLME can be used to remove excess derivatizing reagents, solvents, and catalysts. If not removed, these all can cause severe interferences in separation and detection of analytes.
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3.5.Salting out assisted homogenous liquid-liquid extraction combined with DLLME
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Homogeneous liquid-liquid extraction (HLLE) is based on a phase separation phenomenon in a homogeneous solution with a very small final volume. As HLLE has initially a homogeneous solution because there is no interface between the water and water-miscible organic solvent or between the water and water-immiscible solvent. Phase separation is achieved through salting-out phenomenon. This method is preferable due to its simplicity, rapidly achievable partition equilibrium, and enrichment of analytes in the extract. In addition, the water-soluble organic solvents used by this extraction technique are relatively environment friendly. SHLLE has also been performed in a narrow-bore tube for extraction of phthalate esters in real water samples. The phase separation was obtained using salting-out effect, and analytes were extracted into the fine droplets of extraction solvent that was collected on the surface of aqueous phase [80].
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Another version of SHLLE (where extraction solvent moves up and collected as upper layer) named counter current salting-out homogenous liquid-liquid extraction (CCSHLLE) followed by DLLME was introduced to attain high extraction recovery and EFs. In this method, firstly analytes are extracted into fine droplets of a mixture of 1,2dibromoethane and acetonitrile during CCSHLLE from the relatively high volume of aqueous sample. It does not require all sample pass through the narrow bore tube filled with NaCl making extraction more facile. Further enrichment is achieved by subjecting the final organic extract to DLLME. This combination has been used to determine some pesticide residues in well water, river water, and apple, sour cherry, and grape juices. EFs were in the range of 3480–3800 and LODs were 0.1 – 5 µg/L [29]. This combination has also been used for determination of pesticides in fruit juices [81]. CCSHLLE-DLMESFO was used for extraction of amphetamines in urine samples. This combination provides high EFs, and suitable for complex matrices without any pretreatment or dilution [82]. HLLE-DLLME was also used for extraction of PAHs in water samples and EFs in the range of 616 – 752 were obtained [83].
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3.6.Stir-bar sorptive extraction followed by DLLME
SBSE is a sample preparation technique that involves the extraction and enrichment of organic compounds from a liquid sample. In SBSE, the sorbent is coated on a magnetic stir bar which is stirred in the sample solution for an optimum time. After the extraction, the analytes can be introduced into the analytical system by thermal or liquid desorption. The key difference between SPME and SBSE is the much larger volume of sorbent used in the latter, which provides higher recoveries and higher sample capacity. SBSE can be combined with DLLME to achieve higher EFs and lower detection limits.
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The first application of SBSE-DLLME was reported probably in 2010 for extraction of pesticides in aqueous samples prior to their determination by GC-FID and GC-MS. EFs were in the range of 282–1792 [19].
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SBSE was combined with DLLME-SFO for extraction of PAHs in water samples followed by HPLC-UV analysis. This resulted in low LODs (0.0067 – 0.010 µg/L) and high EFs (1630 – 2637) [84].
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3.7. Micro-solid phase extraction followed by DLLME
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Micro-solid phase extraction (µ-SPE) is a miniaturized format of conventional SPE. It involves packing of few mg of the inside of a porous polymer membrane bag (µ-SPE device) packed through heat sealing [2]. µ-SPE can be directly immersed in samples of complex matrix composition as the sorbent is suitably protected inside the membrane. It significantly reduces the amount of sorbent and desorption solvents [85,86]. Such µ-SPE devices can be reused for 20 to 30 extraction/desorption cycles without substantial carryover effects as well as signs of tears and wears due to mechanical stress [87]. In other versions, µ-SPE is also performed by keeping few mg of the sorbent inside two frits and packing in a micro-cartridge [88]. In both cases, much-decreased volumes of the solvents are required. Interestingly, µ-SPE can be combined with other extractions.
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Vortex-assisted µ-SPE (VA-µ-SPE) followed by low-density solvent based DLLME (LDS-DLLME) was used for trace level determination of phthalate esters in environmental water samples. The analytes were first extracted by VA-µ-SPE and then desorbed in acetonitrile with the aid of sonication. Acetonitrile extract served as disperser solvent in subsequent LDS-DLLME. 4 mg of MWCNTs were used as a sorbent in VA-µSPE, while 30µL of n-hexane was used as an extraction solvent in DLLME. The LODs were as low as 0.006 µg/L [27].
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Apart from the above listed combinations, EME [24,25], HF supported liquid membrane [30], microextraction in packed syringe (MEPS) [34] have also been combined with DLLME.
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The key features of DLLME based methods combined with other extraction techniques are provided in Table 3.
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4. DLLME followed by other extractions 4.1.DLLME combined with SDME
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Low density solvent based DLLME was followed by SDME for extraction of chlorophenols in environmental water samples prior to their determination by HPLC-UV. A layered of LDS was formed over the aqueous layer after centrifugation. This layer was then brought into contact with a drop of acceptor phase and SDME was performed. The EFs were in the range of 67 – 309 [26].
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DLLME based on low-density solvent demulsification was also combined with SDME. It would be more appropriate to describe the procedure for understanding the objectives of 17
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the combination. A mixture of an extraction solvent and disperser solvent was rapidly injected into the aqueous sample to form a cloudy solution. Then a demulsifier solvent (acetonitrile) was injected. The emulsion became clear and the organic phase accumulated at the top of the aqueous phase. Then, a drop of acceptor solution was introduced into the upper layer and SDME was performed for the back-extraction. This combination does not require any electric equipment (centrifuge, stirrer or ultrasonic cleaner) because this prevents the centrifugation in DLLME and the stirring involved in SDME and LLLME. This combination was successfully used for extraction of sulfonamides in environmental waters prior to their analysis by HPLC. The LODs were in the range of 0.22 to 1.92 µg/L [89]. 4.2. DLLME with dispersive micro solid phase extraction
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DLLME and dispersive microsolid-phase extraction (D-µ-SPE) was developed for the fast extraction of PAHs in environmental samples. The new technique gives the flexibility to use any organic solvent immiscible with water (high or low density) as an extraction solvent in DLLME. It also eliminates the need for special apparatus, such as conical-bottom test tubes, and tedious procedural steps of centrifugation, refrigeration of the solvent, and then thawing it, associated with classical DLLME. In the first step, organic solvent is injected and vortexed in sample solution to extract the analytes. In the second step, a derivatized magnetic sorbent is used to capture the analyte containing solvent droplets. The magnetic sorbent is derivatized to interact with the organic solvent instead of the analytes. Brief procedure is given below.
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The first step involved the rapid injection of 20 µL of 1-octanol into 20 mL sample solution vial for DLLME. Then, the vial was sealed and swirled on a vortex agitator 3200 rpm for 120 s. After that, 10 mg of the derivatized magnetic nanoparticles were quickly added to the vial to target the extractant droplets instead of PAHs. The vortex was turned on for another 60 s. The external magnet was used at the bottom of the vial to isolate the nanoparticles and sample solution was discarded. With the magnet still in place, an aliquot of water (0.5 mL) was added to the vial to rinse the residue. After that magnet was removed, and 1-octanol as well as the PAHs from the nanoparticles, were desorbed in 100 µL acetonitrile by sonication for 4 min. Finally, the magnet was again used to separate the adsorbent, and the supernatant was collected for analysis. This method provided EFs ranging from 110- to 186-fold. The limits of detection were in the range of 11.7−61.4 pg/mL [16].
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4.3. DLLME followed by magnetic solid phase extraction
A two-step extraction technique combining IL-DLLME with magnetic solid-phase extraction (MSPE) was developed for the preconcentration and separation of aflatoxins in animal feedstuffs prior to their analysis by HPLC with fluorescence detection. An ionic liquid 1-octyl-3-methylimidazolium hexafluorophosphate was employed as an extraction solvent in DLLME, and hydrophobic pelargonic acid modified Fe3O4 MNPs were used to retrieve the aflatoxins-containing ionic liquid. The objective of using MNPs was to target the ionic liquid rather than the aflatoxins. Because of the rapid mass transfer related to DLLME and magnetic solid phase steps, fast extraction can be attained. The detection 18
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limits were 0.632, 0.087, 0.422 and 0.146 ng/mL for aflatoxins B1, B2, G1, and G2, respectively. IL-DLLME-MSPE provided superior results than direct MSPE [90]. DLLME followed by magnetic nanoparticles based D-µ-SPE for extraction of PCBs in juices [91]. 4.4.DLLME followed by SPME
In SPME, analytes are extracted by a sorbent coated on a fiber. Depending on the vapor pressure of the analytes, SPME can be performed in the headspace or direct immersion mode. SPME has many advantages such as simplicity, solvent-free nature, high EFs, applicable to wide range of matrices, in vivo sampling and offline or online coupling with analytical instruments. The nature of the fiber coating plays an important role for the extraction of polar, semi-polar and non-polar compounds. Therefore, the choice of sorbent phase can provide selectivity in this method. However, the disadvantages of SPME include limited available polar-sorbent coatings for the extraction of polar analytes, the damage of fiber coating by an organic solvent, and acidic or basic solution. In addition, the partitioning of the analyte among the sample, headspace and fiber coating can affect the extraction efficiency. Complex matrices may affect the active adsorption/absorption sites on SPME coating.
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DLLME offers many advantages such as low consumption of solvents, short extraction times, and flexibility to use low or high-density solvents, better cleanup and easy operation. Besides the advantages, DLLME has some limitations related to the matrix effect and the use of toxic solvents, very little volume injection to the detection system out of total DLLME extract that may reduce sensitivity especially at ultra-trace levels in the complex matrices. DLLME with SPE and µ-SPE as sorbent-based extraction techniques have been discussed with advantages of high EFs and high clean up capability. However, the limitations of these combinations are the use of large sample and solvent volumes.
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The combination of DLLME and SPME was proposed to take benefit of the advantages of two methods while overcoming their abovelimitations. In this combination, DLLME was performed first and its extract was transferred to another vial with septum where the extract including solvent and analytes were subjected to total vaporization. SPME was performed in the headspace. However, this approach has limitations related to nonvolatile analytes and stripping of SPME coating [33]. The GC analysis of the whole organic extract obtained by DLLME can also be accomplished by the placing it in a microvial insert thermal desorption, an approach that uses a thermal desorption injector [56,92].
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5. Green aspects of DLLME based binary extraction techniques
Recent developments in sample preparation techniques are aimed to introduce green character in extraction procedures. There are several ways which contribute greenness in an extraction procedure: (i) (ii) (iii)
Eliminating or minimizing the use of solvent Replacing the conventional sorbents and solvents with the green alternatives Reducing the scale of extraction from macro to micro and nano. 19
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Use of the green energy media such as microwave and ultrasound instead of conventional heating.
DLLME is a modern solution to classical LLE, it is a solvent minimized microextraction technique that offers an efficient extraction of target compounds in variety of sample media. However, it cannot handle solid or complex matrixed samples directly. Thus, its combination with other conventional or micro- extraction techniques has been suggested a viable way to solve the potential limitations of DLLME while maintaining its advantages of better sensitivity and high EFs.
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DLLME based binary extractions involve the combination of two extraction techniques which ultimately increases the overall number of steps. This aspect is not favored by GAC. However, based on the literature survey, still there is a room to make the binary procedures green in a way that an agreement can be reached between method’s performance and greenness. For example, the solvents for binary procedures can be selected in a way that extract of first technique can be used as disperser solvent of the DLLME. This will reduce overall consumption of the solvents. In DLLME, dispersion can be achieved using alternative ways such as use of dispersing solids, air, multiple withdrawing and injecting by a syringe, etc. In case derivatization is required, DLLME and derivatization can be performed simultaneously. The derivatization solvent can be selected to act as disperser solvent as well. Apart from all the claims of greenness in any extraction procedure, it would be scarce to declare any method green without taking into account the volumes of the solvents and reagents used, health and safety hazards associated with them, energy requirements, and status and handling of the generated waste.
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When discussing the green aspects, it would be more appropriate to consider the whole analytical method from sample collection to final determination. During the sample preparation different steps are involved that may utilize the solvents, reagents, energy and produce a waste. Similarly, the analytical instruments may utilize some solvents and energy and produce some waste. It is therefore difficult to claim, or present one method as green analytical method only based on the amount of the solvent. It is therefore necessary to have some scale to evaluate the greenness of an analytical methods.
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Over the years, number of tools have been developed to evaluate the green nature of the analytical processes accounting the different parameters. The first tool that was introduced in this regard was NEMI labelling [93]. It is based on a circle that consists of four partitions. Each partition is labelled green if the certain requirements are filled. The first partition is related to reagents employed, it is represented as PBT (Persistent, bioaccumualtive, toxic). This partition will only be considered green if none of the solvents or reagents in analytical procedure belong to PBT category. The second partition is related to nature of the waste generated during the analytical procedure. This partition will be labelled as green if none of the chemicals employed in an analytical procedure belong to U, P, D, or F hazardous waste category. The third partition belongs to the corrosive nature of the chemicals. If the pH is in the range of 2 – 12, the corrosive
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partition is filled green. The fourth partition is related to amount of the waste, if it is less than 50 g, the partition will be filled with green color. The advantage of NEMI labelling is one can guess the nature of analytical procedure by just having a look on the pictogram. However, it provides only qualitative information scale. Some improvements in the NEMI procedure were suggested by de la Guardia and Armenta [94]. They suggested to use red, yellow, and green colors in each partition of NEMI pictogram representing non-environment friendly, moderate environment-friendly, and benign environment friendly respectively. Based on this three-degree scale, NEMI seems more quantitative.
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The third tool in this connection is Analytical Eco-Scale [95]. This is based on assigning the penalty points to the reagents, waste, energy, their amount with regards to health and safety hazards associated with them. This tool considers all the steps involved in an analytical procedure from sample collection to final determination. The penalty points are subtracted from 100 to get the total score of the analytical Eco-Scale. The closer the score to 100 the greener the procedure is. This method provides even improved and quantitative information on the greenness of an analytical procedure. Although, Eco-Scale compares different parameters and steps in the analytical process, it still does not provide comprehensive information about the evaluated protocols. It is not conclusive about the nature and structure of hazardous chemicals.
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With the passage of time, new tools are being introduced for assessing the greenness of an analytical procedure which can reveal more information about the nature of the procedure. The most recent tool in this regard has been introduced by Plotka-Wasylka, named as green analytical procedure index (GAPI) [96].
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In GAPI, a specific symbol with five pentagrams can be used to assess and enumerate the environmental impact involved in each step of an analytical procedure, mainly from green through yellow to red portraying low, medium to high impact, respectively. It assesses the nature of entire analytical procedure based on values assigned to the reagents and their volume, energy and its amount, waste and its amount plus handling. It also considers whether the sample preparation/extraction is required or not and its scale such as nano-, micro-, and macro- extraction. A simple look at the resulting diagram will give a comparative idea of greenness among different methods. Compared to NEMI, more parameters can be glanced in a single view using GAPI. The GAPI has been employed to access the greenness of some selected DLLME based binary extraction methods (Fig 6).
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6. Conclusion and future recommendations
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Figure 6. Evaluation of greenness of some methods based on GAPI (a) SFC-DLLME [44] (b) UAE-DLLME [18] (c) T-DLLME [77]
The concept of combined DLLME based methods has been introduced to deal with special sample preparation scenarios or to eliminate the drawbacks associated with individual techniques. DLLME has been combined both with conventional and microextractions. DLLME is either performed after or before the other extraction. The combinations where DLLME is performed after the other extractions are aimed to provide a clean extract for DLLME application that can further enrich the analytes. In most of the applications, the role of DLLME based combined methods is centered on achieving one or more of the following objectives (i) (ii) (iii) (iv)
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Dealing with the samples originating from complex matrix composition To obtain higher cleanups To get higher EFs that will enhance the sensitivity of analysis To make trace or ultra-trace level analysis possible
SPE-DLLME is the best choice to deal with complex samples particularly when one has the liberty of sample size. Ultra-high EFs up to 50,000 and ultra-low LODs down to ppq level have been reported. However, the requirement of the large volume of samples is a limitation. Dual or tandem DLLME can be a good choice to deal with complex or low volume liquid samples. Both sample cleanup and EFs can be achieved. QuEChERs or DSPE followed by DLLME is another solution for getting cleanup as well as preconcentration. Despite all the advantages of DLLME based combined methods, they may be time-consuming, as one has to perform two methods separately and look for optimum conditions for both. As such methods are performed in steps, a poor precision may result because an additional step may introduce potential errors. Moreover, working at ultra-trace concentrations may result in poor repeatability.
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Apart from the above said limitations, two major drawbacks associated with DLLME based combined extraction methods are
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Difficulties associated with automation of the both combined techniques, as in majority of the cases, they are performed separately and manually. 22
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Online coupling with the analytical instruments
These two problems should be well thought out to further the research in this area. The automation and online coupling will reduce the manual labor as well as chances of error. This is true that a lot has been done concerning the automation of DLLME with chromatographic instruments [97], the automation opportunities of DLLME based combined methods still need to be studied/investigated in the future.
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Acknowledgements
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The authors gratefully acknowledge the support of King Fahd University of Petroleum and Minerals. Muhammad Sajid would like to thank and acknowledge Center for Environment and Water (CEW), Research Institute, King Fahd University of Petroleum and Minerals, Saudi Arabia.
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The authors certify that they have no conflict of interest in the subject matter or materials
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discussed in this manuscript.
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1200
Table 1. Key features of the methods combining SPE and DLLME
RI PT
1201
NC
Matrix
SPE sorbent
SPEDLLME
Fungicides
7
Wine
SPEDLLME
PBDEs
7
Water
RP-OASIS Acetone HLB (60 mg) LC-C18 n-hexane column (1 g)
SPEDLLME
Chloropheno ls
19
Water
SPEDLLME
OPPs
6
Water
SPEDLLME
Pyrethroids
8
SPEDLLME SPE-
aflatoxins
4
Acetone
TE D
Functionaliz ed styrenedivinylbenze ne polymer (PPL) (100 mg) RP C-18 stationary phase (500 mg) Cleanert florisil (1000 mg/6 mL)
SPE eluent
DLLME extraction solvent 1,1,1trichloroeth ane 1,1,2,2tetrachloroe thance chlorobenz ene
Instrument
EFs
GC-ECD GC-MS
156 254
GC-ECD
6838 – 4.2 – 7.9 9405
GC-ECD
CCl4
GC-MS
4390 – 1.1 – 6.4 0.0005 – 0.1 [13] 17870 (with IS) and 2.5 – 9.7 (without IS). 20000 – 8.6 – (38 – 230) × [37] 50000 10.4 10-6
SC
Analytes
M AN U
Method
AC C
1202
EP
Acetone
Benzodiazepi 3
Cereals
Pistachi os Human
C18 (3 mL)
nⅢ Chlorobenz hexane/acet ene one (v/v, 8:2) Methanol CHCl3
HPLC-FD
Ethanol
HPLC-UV
DCM
GC-MS
18.1 25.7
RSDs (%) –
LODs (ppb ppb) ppb
1 – 15
– 3.6 10.9
Ref.
[35]
0.04 – 0.16
– 0.2 – 4.0
7.4 – 0.02 – 0.04 12.5 3.2 – 8.8 0.07 – 0.7
34
[36]
[38]
[43] [39]
nes
SPEDLLME
Amphetamin es
4
SPEDLLME
Carbamazepi ne
1
urine and plasma Urine and plasma
Carbon disulfide
6.1 13.5
– 0.1 – 0.5
1206 1207 1208
M AN U
TE D
EP
1205
HPLC
AC C
1204
CHCl3
HPLC-UV
[40]
170 4.2 (aq), 0.4 (aq), 0.8 [41] (aq), 7.8 (urine) and 132 (urine), 1.7 (plasma) (urine), 9.6 105 (plasma) (plasma ) *extraction solvents indicate only the extraction solvents of DLLME. Any conditioning, washing, reconstituting, derivatization or disperser solvents are not mentioned here. NC, number of compounds; ACN, acetonitrile; CCl4, Carbon tetrachloride; DCM, dichloromethane; CHCl3, chloroform; 1203
Urine and plasma
Fe3O4 Methanol nanoparticle s was coated by sodium dodecyl sulfate C18 ACN
SC
DLLME
RI PT
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Table 2. Key features of the methods combining some conventional extraction techniques and DLLME Matrix
Solvent for 1st technique ACN (CS)
SFEDLLME SFEDLLME
PAHs
10
OPPs
7
MAEDLLME MAEDLLME MAEDLLME MAE-SPPDLLME
Nnitrosamines PAHs
9
Marine sediments Soil and ACN marine sediments Meat NaOH
16
Polyamines
3
Smoked fish Meat
Antimicrobial pharmaceutica ls MAEHaloanisoles DLLMEand Derivatizatio halophenols n
6
Fish
8
Cork Methanol stoppers and oak barrel sawdust
UAEDLLME UAEDLLME
OPPs
13
Tomatoes
Acetone
Caffeine
42
Tea
Methanol
Extraction solvent of DLLME Chlorobenze ne CCl4
CCl4
EFs
RSDs (%)
LODs (ppb)
Ref.
GC-FID
88 – 286
1.3 – 10.3
200
[17]
GC-FID
67 – 144
3.1 – 7.5
1.0 – 9.0
[44]
GC-MS
220 342 244 373 190 305
Ethylene tetrachloride 1-octanol
GC-MS HPLC-UV
DCM
LC-MS/MS
CCl4
GC-ECD
Chlorobenze ne CHCl3
GC-FPD
EP
TE D
KOH:Ethano l (1:1) Perchloric acid ACN
Instrumen t
RI PT
NC
SC
Analytes
M AN U
Method
AC C
1210
GC-MS
4.0 42.6
– 5.9 – 10
0.12 – 0.56 – 2.8 – 9.0 0.11 – 0.43 – 6.72 – 0.24 – 7.30 0.42 1.7 – 3.6 (4.54 – 101.3) ×10-6 <11.2 0.032 – 0.092 (Cork stoppers) 0.016 – 0.046 (Oak barrels) <10 0.1 – 0.5
– 4.8
0.3
[45] [46] [47] [48]
[49]
[18] [51]
36
ACCEPTED MANUSCRIPT
28
Saffron
Methanol/A CN Acetone
CHCl3
GC-MS
7
OPPs
4
Nitrophenols
6
Marine sediments Soil samples Soil
Isooctane
GC-MS
Methanol
1-undecanol
Methanol
DCM
UAEDLLME ASEDLLME PLE-D-UADLLME
Phthalate metabolites Phenols
7
Nails
TFA:MeOH
4
Soil
Water
Carbohydrates
11
Tobacco
50:50 ethanol/wate r ACN
3.6 41.3 -
RI PT
Volatile components PCBs
GC-MS
6890– 8830
LVI-GCMS
TE D
M AN U
SC
UAEDLLME UAEDLLME USL-SPEDSLLME UAEDLLME
AC C
EP
PLEVitamin E Cosmetics DLLME SWEEDCs 13 Sediments Water with DLLME10% acetone Derivatizatio n SWEOH-PAHs 8 Sediments Water with DLLME20% ACN Derivatizatio n Solvent for 1st technique refers to collecting solvent in case SFE.
Trichloroeth ylene chlorobenzen e CHCl3
CCl4 Chlorobenze ne
Chlorobenze ne
UPLCMS/MS GC-MS
-
GC-FID
Capillary LC-UV GC-MS
GC-MS
-
– 2.48 9.82 <7.6
– (6 – 123) ×103 0.021 – 0.057 4.06 – 8.9 0.012 – 0.2 12.2 – 0.4 – 0.8 18.5 (without IS) 4.2 – 11.1 (with IS) 8.8 – 17.1 2 – 14
[53] [54] [55] [56]
[57]
5.06 – 0.006 – [58] 9.17 1.83 2.1 – 6.6 60 – 900 [59]
<7.8
3 – 15
[60]
1.5 – 15
0.006 0.639
– [61]
2.81 11.07
– 0.0139 – [22] 0.2334
37
ACCEPTED MANUSCRIPT
1211
Table 3. Key features of the miniaturized extraction techniques combined with DLLME methods
Sulfonylurea herbicides Aliphatic amines Benzoylurea insecticides Megestrol acetate and levonorgestrel Phthalates
4
2
OCPs
13
BPA and BPB
2
BPA
1
QuEChERSDLLME (SFOD) QuEChERSDLLME QuEChERSIL-DLLME MIP-MSPDDLLME MSPDDLLME MMSPDDLLME
Sudan dyes Triazine herbicides PCBs
8 2
RSDs (%)
Canned seafood Canned food
AC C
MSPEDLLME
10
Extraction solvent Instrument EFs of DLLME Soil Chlorobenzene HPLC102 – DAD 216 Atmospheric DCM GC-MS 307 – fine particles 382 Soil and sludge 1-undecanol HPLC-UV 104 – 118 Biological Dihexyl ether HPLC-UV 3680 samples – 3750 Water Tetrachloroethylene GC-FID 17749 – 21278 Fish 1-undecanol GC-ECD
SC
DSPEDLLME DSPEDLLME DSPE-VADLLME MSPEDLLME
Matrix
M AN U
NC
TE D
Analytes
EP
Combination
RI PT
1212
Ref.
5.2 – 7.2
LODs (ppb) 0.5 – 1.2
<7.0
0.03 – 0.09
[62]
2.16 – 6.26
0.08 – 0.56
[63]
5.3 – 5.9
0.03
[64]
6.8 – 10.4
0.002 0.003
<15
0.65 – 1.58
[68]
<20
0.2 – 0.4
[69]
0.1
[71]
2.3 – 6.1
[21] [74]
C2Cl4
GC-MS
[C6mim][Tf2N]
HPLC-UV
98
<7.2
55 59
– 2.9 – 6.7
4
Egg yolk
Tetrachloroethylene
HPLC-UV
6
Oilseeds
[C4mim][FeCl4]
UFLC-UV
<7.7
1.20 – 2.72
5
Water
Chlorobenzene
GC-ECD
4.9 – 8.2
0.00005 0.0001
[15]
– [65]
– [75]
38
Psychotropic drugs
3
CCSHLLEDLLME
Pesticides
11
CCSHLLEDLLME CCSHLLEDLLME-SFO HLLEDLLME SBSEDLLME SBSEDLLME-SFO
Pesticides
7
Fruit juices
Amphetamines
2
Urine
PAHs
5
Water
Triazole pesticides PAHs
LDS-SD-
Sulfonamides
TDLLME
3
6
3
UHPLCMS/MS HPLC-UV
164 182 75 – <6.5 100
0.010 0.015 0.8 – 1.0
HPLC-UV
63 – 4.5 – 9.2 94 50 – <6.2 101
3 – 10
[79]
0.7 – 1.0
[32]
HPLC-UV
88 99
1.0 – 1.5
[78]
GC-FID
3480 3800 544 600 157 – 168 616 – 752 282 – 1792 1630 – 2637 6 – 91
2–7
0.1 - 5
[29]
2–6
2 – 12
[81]
<5
0.5 – 2
[82]
<6
0.08 – 0.20
[83]
<5.2
0.53 – 24.0 [19] (GC-FID) 0.0067 – [84] 0.010
RI PT
3
M AN U
TDLLME
Rat plasma
TE D
2
Pharmaceutical drugs TCAs
2
EP
DUADLLME- PPD and PPT MAD TDLLME Beta blockers
SC
TDLLME
Bromocyclohexane, Bromobenzene Human plasma 1,2-dichloroethane, and water pharmaceutical wastewater Aqueous CCl4, acidic aqueous matrices solution Wastewater 1,2-dichloroethane, and plasma acidic aqueous solution Pharmaceutical CCl4, acidic aqueous wastewater solution and human plasma Aqueous 1,2-dibromoethane
AC C
ACCEPTED MANUSCRIPT
1,1,2,2tetrachloroethane 1-undecanol
HPLC-UV
GC-FID HPLC-UV
1,1,2‐trichloroethane GC-FID
Aqueous samples Water
1,1,2,2‐ tetrachloroethane
Environmental
1-octanol
GC-FID, GC-MS HPLC-UV
HPLC-UV
– <9.3
2.17 – 6.92
<4.6
– [76] [77]
0.22 – 1.92
[89]
39
ACCEPTED MANUSCRIPT
DLLMESDME IL-DLLMEMSPE
waters Animal feed
1-octyl-3HPLC-FD methylimidazolium hexafluorophosphate DLLMEParathion and 2 Environmental 1,1,2,2GC-CDSPME diazinon waters and tetrachloroethane IMS fruit juices Dual-DLLME Phenylpropenes 6 Oils Triton X-100 in GC-MS ACN, Ethyl acetate NC: number of compounds; only DLLME extraction solvents are listed.
1214
1220 1221 1222 1223
0.007 0.020
– [33]
1.0 – 3.0
[31]
EP
1219
– [90]
AC C
1218
2965 <10 – 3150 3.2 – 2.61 – 4.33 37.1
0.087 0.632
TE D
1215
1217
– 3.2 – 6.4
M AN U
1213
1216
22 25
RI PT
4
SC
Aflatoxins
1224
40
ACCEPTED MANUSCRIPT
1225
List of abbreviations
RI PT
1226 1227
DLLME: Dispersive liquid-liquid microextraction
1229
SPE: Solid phase extraction
1230
EFs: Enrichment factors
1231
SFE: Supercritical fluid extraction
1232
MAE: Microwave assisted extraction
1233
UAE: Ultrasound-assisted extraction
1234
SWE: Subcritical water extraction
1235
OPPs: Organophosphorus pesticides
1236
PBDEs: Polybrominated diphenyl ethers
1237
OCPs: Organochlorine pesticides
1238
PPCPs: Pharmaceutical and personal care products
1239
PAHs: Polyaromatic hydrocarbons (PAHs)
1240
GC–FPD: Gas chromatography-flame photometric detection
1241
PLE: Pressurized liquid extraction
1242
DSPE: Dispersive solid phase extraction
1243
VA: Vortex assisted
1244
MSPE: Magnetic solid phase extraction
AC C
EP
TE D
M AN U
SC
1228
41
ACCEPTED MANUSCRIPT
SFO: Solidified floating organic drop
1246
GC-MS: Gas chromatography mass spectrometry
1247
GC-FID: Gas chromatography flame inonization detection
1248
GC-ECD: Gas chromatography electron capture detection
1249
HPLC: High performance liquid chromatography
1250
LC-MS/MS: Liquid chromatography tandem mass spectrometry
1251
QuEChERS: Quick, Easy, Cheap, Effective, Rugged, and Safe Method
1252
MSPD: Matrix solid phase dispersion
1253
MMSPD: Magnetic matrix solid phase dispersion
1254
DDLLME: Dual DLLME
1255
TDLLME: Tandem DLLME
1256
BPA: Bisphenol A
1257
BPB: Bisphenol B
1258
MAD: Microwave assisted derivatization
1259
ACN: Acetonitrile
1260
MIPs: Molecularly imprinted polymers
1261
ILs: Ionic liquids
1262
MILs: Magnetic ionic liquids
1263
TCA: Tricyclic antidepressant drugs
1264
LODs: limits of detection
AC C
EP
TE D
M AN U
SC
RI PT
1245
42
ACCEPTED MANUSCRIPT
UA-DLLME: Ultrasound-assisted DLLME
1266
HLLE: Homogeneous liquid-liquid extraction
1267
SHLLE: Salting out assisted HLLE
1268
CCSHLLE: Counter current SHLLE
1269
SBSE: Stir bar sorptive extraction
1270
HF-LPME: Hollow fiber liquid phase microextraction
1271
SPME: Solid phase microcextraction
1272
µ-SPE: Micro-solid phase extraction
1273
SDME: Single drop microextraction
AC C
EP
TE D
M AN U
SC
RI PT
1265
43
ACCEPTED MANUSCRIPT
Highlights •
AC C
EP
TE D
M AN U
SC
RI PT
• •
Sample preparation methods combining DLLME with other extraction techniques for chromatographic analysis are discussed. The objectives and merits of each combination are critically appraised. Applications of DLLME based combined extraction methods are provided.