Accepted Manuscript Title: Membrane-based microextraction techniques in analytical chemistry: a review Author: Eduardo Carasek Josias Merib PII: DOI: Reference:
S0003-2670(15)00227-5 http://dx.doi.org/doi:10.1016/j.aca.2015.02.049 ACA 233763
To appear in:
Analytica Chimica Acta
Received date: Revised date: Accepted date:
13-12-2014 13-2-2015 17-2-2015
Please cite this article as: Eduardo Carasek, Josias Merib, Membrane-based microextraction techniques in analytical chemistry: a review, Analytica Chimica Acta http://dx.doi.org/10.1016/j.aca.2015.02.049 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.
Membrane-based microextraction techniques in analytical chemistry: a review
Eduardo Carasek*, Josias Merib
Departamento de Química, Universidade Federal de Santa Catarina, Florianópolis 88040-900, SC, Brazil
*Corresponding Author (E. Carasek) E-mail address: [email protected] Fax: +55 48 3721 6850
Highlights
► Sample preparation step is crucial in the development of a large number of
analytical methodologies ► This review describes aspects concerning to the growth in the development and improvement of sample preparation techniques ► Membrane-based microextraction techniques emerge as efficient, simple, low cost and environmentally friendly procedures ► Some critical points about each discussed membrane-based microextraction techniques are presented ►
Table
containing
different
applications
of
each
membrane-based
microextraction technique is presented
Graphical abstractEduardo Carasek received his PhD degree at the
University of Campinas – Brazil in 1997, and concluded postdoctoral research fellow at the University of Waterloo – Canada in 2006, 2010 and 2014 working with Professor Janusz Pawliszyn, where he developed analytical methods based on solid phase microextraction. He works as Associate Analytical Chemistry Professor at the Federal University of Santa Catarina, Florianópolis – Brazil. His research interest is to develop microextraction methods (SPME and LPME) for the determination of organic and inorganic compounds in several matrices and detection by chromatography and spectrometry.
Abstract
The use of membrane-based sample preparation techniques in analytical chemistry has gained growing attention from the scientific community since the development of miniaturized sample preparation procedures in the 1990s. The use of membranes makes the microextraction procedures more stable, allowing the determination of analytes in complex and “dirty” samples. This review describes some characteristics of classical membrane-based microextraction techniques (membrane-protected solid-phase microextraction, hollow-fiber liquid-phase microextraction and hollow-fiber renewal liquid membrane) as well as some alternative configurations (thin film and electromembrane extraction) used successfully for the determination of different analytes in a large variety of matrices, some critical points regarding each technique are highlighted.
Keywords:
solid-phase
microextraction;
hollow-fiber
liquid-phase
microextraction; hollow-fiber renewal liquid membrane; sample preparation; membrane-based techniques.
Summary 1.
Introduction.......................................................................................................................... 4
2.
Membranes used for extraction procedures................................................................... 7
3.
Membrane-Protected Solid-Phase Microextraction (MP-SPME) ................................ 9
4.
Thin Film Microextraction (TFME).................................................................................. 15
5.
Hollow-Fiber Liquid-Phase Microextraction.................................................................. 17 5.1 A general overview ........................................................................................................ 17 5.2 Three-phase HF-LPME................................................................................................. 19 5.3 Two-phase HF-LPME................................................................................................... 24 5.4 Automation of HF-LPME procedure............................................................................ 27
6.
Eletromembrane Extraction (EME) ................................................................................ 28
7.
Hollow-Fiber Renewal Liquid Membrane (HFRLM) .................................................... 31
8.
Main optimization factors in membrane-based microextraction procedures........... 36 8.1
Choice of membrane................................................................................................ 36
8.2
Sample temperature................................................................................................. 36
8.3
pH adjustment ........................................................................................................... 37
8.4
Ionic strength............................................................................................................. 38
8.5
Extraction time .......................................................................................................... 39
8.6
Organic solvent ......................................................................................................... 40
8.7
Sample stirring .......................................................................................................... 41
9.
Critical points regardingto membrane-based microextraction techniques .............. 41
10. Scientific studies involving membrane-based sample preparation techniques reported in the literature .......................................................................................................... 45 11.
Conclusions and future trends.................................................................................... 45
12.
References .................................................................................................................... 47
1. Introduction Sample preparation procedures are usually applied in chemical analysis to overcome difficulties with sample introduction in the analytical equipment, to separate the analytes from the sample matrix and/or to concentrate them for trace analysis. This step is often considered to be the Achilles’ heel in chemical analysis, mainly due to the risk of analyte loss and sample contamination. In addition to these sources of systematic errors, sample preparation is often the most time-consuming step in analytical procedures [1]. The sample preparation step is generally analyte and matrix-dependent, requiring suitable optimization of the different influencing parameters. The sample preparation and analysis methodologies, which originally involved traditional laboratory liquid-liquid, liquid-solid and gaseous extraction are associated with a number of limitations, including the requirement for arduous time-consuming manual labor and/or, in some cases, the use of large quantities of hazardous extracting solvents. The mode of operation in liquid-liquid extractions also gives rise to limited preconcentration factors as a consequence of the limited extractant-to-sample volume ratios employed. Moreover, coalescence and phase separation can be a slow step, especially when emulsions are formed [2, 3]. Over recent decades, sufficient attention has not been paid to the sample preparation step, especially considering the advances achieved in terms of analytical instrumentation, but efforts are currently being focused on its improvement. In this regard, current trends are moving toward its simplification, miniaturization and automation involving also the use of solventfree
and
other
environmentally-friendly
procedures,
while
maintaining
good/acceptable extraction efficiencies [4]. The past 24 years have been very
rich in relation to this issue and of great importance due to the development and improvement microextraction
of
so-called techniques
miniaturized developed
extraction in
this
techniques.
period
are
Notable
solid-phase
microextraction (SPME), developed by Pawliszyn and co-workers [5], and earlier studies which resulted in the development and application of liquid-phase microextraciton (LPME) by Dasgupta`s group [6-11]. These research studies have allowed the introduction of new concepts which have enabled the extraction and determination of different analytes in several matrices with a small volume of extracting solvents and, in the case of SPME, the possibility of a solventless extraction procedure. The use of alternative microextraction techniques for sample preparation reduces the number of errors that commonly result from multi-stage procedures, and limits the negative impact on the environment and the health of those performing the laboratory work. A reduction in the amount of organic solvents employed in the extraction process allows economic benefits and reduces the problems associated with waste treatment [12]. Another important advance in sample preparation techniques is the use of membranes in the microextraction procedures. In general, these approaches have wide applicability to matrices of great complexity or those containing molecules which interfere with the efficiency of the procedure [13]. Notable variants of such sample preparation techniques are the use of a microextraction mode in SPME called membrane-protected SPME, which can be applied to samples containing particulate material which could damage the SPME fiber [14-16]. Another important sample preparation technique that makes use of membranes is hollow-fiber liquid-phase microextraction (HF-LPME) proposed
by Pedersen-Bjergaard and co-workers [17]. This technique allows the analysis of complex samples, including those containing suspended or particulate material. HF-LPME can generally be used applying two different approaches according to the number of phases involved in the procedure. The two-phase approach (HF(2)-LPME) is known as microporous-membrane liquid-phase microextraction (MMLPME) while the three-phase HF-LPME approach (HF(3)LPME) is referred to as liquid-liquid-liquid microextraction (LLLME). In addition, more recently, the use of another variant of the application of membranes in extraction procedures has been developed, called hollow-fiber renewal liquid membrane (HFRLM) extraction [18-21]. This approach has some differences compared with classical HF-LPME procedures, such as the use of one aliquot of extractor solvent applied directly into the sample to allow renewal of the membrane liquid during the extraction procedure. In addition, the development of new configurations for membrane-based microextraction procedures have been proposed and some advances can be pointed out as the development of Thin Film Microextraction (TFME) as well as Electromembrane Extraction (EME). Thus, it can be observed that the use of membranes in analytical procedures has been the object of several studies and many authors have applied these microextraction techniques to a variety of matrices. Also, some reviews have been published [13, 22, 23], evidencing the great importance of these membrane-based procedures in the sample preparation step. Regarding the use of membranes in certain analytical procedures, this review addressed the characteristics, basic theoretical aspects, differences and applications of the membrane-protected-SPME, HF(3)-LPME, MMLLE or HF(2)LPME,and HFRLM techniques, as well as some aspects regarding different
configurations involving TFME and EME are discussed. Also, some highlights of the critical aspects of each procedure are presented. A table containing summarized details of some studies involving these approaches reported in the literature is provided.
2. Membranes used for extraction procedures Following the development and improvement of extraction techniques, several membrane-based methods have been developed as alternatives to the conventional techniques. A large variety of membranes with different structures, transport properties and separation mechanism are available. These distinct membrane characteristics generally originate from dissimilar raw materials or preparation methods. In general, in the microextraction techniques synthetic membranes are applied, both organic (polymeric) and inorganic membranes [24, 25] A membrane is a selective barrier through which different gases, vapors and liquids move at varying rates. The membrane facilitates the two phases coming into contact with each other without direct mixing. Molecules move through membranes via the process of diffusion and are driven by a concentration, pressure or electrical potential gradient. The diffusion-based transport can be expressed by Flick’s first law of diffusion according to equation 1 [25]. j = −D
dc dx
(1)
where the J is the rate of transfer (or flux) (g/cm2 s), D is the diffusion coefficient (cm2/s) and dc/dx is the concentration gradient.
The integration of the above equation gives equation 2. j=
D(Cis − Cil ) L
(2)
where Cis is the concentration of i at the outer membrane surface, cil is the concentration of i in the lumen and L is the membrane thickness. The flux of analytes across the membrane is also affected by temperature since this determines the diffusion coefficient. In the case of liquids, this can best be described by the Stokes–Einstein equation, shown in the equation 3. D=
kT 6παη
(3)
where k is the Boltzmann constant, T corresponds to absolute temperature, π is the pi number, α is the radius of the solute and η is the solution viscosity.
The quantity, size and distribution of pores throughout the membrane structure represent important characteristics of the membrane morphology. Membranes which have no pores in their structure are known as non-porous, while those which possess pores are referred to as porous. The size, shape and distribution of pores in a membrane are largely dependent on the processes through which they are made and play a significant role in their mode of separation. Selected molecules pass through the openings in porous membranes and movement through these membranes involves size exclusion. Therefore, these membranes are useful in applications such as nanofiltration and dialysis. Non-porous membranes are solid (pore-free) structures and the molecules move through them via diffusion, and therefore, their compatibility with the analyte is critical [25].
Concerning the chemical nature and the kind of analyte, membranes can be classified on the basis of their hydrophobic or hydrophilic nature. Cellulose acetate,
regenerated
cellulose,
polysulfone,
polycarbonate,
polyamide,
polyethersulfone and ion exchange membranes are well suited for the isolation of ionic or polar species from aqueous/organic solutions. On the other hand, hydrophobic membranes (e.g., polytetrafluoroethylene, polypropylene, silicone rubber, latex, polyvinylchloride or polyvinylidene difluoride) are commonly exploited for the selective on-line separation of gases and volatile inorganic or organic compounds [26]. The membrane most commonly used in microextraction procedures is Acurel 3/2 Q, comprised of a hollow microporous polypropylene tube (Membrana GmbH, Wuppertal, Germany) with an inner diameter of 600 µm, a wall thickness of 200 µm, a pore size of 0.2 µm and a wall porosity (by volume) of around 70% [27]. Other types of capillary membranes, such as those composed of polysulfone [27] and cellulose [28], have also been used for sample
preparation
purposes.
For
thin-film
microextraction
approach,
membranes composed by polydimethylsiloxane, carboxen/polydimethylsiloxane and polydimethylsiloxane/divinylbenzene have been produced and applied; in this case, the thin polymeric membranes sheets are used not only to sample clean-up but also as extraction phases (preconcentration).
3. Membrane-Protected Solid-Phase Microextraction (MP-SPME) The SPME procedure represents a great advance in the miniaturization of sample preparation techniques. In SPME, a small amount of the extracting phase associated with a solid support is placed in contact with the sample
matrix or in the headspace above the matrix for a predetermined time. If this time is sufficiently long, a concentration equilibrium is established between the sample matrix and the extraction phase. When equilibrium conditions are reached, exposing the fiber for a longer amount of time does not lead to a greater accumulation of analytes [29]. The constant for the distribution between the amount analyte contained in the matrix (A(matrix)) and the amount extracted by the SPME fiber (A(fiber)) can be represented as shown in equation 4. A(matrix) ⇆ A( fiber ) K mf =
Cf Cm
(4)
where K mf represents the matrix – fiber distribution constant; Cf represents the analyte concentration in the SPME fiber and Cm represents the analyte concentration in the matrix.
The total analyte concentration can be described as the sum of the amount of analyte present in the matrix, in the headspace and in the SPME fiber, as described in equation 5. n0 = n f + nhs + nm
(5)
where n0 represents the total amount of analyte; n f represents the amount of analyte in the SPME fiber; nhs represents the amount of analyte in the headspace; nm represents the amount of analyte present in the matrix. Using equation 5 with some mathematical adjustments, the total amount of analyte mass extracted by the SPME fiber can be described by equation 6. nf =
C0 .Vm .V f .K mf Vm + V f .K mf
(6)
where n f represents the total mass of analyte extracted by the SPME fiber; V f represents the fiber coating volume; K mf represents the fiber coating – sample matrix distribution constant;
c0 represents initial concentration; and Vm
represents the matrix volume [29]. In general, this type of microextraction involves the adsorption/absorption of the analytes by a fused silica fiber coated with an adequate stationary phase and its subsequent desorption immediately prior to gas chromatography analysis [30]. Various types of polymeric coating are commercially available, such as polydimethylsiloxane (PDMS), PDMS-divinylbenzene (PDMS/DVB), and DVB/Carboxen/PDMS (DVB/Car/PDMS). The SPME procedure is simple, relatively quick and does not require the use of organic extraction solvents [31]. Traditionally, SPME is used in the headspace mode (HS-SPME) for the analysis of highly volatile compounds and in the direct immersion mode (DI-SPME) for the determination of compounds with lower volatility [32]. Another extraction mode used in SPME is membraneprotected SPME. A scheme showing these three extraction modes used in SPME can be seen in Figure 1.
FIGURE 1
In the membrane-protected SPME mode a membrane is placed around the SPME fiber to protect it. This is a useful precaution when matrices
containing solids in suspension or particulate material, such as soil, milk, urine and blood, are analyzed [16]. In general, the use of SPME in complex matrices (food samples, soil samples, biological fluids) requires sample pretreatment or modification of the sampling protocol in order to simplify the matrix and to prevent damage of the fiber. The complexity of the sample can affect the recovery of the analytes, the analytical method precision, the accuracy, and the sample compatibility with a subsequent chromatographic technique. In a sample which contains nonvolatile and strongly interfering compounds, such as proteins, humic acids and fatty material, analysis using either DI-SPME or HS-SPME is difficult to perform [14, 33-35]. To overcome some problems associated with applying SPME to complex matrices a new approach to SPME has been proposed [28], which enables the analysis of high boiling-point and non-volatile analytes in complex aqueous or other liquid matrices. In this approach, the SPME fiber device is placed inside a hollow cellulose membrane with a molecular weight cut-off (MWCO) of 18000 Da. The membrane, forming a concentric sheath around the fiber, allows the target analytes, which typically have a molecular weight of less than 1000 Da, to diffuse through while excluding interfering compounds of high molecular weight, such as humic acids which have molecular weights up to several million Da. With membrane protection, direct immersion of this protected-SPME fiber can be used successfully for the extraction of heavy PAHs, such as chrysene and perylene, from aqueous samples containing humic acids. In another study [14] it is proposed the use of a porous hollow polypropylene fiber in a membrane-protected solid-phase microextraction
procedure for the determination of triazine herbicides in complex samples with separation/detection by gas GC-MS. The authors called this approach hollowfiber-membrane solid-phase microextraction (HFM-SPME) and bovine milk and sewage sludge were used as matrices. A 65 µm PDMS/DVB SPME fiber was protected by a hollow polypropylene fiber membrane and a scheme of the experimental set-up is described in Figure 2.
FIGURE 2
The extractions were performed by direct immersion of the protectedSPME fiber into the bovine milk samples. The internal diameter of the HFM (polypropylene membrane) of 600 µm was large enough to accommodate the SPME stainless steel protective tubing of the fiber. The SPME fiber assembly was inserted into a 7-cm long HFM (one end sealed using a flame) which completely covered the stainless steel tubing and the polymeric fiber. A bovine milk sample volume of 5 mL was used and an oil bath was used to adjust the sample temperature. After the microextraction procedure, the HFM was discarded and the SPME fiber was subjected to thermal desorption for 5 min. The results obtained in this study presented relative standard deviations ranging from 4.30 to 12.37% and correlation coefficients for the calibration curves of between 0.9799 and 0.9965 for triazines in bovine milk. Regarding the sewage sludge samples only recovery studies with two different spiked concentrations (20 and 100 µg L−1) were performed. The recovery dates varied between 93.33 and 107.78% and the RSDs were lower than 13%.
The same SPME extraction mode was applied successfully [36] for the determination of the free concentration of the medicament placitaxel in liposome formulations with separation/detection by LC-ESI/MS. For the effective direct extraction of low molecular weight compounds from complex liquid samples, a hollow membrane (molecular weight cut-off of 15 kD, for proteins, and 10 nm pore size) was used to form a concentric sheath around a coated SPME fiber. In this case, the best optimized SPME coating was comprised of a Carbowaxtemplated resin (CW/TPR). The end of the membrane was sealed and great care was taken to avoid air entering the space between the fiber and the membrane. The membrane blocked the access of large particles to the coating surface like liposomes, while target analytes with low molecular weight diffused through the membrane and reached the extraction phase. A dialysis membrane was used which inhibited the direct interaction between the SPME extraction phase and the liposome content of the liposome formulations. The set-up for the membrane-protected SPME used in this study is shown in Figure 3.
FIGURE 3
This microextraction mode was applied successfully to the determination of the free paclitaxel in liposome formulations, with good linearity over the range of concentrations of interest, this being a very useful alternative to the application of SPME for complex samples. More recently, a very promising approach involving SPME to overcome problems associated with the complexity of the samples was developed [37, 38]. In this approach the researches proposed the use of an external PDMS
layer over the commercial PDMS/DVB fiber. According to the authors the coating procedure consists of immersing the commercial PDMS/DVB fiber in the PDMS solution and subsequently withdrawing it slowly at a rate of approximately 0.5 mm s-1. Passing it through a micropipette tip of around 350 µm diameter aperture ensured that a thinner layer was formed, with the excess polymer being removed. After the coating process, the coated fiber was placed in a vacuum oven at 50 °C under N2 flow for 12 h. The coating/curing process was repeated twice to ensure complete and uniform coverage. Procedures for the microextraction of triazole pesticides [37] obtained with this new approach presented an extraction capability similar to that of the PDMS/DVB commercial fiber in water samples, evidencing that the presence of the PDMS layer did not negatively affect the extraction efficiency. In addition, the PDMS/DVB/PDMS was successfully applied to complex samples, such as whole grape pulp, for over 100 cycles with no sample pretreatment being required. In another study [38] the same strategy was used for a PDMS/DVB/PDMS coating to determine 10 triazole pesticides in grape and strawberry pulps.
4. Thin Film Microextraction (TFME) Another
important
advance
in
membrane-based
microextraction
techniques has been the development of the Thin-Film Microextraction. This microextraction approach consists basically on the use of a thin sheet of a polymeric membrane with high surface area as the extraction phase [39]. In the earlier studies involving membrane-based sample preparation approaches, the polymeric membranes were most used as a barrier to isolate the analytes from the sample matrix (clean-up). However, in the TFME approach the polymeric
membrane has a preconcentration capacity and it acts as an extraction phase for analyte species before the measurements in an analytical system [40]. Pawliszyn and co-workers [39] proposed the use of a thin PDMS sheet to extract some PAHs from aqueous samples with separation/detection by GCMS; in this experimental set-up a PDMS membrane was attached to a stainless steel rod, this membrane was shaped like a flag with two tested dimensions (1 cm x 1 cm and 1 cm x 2 cm) and placed in a 40 mL vial containing 10 mL of aqueous sample, both direct immersion and headspace modes were applied. After the required extraction time, the membrane was rolled around the rod and placed into the heated chromatographic injector to thermal desorption. This experimental set-up of TFME is presented in the Figure 4 (A and B).
FIGURE 4 (A and B)
Excellent results to the analytical parameters of merit were obtained using this technique for extraction of PAHs from aqueous samples. The limits of detection varied from 2.5 to 19 pg mL-1 for acenaphthene and pyrene, respectively; correlation coefficients above 0.9972 with relative standard deviations lower than 13.6% were obtained. One important factor to be taking into account when the TFME is employed is the achievement of higher extraction rates, this occurs due to larger surface area to extraction-phase volume ratio of the thin film, without sacrificing the sampling time if compared to other microextraction techniques [40], More recently, several studies involving the use of a thin membrane as extraction phase in microextraction procedures have been developed, including
reviews containing theoretical aspects, calibration methods, TFME formats, extraction phases and applications of this approach [40, 41]. Among these works, the development of extraction phases with high extraction capacities has been explored. Mixed extraction phases were introduced to TFME procedures; in this sense, the production of extraction phase formed by divinylbenzene particle-loaded membrane combined with PDMS for trace gas sampling [42], as well
as
the
development
of
carboxen/polydimethylsiloxane
polydimethylsiloxane/divinylbenzene extraction
and
phases for determination of
polar compound in water samples [43] can be highlighted. Also, the use of a cooled membrane for gas sampling was reported [44], this strategy allowed the combination of the advantages from large and cold surface area and the achievement of high sensitivity for volatile compounds. In addition, important works involving the determination of quaternary ammonium compounds from water samples were developed using TFME approach [45, 46], as well as the development of coatings based on thin films combined with automated 96-blade system was successfully developed for determination of benzodiazepines [47] and analytes of wide polarity range from biological fluids [48] .
5. Hollow-Fiber Liquid-Phase Microextraction 5.1 A general overview Sample preparation using membrane-based liquid-phase microextraction techniques is seen as an alternative to common approaches involving solidphase extraction (SPE), solid-phase microextraction (SPME) or traditional liquid-liquid extraction (LLE) [23]. This type of microextraction also represents an important variant of the LPME techniques, mainly regarding single-drop
microextraction (SDME) [7]. SDME is the simplest operational mode of the LPME techniques, in which a single liquid drop is used as the extractor phase. It is based on the principle of the distribution of the analytes between a microdrop of extraction solvent placed at the tip of a micro-syringe and an aqueous phase. Solvent extraction is based on the principle that the equilibrium ratio for the concentrations of solute in the organic and aqueous phases is constant. In SDME, a solvent microdrop is exposed to an aqueous sample, wherein the analyte is extracted by the drop. After extraction, the microdrop is retracted back into the microsyringe and then injected into the respective instruments for further analysis. In this case, high enrichment factors are obtained due to the high ratio of sample volume to organic phase volume with the use of few microliters of organic solvent, representing a great advance in sample preparation techniques [49]. In spite of its simplicity and direct compatibility with chromatographic systems, SDME has gained limited popularity within the analytical community. The major reason is related to the stability of the drop during extraction. In order to speed up extractions, stirring or agitation is required, but the mechanical stability of a single drop suspended at the tip of a microsyringe is relatively poor, and the drop is easily lost in the sample solution. In addition, biological samples, such as plasma, may emulsify substantial amounts of organic solvents, and this may even enhance the instability problem [50]. To overcome the problems associated with the instability of the microdrop of extraction solvent, in 1999 Pedersen-Bjergaard and Rasmussen [17]
proposed
membrane-based
another
important
approach,
microextraction
initially
referred
to
technique as
using the
liquid-liquid-liquid
microextraction (LLLME). In this technique, the analytes are firstly extracted into a supported liquid membrane (SLM) sustained in the pores of a hydrophobic hollow porous fiber, and later into an acceptor phase placed inside the lumen of the fiber. Later, with the publication of further studies involving this technique, this procedure also became known as hollow-fiber liquid-phase microextraction (HF-LPME). This microextraction technique was developed as a promising method of sample preparation owing to its simplicity, efficiency, low cost, negligible volume of solvents used and excellent sample cleanup ability [51]. HF-LPME modes can be classified according to the number of phases involved in the system, with two-phase or three-phase HF-LPME generally being applied [4, 17, 52, 53]. One of these proposed HF-LPME set-ups is shown in Figure 5.
FIGURE 5
According to these schemes it can be observed that the main difference between the two approaches of HF-LPME is the extraction solution contained in the lumen of the hollow membrane: in the three-phase system an aqueous acceptor phase is used and in the case of the two-phase approach an organic phase is used as the acceptor phase. Properly sealed vials and, in the case of the above scheme, small conical tubes are used as guides.
5.2 Three-phase HF-LPME In the first study involving this type of microextraction, HF(3)-LPME was investigated by Pedersen-Bjergaard and Rasmussen in 1999 [17]. The principles of this microextraction are based on the so-called SLMtechnique
which is based on a three-phase (aqueous–organic–aqueous) system, where the organic solvent is held in the pores of a porous membrane supported by capillary forces. The membranes used for microextraction purposes can have the flat format flat or hollow fibers. The SLM is in contact with the two aqueous phases (the donor phase, that is the aqueous sample, and the acceptor phase, usually an aqueous buffer) in the hollow fiber configuration placed in the lumen of the fiber [13]. The hydrophobic polypropylene membranes, such as that cited above, are among the most commonly used to perform this microextraction technique. The experimental procedure involving the HF(3)-LPME configuration is generally composed of an SLM, which is formed in the pores in the wall of the hollow fiber. This may be accomplished by dipping the hollow fiber into an organic solvent of low polarity (like n-octanol, dihexyl ether or toluene) for few seconds. Alternatively, a small quantity of the organic solvent can be injected into the lumen of the hollow fiber and immobilized into the porous of the membrane. After loading the SLM, the lumen of the hollow fiber is filled with the acceptor phase. In HF(3)-LPME the acceptor solution may be an acidic or alkaline aqueous solution resulting in a three-phase extraction system [52]. Equation 4 establishes a relation, in the case of equilibrium, between the analyte concentrations in sample (A sample), in the organic extractor phase (A organic phase) and in the aqueous acceptor phase (A acceptor phase).
A ( sample) ⇆ A (organic phase) ⇆ A (acceptor phase)
(4)
The overall extraction process is affected by the partition coefficients for the partitioning between the organic phase and the donor solution (Korg/d) and between the acceptor phase and the organic phase (Kacc/org), which are defined by equations 5 and 6, respectively. K org / d =
Ceq ,org
(5)
Ceq ,d
K acc / org =
Ceq , acc Ceq ,org
(6)
where Ceq,org is the analyte concentration at equilibrium in the organic phase, Ceq,d is the analyte concentration at equilibrium in the donor solution and Ceq,acc is the analyte concentration at equilibrium in the acceptor phase.
The partition coefficient for the partitioning between the acceptor phase and the donor phase, which may be considered as the overall driving force for the extraction, is calculated as the product of (Korg/d) and (Kacc/org) [22] as shown in equation 7.
Kr / d =
Ceq ,acc Ceq ,d
= K org / d .K acc / org
(7)
The pH is an important parameter which affects the extraction efficiency when working with a system of HF(3)-LPME. The pH of the donor phase (sample) should be adjusted to maintain the analytes in the non-ionized form, while the acceptor phase pH should be adjusted to a value at which the analytes remain ionized. The difference between the pH values for the donor and acceptor phases is one of the key parameters which can promote the
transfer of analytes from the donor phase to the immobilized organic solvent and subsequently to the acceptor phase. Thus, the pH values for the donor and receptor phase selected are slightly lower and higher, respectively, than the pKa value for the analyte [54]. Pedersen-Bjergaard and Rasmussen [17] performed a pioneering study using the three-phase approach to determine methamphetamine concentrations in biological fluids. In this study, methamphetamine was extracted from aqueous samples and biological fluids with a 8-cm porous hollow polypropylene fiber and a three-phase system was employed to perform the microextraction using 25 µL of acidic acceptor phase and an SLM filled with 1-octanol and posterior methamphetamine determination by capillary electrophoresis. Figure 6 shows a diagram of the experimental set-up proposed by the authors (initially referred to as LLLME).
FIGURE 6
This study, which was the first using this configuration to be published, demonstrated the great potential of the technique. In addition, the low cost of the material, simplicity and low solvent consumption can be highlighted as important advantages with regard to the development and improvement of the HF-LPME procedures. Another study using the HF(3)-LPME approach [55] to determine two mianserin enantiomers in plasma samples with capillary electrophoresis was published. In this study, di-n-hexyl ether was impregnated in the pores of the hollow fiber and an acidic solution was used as the acceptor phase. Efficient
sample clean-up and satisfactory results to analytical parameters of merit were achieved. The
HF(3)-LPME
approach
was
applied
to
the
extraction
of
antidepressant drugs [56]. In this case, amitriptyline, imipramine and sertraline in aqueous and biological fluid samples (such as plasma and urine) were determined using chromatographic detection performed by HPLC-UV. The solvent used to impregnate the pores of a polypropylene hollow fiber membrane was n-dodecane and the pH values for the donor phase and acceptor (aqueous) phase were set at 12 and 2.1, respectively. Enrichment factors of up to 300 were achieved and the relative standards deviations were lower than 12%. A three-phase configuration to extract valerenic acid [57] was applied prior to separation/detection by HPLC-UV. To perform this study the researchers used dihexyl ether as an organic extracting solvent in the pores of a hollow fiber and then back extracted them into an aqueous solution with pH 9.5 located inside the lumen of the hollow fiber, the sample pH used for this extraction being 3.5. The HF(3)-LPME approach has been applied not only to the determination of organic compounds but also in studies on metals. This technique was used to determine trace concentrations of mercury in water samples with detection by electrothermal atomic absorption spectrometry [58]. To perform the extraction, the researchers added a solution of 1-(2-pyridylazo)2-naphthol (PAN) to the donor sample at pH 7. The hollow polypropylene fiber membrane was impregnated with toluene and the lumen was filled with 10 µL of ammonium iodide solution.
A miniaturization of HF(3)-LPME has been proposed by Sikanen and coworkers [59]; in this new concept, called droplet-membrane-droplet liquid-phase microextraction, sample volume of 15 µL, acceptor phase of 10 µL and a flat porous polypropylene membrane as SLM were used. The flat membrane was arranged bellow the sample droplet and above the acceptor phase. Another important advance in HF-LPME is called Parallel Artificial Liquid Membrane Extraction (PALME) [60] and consists basically on a system where the sample and acceptor phase are separated by a flat membrane impregnated with the organic solvent. This system is compatible with a 96-well plates device and it has great advantages such as low sample and solvent consumption, as well as the possibility of extraction of multiple samples. This new configuration can be much explored in a near future to investigate new possibilities of automation for the HF-LPME procedure with 96-well plates device.The miniaturization of the microextracion procedures is one of the trends in the membrane-based sample preparation techniques. A microfluidic-chip to liquid phase microextraction was developed and applied to study drug metabolism [61]. This approach consists basically on the introduction of a low sample volume with aid of a pump at 3 – 4 µL min-1, this sample was placed in contact with a SLM and, on the other side of the membrane an acceptor solution was present (pumped at 1 µL min-1). Excellent enrichment factors were obtained with this device, which is emerging as an alternative to limited volume samples.
5.3 Two-phase HF-LPME In HF(2)-LPME, a microsyringe is filled with a few microliters of an organic solvent which is immiscible with water. A small piece of porous hollow
fiber is filled with this organic solvent, subsequently, the piece of hollow fiber is connected to the needle of the microsyringe containing a determined volume of this organic solvent, after this the system is placed into the sample to perform the microextraction of the analytes; the organic solvent in both wall porous and in the lumen of the fiber acts as extraction phase. Equation 7 establishes a relationship, under equilibrium conditions, between the analyte concentration in sample (A sample) and in the organic acceptor phase (A organic acceptor). A ( sample) ⇆ A (organic acceptor )
(7)
In the HF(2)-LPME approach the analytes are extracted by passive diffusion from the aqueous sample directly into the organic acceptor phase. This process is described in equation 8, and is dependent on the partition coefficient (Kacc/d) for the partitioning between the organic acceptor phase and the donor solution (sample). K acc / d =
Ceq ,acc Ceq , d
(8)
where Ceq,acc is the analyte concentration at equilibrium in the organic acceptor phase and Ceq,d is the analyte concentration at equilibrium in the donor solution (sample).
The HF(2)-LPME approach in which the solvent is held within the pores and inside a hollow porous fiber is analogous, in terms of the mass transfer behavior, to solid-phase microextraction. Equation 9 describes the mass of
analyte extracted as a function of time, for short exposure times, during the SPME process [29]. n=
2π Dw .L.Cwt b + δ ln b
(9)
where Dw is the diffusion coefficient of the analyte in the real sample phase (cm2 s-1), L is the length of the fiber (cm), Cw is the analyte concentration in the sample (ng mL-1), b is the outer radius of the fiber (cm) and δ is the diffusion film thickness (cm) [3].
A dynamic configuration to HF(2)-LPME has been reported [22]. In this case, the needle of the syringe and the piece of hollow fiber are placed into an aqueous sample and, during the extraction, small volumes of the aqueous sample are repeatedly pushed and pulled in and out of the hollow fiber using the syringe plunger. During withdrawal of the aqueous sample, a thin film of organic solvent is built up in the hollow fiber and this vigorously extracts the analyte from the sample segment. Dynamic systems have also been reported to HF(3)-LPME [62] and the great advantage of these systems is an improvement of the extraction speed when compared with the static conditions. As in the case of HF(3)-LPME, the approach involving HF(2)-LPME can be applied to the analysis of a large variety of matrices. A method based on HF(2)LPME with 2-octanol impregnated in a hollow polypropylene fiber membrane to extract dichlorophenol isomers in urine samples with separation/determination by gas chromatography-negative chemical ionization mass spectrometry was proposed [63].
A two-phase approach was applied for the determination of six fungicides (chlorothalonil, hexaconazole, penconazole, procymidone, tetraconazole, and vinclozolin) in water samples adjusted to pH 4 [64]. A hollow polypropylene fiber membrane was impregnated with toluene, which was used as the extraction solvent. The researchers obtained enrichment factors ranging from 135 to 213 and recovery tests were between 90.7% and 97.6%. Satisfactory results for the determination of some organochlorine pesticides from environmental matrices with the two-phase approach [65] were obtained performing extractions with a 1.3-cm length of hollow polypropylene fiber membrane fitted into a 10 µL microsyringe and with 5 µL of toluene immobilized in the pores of the hollow membrane.
5.4 Automation of HF-LPME procedure Several sample preparation methods involving microextractions have high extraction efficiencies and at the same time allow a lower consumption of organic solvents, as previously commented in this text. However, these techniques can present some manual labor associated with the handling and transfer of the collected extract to the analytical equipment. These difficulties can lead to the possibility of losses of analytes during the procedure, decreasing the extraction efficiency and, many times, causing problems associated with reproducibility in the analytical measures. In this sense, emerges the possibility of automation of these techniques. One great advance in the field of automation of HF-LPME was the development of a fully automated HF-LPME procedure using a CTC CombiPal autosampler, as well as the use of kinetic calibration for determination of
carbaryl from red wine samples with separation/detection by CG-MS [66]. All steps of the HF-LPME procedure were performed by the autosampler, decreasing significantly the manual labor and improving the reproducibility with using the proposed device. In another work [67] it was proposed the use of a fully automated HF-LPME procedure for determination of flunitrazepan in plasma
and
urine
samples
with
separation/detection
by
GC-MS/MS.
Polyvinylidene difluoride hollow fiber was used in this study because it showed good stability and also presented less adsorption of biomolecules, which is an important factor for analysis in complex biological samples. In addition, the automation of HF-LPME procedure showed great accuracy allowing satisfactory analytical results.
6. Eletromembrane Extraction (EME) The electromembrane extraction is one of the variants of the liquid phase microxtraction that has been gaining great attention of the scientific community in the sample preparation field. Since its development in 2006 [68] the number of scientific publications involving application and improvement of this technique is growing. The basic principle of this technique is the application of a d.c. potential across a SLM as a powerful driving force for migration of charged species toward the electrode of opposite charge in the acceptor phase [69-71]. The apparatus used to the EME is similar to the one used in HF-LPME procedures. However, for the EME is necessary a power supply and two electrodes. A power supply provides d.c. potential (generally 1 – 300 V) to enhance the extraction rate of ionizable analytes from the donor solution (sample) to acceptor phase, which is contained in the lumen of a hollow fiber;
two platinum electrodes are used to perform the migration of the analytes, one of this electrodes is placed into the sample and the other is placed inside the hollow fiber into the acceptor phase. Generally, a polypropylene hollow fiber membrane is used and an organic solvent is immobilized into the porous to create a SLM. To perform the electro-migration of the analytes is necessary that the electrode located into the acceptor phase is charged oppositely to the analytes; for example, to extract cationic analytes the electrode placed into the acceptor phase may be charged negatively (cathode) and the positively charged electrode (anode) may be placed inside the sample; in other hand, to determine anionic analytes, the electrode placed into the acceptor phase may be charged positively (anode) and the negatively charged electrode (cathode) may be placed inside the sample [72]. The EME technique was used for the first time to extract basic drug from aqueous samples [68]; the scheme of this experimental set-up is showed in the Figure 7.
FIGURE 7
Due to the use of d.c. potential to force the migration of the analytes across the SLM, faster extractions generally are obtained with the application of this technique in comparison with traditional HF-LPME procedures. Other advantages such as efficient clean-up of the samples and high preconcentration capacity can also be mentioned, becoming the EME technique a powerful tool to sample preparation in analytical chemistry [73, 74]. The EME technique has been explored by several researches, having recent reviews containing basic principles, theoretical aspects and applications
about this promising technique in the literature [75, 76]; in addition, studies involving flux simulation [77] and some kinetic aspects [78] have also been reported. Different studies regarding improvement of the EME can also be pointed out. Ramos-Payán and co-workers [79] introduced a new hollow fiber polypropylene membrane to EME procedure; in this study, nanometallic particles (silver nanoparticles) were deposited in a polypropylene hollow fibers which were used for extraction of non-steroidal anti-inflammatory drugs with separation by HPLC; these new membranes allowed an increase in the electrokinetic migration across the SLM. Another important modification on membranes used for the EME procedure was the introduction of carbon nanotubes into the membranes [73, 80]. The presence of the nanotubes allowed a larger surface area, and also contributed to increase the overall analyte partition and the transport of the compounds across the membrane. The EME technique has also been used not only for determination of organic compounds, but also for extraction of metallic species in aqueous samples [81]. A study related to the concept of dual-EME procedure for speciation of the metallic species Cr(III) and Cr(VI) in aqueous samples by migration of these species toward electrodes placed into two acceptor phases contained in different hollow fibers was proposed [71]. The separation was performed by HPLC and a complexation step was previously necessary prior to the detection by UV. Following the improvement of the EME technique, Petersen and coworkers [82] developed a miniaturized EME system with a flat membrane using few microliters of aqueous sample and acceptor phase, this approach was called drop-to-drop EME. In this procedure, the researchers performed the
extraction of pethidine, nortriptyline, methadone, haloperidol and loperamide from 10 µL of aqueous sample to 10 µL of acidic acceptor phase using 15 V in a micro-scale EME procedure.. More recently, a new configuration to the EME procedure based on a flat membrane device [83, 84] was proposed. The application of a flat membrane instead of traditional hollow fiber membranes allowed the use of a larger acceptor phase volume, this factor combined with using a higher extraction time leads to the achievement of exhaustive extractions of peptides [83] and basic drugs from plasma samples [84]. In another recent
study, a very promising configuration to the EME,
called Parallel Electromembrane Extraction (Pa-EME) was proposed [85]. In this new configuration, four antidepressant drugs were extracted from human plasma samples. The samples were placed inside a 96-well plates device and 8 microextractions with voltage of 200 V were performed simultaneously, the separation/detection was performed by LC-MS/MS. This configuration emerges as a future alternative to automation of the EME technique.
7. Hollow-Fiber Renewal Liquid Membrane (HFRLM) The HFRLM approach, based on surface renewal theory, was proposed in 2005 [86-88]. The main modification introduced with this extraction technique is the addition of an extra amount extractor solvent injected directly into the sample
simultaneously
with
the
microporous
hollow
fiber
membrane
impregnated with an organic solvent [21]. In the HFRLM procedure the extractor solvent is introduced into the sample, resulting in a solution with a high aqueous/organic solvent ratio, which
is stirred outside of the hollow membrane. Due to the wetting affinity of the organic phase and hydrophobic membrane, a thin organic film of solvent is developed at the interface between the donor phase and the membrane. The shear force due to the sample agitation causes the formation of organic microdroplets on the surface of the liquid membrane layer, which separate from the surface of the liquid membrane. At the same time, the organic microdroplets present in the sample greatly increase the contact area between the extractor solvent and the sample. Simultaneously, these microdroplets are reintroduced into the solvent film renewing the liquid membrane, which can accelerate the mass transfer rate, reducing significantly the mass transfer resistance in the hydrodynamic boundary layer at the donor phase/membrane interface. The additional organic phase in the donor phase is required only for the renewal, and continuously replenishes the loss of membrane liquid due to its solubility and emulsification, to avoid liquid membrane degradation. On the other hand, the resistance of back-extraction in the lumen side of the membrane can be greatly reduced by the chemical reactions [20, 89]. Figure 8 shows a scheme of the HFRLM process proposed by Ren et al. [89].
FIGURE 8
In a classic HFRLM process, the mixture of organic phase and stripping phase flows through the lumen side of the hollow fiber module, the feed phase flowing through the shell side. Zhang et al. [90] performed a study on the extraction of Cu(II) from aqueous samples and determined that the mass transfer can be calculated with the use of equations 10 and 11.
K=
∆C =
(C inf –
Q f .(C inf − C out f )
(10)
n.π .d 0 .L.∆C
D ' out D ' in Cs ) – (C out – Cs ) f D D D ' out (C inf – Cs ) D ln D ' in (C out – Cs ) f D
(11)
where K is the overall mass transfer coefficient (m s-1), Qf is the flux of the feed phase (m3 h-1),
in out C inf , C out are the copper (II) concentrations at the f , Cs and Cs
inlets and outlets of the feed and stripping phases (g m-3), respectively, D and D’ are the distribution coefficients of the extraction and back-extraction respectively, L is the effective length of the shell side, d0 is the inner diameter of the fiber and n is the number of fibers.
Also, the mass transfer flux, J (g m-2 h-1) can be calculated according to equation 12. J=
Q f .(C inf − C out f ) n.π .d 0 .L
(12)
The use of this variant of the membrane-based extraction techniques has been applied successfully in the extraction and isolation of metallic species, such as Cu (II) [91-93] and Co (II) [92], from aqueous samples. In an earlier study [89, 93] was applied this extraction technique to the simultaneous extraction and stripping of Cu (II) from wastewater. A system of CuSO4 + di-ethylhexyl phosphoric acid in kerosene + HCl was used in the HFRLM process and showed good stability in the constant renewal of the liquid
membrane during the process, with direct contact of the organic droplets and a large mass transfer area provided by the aqueous phase. Hollow hydrophobic fibers are used in this procedure, and their pores are filled with the organic phase. The stirred mixture of the organic and feed (or stripping) phases at a high w/o volume ratio was pumped through the lumen side of the module. The flow rates on the two sides were controlled to maintain a positive pressure on the shell side with respect to the lumen side, in order to prevent penetration of the organic phase into the shell side and permit stabilization of the interface between the phases at the hydrophobic membrane pores. A set-up of the apparatus used for HFRLM in a single-pass mode is shown in Figure 9.
FIGURE 9
This procedure was very efficient for the extraction of Cu (II) and presented a high mass transfer rate, compared with the hollow-fiber-supported liquid membrane and hollow-fiber membrane extraction processes. Carasek’s research group adapted the HFRLM technique for use at the micro-scale, in order to extract not only metal species [20, 94] but also organic compounds [95] from different matrices, allowing the HFRLM to be used as a sample preparation technique to clean up and preconcentrate analytes prior to analysis by chromatography or atomic absorption spectrometry. These researchers applied HFRLM to the extraction of Cd (II) from environmental samples, with determination by flame atomic absorption spectrometry [20]. The sample vials were introduced into the temperature-
controlled bath unit at the appropriate temperature. Ammonium O,O diethyl dithiophosphate (DDTP) and a mix of N butyl acetate and hexane (60/40% v/v) were added to the sample. A hollow PDMS fiber was cut into 8-cm lengths. One end of each piece of membrane was connected to a needle attached to a 250 µL microsyringe. A mix of organic solvents was introduced into the sample for the extraction of the target Cd–DDTP complex and to carry it over the PDMS membrane, the walls of which had been previously filled with the same organic solvents. The organic solvents were solubilized inside the PDMS membrane, leading to a homogeneous phase. The complex strips the lumen off the membrane and, at higher pH, the Cd–DDTP complex is broken down and Cd (II) is released into the stripping phase. EDTA was used for the complexation of the Cd (II), helping to trap the analyte in the stripping phase. A scheme of the apparatus used to perform the HFRLM is shown in Figure 10.
FIGURE 10
The methodology employing HFRLM was also applied to the determination
of
sulfonamides
in
honey
samples
with
subsequent
separation/detection by LC-MS/MS [21]. A mixture of 1-octanol:1-pentanol (55:45 v/v) was used as the extracting solvent, which was placed directly onto the sample. It was also used to obtain a three-phase system containing carbonate buffer, at pH 10, as the receptor phase solution. Multivariate analysis was applied to determine the best extraction conditions. Variables such as extraction time, pH (donor and acceptor phases), solution volumes, extraction solvent type and ionic strength of the solution were investigated. Good results
were obtained for the analytical parameters of merit. The repeatability and accuracy were also evaluated and were 15% and 13%, respectively.
8. Main optimization factors in membrane-based microextraction procedures
8.1 Choice of membrane In HF-LPME, EME and HFRLM procedures the membranes of greatest interest are those which have a hydrophobicity which allows interaction with the organic solvent as well as high porosity for the immobilization of this solvent. In general, polypropylene membranes are considered to be the best option, and their specifications have been mentioned above [96]. In membrane-protected SPME the membrane can act as a barrier and thus a flexible and malleable material can be applied to form a concentric cylinder around the SPME fiber. Additionally, the membrane must allow the passage of the target compounds toward to the microextraction fiber and molecules with high molecular weight must not be able to enter the membrane. In more recent configurations to the EME technique, some metallic particles are included into the membranes to facilitate the application of the d.c potential. Researches are being developed to improve the efficiency of the membranes employed, taking into account that the chosen membrane represents an important factor in a membrane-based microextraction procedure.
8.2 Sample temperature
In the SPME technique, increasing the extraction temperature can significantly reduce the equilibration time and speed up the overall procedure. Two effects, one positive and one negative, take place when the extraction temperature is raised: (i) the positive effect is that the headspace capacity and/or analyte diffusion coefficient is increased and thus the extraction rate is enhanced, and (ii) there is a negative effect on the distribution constant [16]. This negative effect of increasing the extraction temperature can be overcome by using a variant of SPME called cold-fiber SPME [97-100]. In generally, for membrane-protected SPME the fiber is placed into the sample and thus an increase in the temperature can reduce the time require to reach equilibrium. For the HF-LPME, EME and HFRLM procedures, for the determination of non-volatile compounds it is generally necessary to raise the sample temperature, which will increase the diffusion coefficient of the target compound and equilibrium will be reached in a shorter time [3, 96]. However, care must be taken regarding this variable since the temperature affects the sample viscosity and the solubility of the extractor solvent in the sample, causing degradation (degeneration) of the liquid membrane in SLM [20].
8.3 pH adjustment In SPME, in most cases, the non-dissociated/neutral species of the analytes are extracted. Full conversion of the analytes into neutral forms by pH adjustment can significantly improve the method sensitivity. Therefore, low pH values will improve the extraction efficiency of acid compounds and high pH values will improve that of basic compounds [16]. To extract polar or even ionic compounds polypyrole coatings have been employed [50, 101].
For HF-LPME, pH adjustment can increase the extraction efficiency and the equilibrium can be affected by the solubility of acidic or basic analytes. In most systems of solvent microextraction using two phases the sample pH must be modified to prevent the ionization of acid or basic analytes. In such cases, the pH should be adjusted to at least 1.5 units lower than the pKa for acidic species and to at least 1.5 units above the pKa for basic compounds. For acid analytes, the sample pH is generally adjusted to between 0.1 and 3.5, while for basic analytes it varies between 10 and 14. For the EME technique the pH adjustment is an important factor for extraction efficiency. The analytes must be charged to the migration of this species until the electrode oppositely charged, so the pH of the sample is adjusted to guarantee the ionization of the analytes. In HF(3)-LPME, to ensure the extraction of the analyte by the receptor phase and prevent its return to the organic phase located in the pores of the membrane, the acceptor phase pH must be adjusted to ensure ionization of the analytes. Thus, basic receptor solutions should be used for acids and acidic analyte acceptor phases should be used for basic analytes [3]. Also, in HFRLM systems the extraction efficiency is dependent on the equilibrium between the analytes from the donor phase and the organic solvent, as well as that between the analytes from the organic solvent and the acceptor phase. In this case, it is important that this equilibrium is shifted to the acceptor phase, to trap the analytes in this phase [21].
8.4 Ionic strength
In some cases, increasing the ionic strength improves the extraction efficiency, especially for volatile analytes. The salting-out effect causes the analyte molecules to pass more rapidly from the sample matrix to the headspace and thus this step can be useful in the HS-SPME procedure. Sodium chloride is most often used to adjust the ionic strength of the samples. In the case of membrane-protected SPME, modifying the ionic strength needs to be carefully studied since the extraction efficiency of the analytes from complex and “dirty” samples can be affected differently by changes in the ionic strength depending on the characteristics of the compounds and the matrices [3]. For HF-LPME and HFRLM, depending on the analyte, the addition of salt and the consequent change in the ionic strength of the sample solution can significantly affect the results obtained with liquid-phase microextraction. The addition of salt can decrease the solubility of the analytes and thus increase the extraction efficiency due to the effect of salting out. Therefore, it is important to verify the influence of this variable for each case in the system under study. On the other hand, in certain situations this variable may not have a significant effect on the efficiency of the microextraction procedure [96]. For the EME technique the presence of ionic substances in the donor solution causes an increase in the ion balance value in the system, which decreases the flux of analytes across the SLM [76]. However, some studies showed that the addition of salt increases the extraction efficiency [102, 103]; therefore the ionic strength is a very important variable to be carefully optimized when the EME procedure is employed.
8.5 Extraction time and extraction temperature Another very important factor is the optimization of the extraction time, considering that the mass transfer process is time-dependent. The extraction time is theoretically defined as the time the system requires to reach equilibrium. Typically, the extraction time is dependent on various analyte characteristics, such as molecular weight and volatility [3, 96]. In most studies, the sample extraction is the time-limiting step of the SPME procedure. Therefore, selection of the optimum extraction time is one of the critical steps in the development of a method for this microextraction technique. The time required to reach equilibrium is independent of the sample concentration, and its selection is always a compromise between the extraction time, sensitivity and repeatability of the analytical method. In some cases, a pre-equilibrium condition is considered when the equilibrium time is very long, making the microextraction impracticable [16]. Regarding the extraction temperature in membrane-based sample preparation techniques with the presence of an organic solvent is most common the use of temperatures below 40°C. Temperatures above this value can cause undesirable effects due to partial degradation of the SLM [76].
8.6 Organic solvent The organic solvent content in the HF-LPME, EME and HFRLM procedures is also a variable of considerable importance. The solvent used must have certain characteristics, such as high selectivity and good extraction efficiency for the compounds of interest, water-immiscible, compatibility with the analytical technique employed (for example, with the mobile phase used in
HPLC), and high purity without contaminants or interferents which could hinder the analysis. The main solvents used in HF-LPME are 1-octanol, cyclohexane and toluene [3]. 8.7 Sample stirring Sample stirring is commonly applied to accelerate the extraction kinetics. Increasing the stirring rate of the donor solution speeds up the extraction and the diffusion of the analytes through the interfacial layer of the hollow fiber membrane [104]. In the case of HF-LPME, the organic solvent is protected and more vigorous agitation, such as rates of 2000 rpm (HF(2)-LPME) and 1500 rpm (HF(3)-LPME), can be employed [3].
9. Critical
points
regardingto
membrane-based
microextraction
techniques Some considerations regarding the membrane-based sample preparation techniques should be mentioned for each of the topics discussed, as can be observed above in relation to the membrane-protected SPME technique. The main advantage of this approach is the possibility of using SPME to analyze complex matrices or matrices containing particulate or suspended material. The polymeric membrane acts as a barrier to compounds of high molecular weight allowing the diffusion of compounds with low molecular weight through it, facilitating the determination of several analytes in complex matrices such as blood, milk and urine. In general, for the analysis of complex matrices SPME in HS mode is used, but this mode can be impracticable for the determination of less volatile compounds. In this regard, membrane-protected SPME mode represents an interesting alternative for overcoming the problems associated
with damage of the fiber by complex samples when the use of the direct immersion mode is necessary without the use of organic solvents. On the other hand, this SPME mode can offer some disadvantages. One is the possibility of damaging the SPME fiber during the placing of the polymeric membrane around it. In many cases the commercial SPME fibers can be easily damaged during handling due to the fragility of the silica rods traditionally used as supports for coatings in SPME [105, 106]. In addition, few authors have published studies in which this SPME mode was investigated. One of the probable reasons for this is the development and improvement of the HF-LPME technique since, in many cases, this procedure can replace membraneprotected SPME for the analysis of complex samples containing analytes of low volatility. The advantages of HF-LPME include its low cost and simplicity of operation and also this is a virtually solventless microextraction technique with the consumption of only a few microliters of organic solvent. An alternative approach to overcoming the difficulties associated with membrane-protected SPME is the application of a PDMS layer over the SPME fiber [37, 38], as described above. In this approach the sample preparation is simple, fast and can be automated. In addition, the fiber life-time is significantly increased even with its immersion in complex samples. Among the membrane-based sample preparation techniques applied in microextraction procedures, HF-LPME is certainly the most commonly used and it has been investigated in a large number of research laboratories. This represents an important advance in liquid-phase microextraction because HFLPME is not only a good sample preconcentration technique but also an excellent sample clean-up procedure, which makes it directly applicable to
“dirty” and complex samples [107]. The disposable nature of the hollow fiber eliminates the possibility of sample carry-over and ensures high reproducibility, and the impregnated pores in the walls of the hollow fiber offer some selectivity by preventing the extraction of high molecular weight materials [49]. Another important advantage of the HF-LPME approach is the low cost of the materials used in this kind of microextraction, as well as the use of a low volume of organic solvents, in fact, it is virtually a solventless microextraction technique. On the other hand, some negative points are associated with the HFLPME procedure, for instance, manual labor is required to prepare the fibers individually [3], the presence of a membrane barrier between the source (sample) phase and receiving (acceptor) phase reduces the extraction rate and increases the extraction time, the appearance of air bubbles on the surface of the HF reduces the transport rate and decreases the reproducibility of the extraction and in real samples (e.g., blood plasma, urine and wastewater), the adsorption of hydrophobic substances onto the fiber surface may block the pores [108, 109]. HFRLM is not as well known or as widespread in the analytical research laboratories as the membrane-based sample preparation technique for microextraction procedures when compared with other procedures such as HFLPME (2 and 3 phase). Thus, few publications can be found in the literature in which this approach is applied as a microextraction technique for sample preparation prior to analytical determinations [20, 94, 95]. Most authors report the use of this technique for the extraction, removal and isolation of metals from aqueous samples in studies related to engineering sciences [89-93].
Among the potential advantages of the HFRLM technique are the intensification of mass transfer, due to the renewal of the membrane liquid, and the high membrane surface area, which leads to high mass transfer rates and high concentration factors. Other important factors which should be mentioned are that the process remains stable over a long period of time, since it is easy to replenish the membrane liquid, no leakage occurs between two phases and there is no secondary pollution during the emulsification due to lateral shear forces. Notable also are the facility with which the operation can be carried out and the low cost of the constituent materials [89]. Thus, further effort should be directed toward gaining a better understanding of this approach to membranebased sample preparation techniques, due to the great potential of the HFRLM technique as discussed herein. The application of TFME emerges as an excellent alternative for membrane-based sample preparation procedure. In this case the membrane acts as extraction phase, which leads to preconcentration capacity associated with this approach. This enables high extraction efficiencies and sensitivities for the analytes due to the applicability of a sheet membrane with high surface area, allowing trace determinations. One advantage is the possibility of determinations without using extraction solvent. On the other hand, there are some difficulties associated with introduction of the sheet membrane into the chromatographic injector system. The EME approach has been used as faster variant of membrane-based sample preparation techniques, this approach has great capacity of sample clean-up with possibility to perform microextractions in very complex matrices, such as biological fluids. The main advantage associated with this approach is
regarding extraction time, generally few minutes are required to the microextraction step if compared with traditional HF-LPME approaches. On the other hand, additional materials are needed to perform the microextraction, such as two platinum electrodes and an external power supply. In addition, the EME technique, in the original experimental set-up, is difficult to be automated and, due to electrical field applied, the appearance of some “bubbles” into the samples can decrease the extraction efficiency. Very recent developments such as PALME and Pa-EME have emerged as very promising approaches toward the automation of the microextraction procedure; in addition, there is the possibility of using a 96-well plates device in the microextraction procedure, which allows the simultaneous extractions from multiple samples. These new approaches follow the same environmental concerns associated to other microextraction techniques, presenting a very low solvent and sample consumption as an important factor. On the other hand, been relatively new approaches, more characteristics and details of the experimental and theoretical considerations have to be explored and few works involving these membrane-based approaches are found in the literature.
10. Scientific
studies
involving
membrane-based
microextraction
techniques reported in the literature Membrane-based microextraction techniques have been applied for the determination of several compounds in many varieties of matrices, as can be seen in Table 1.. Some characteristics of the studies reported in the literature are detailed along with the microextraction technique applied for the determination in each case.
11. Conclusions and future trends Membrane-based sample preparation techniques are an attractive tool for the extraction of a wide range of compounds in complex and ‘dirty’ matrices, such as biological and food samples. Among the compounds determined using membrane-based techniques are drugs, metabolites, alkaloids, pollutants and metals. The number of research groups working with these techniques is growing due to the attractive features they offer, such as ease of use, timesavings, the need for only small amounts of sample and solvent, and low cost compared to conventional and other microextraction techniques. However, drawbacks related to this procedure include the limited number of commerciallyavailable membranes for HF-LPME and difficulties associated with the automation of membrane-based techniques still remains, even though advances on automation of some membrane-based microextraction procedures have been reported [66, 67]. In addition, the need for a large number of analyses per day is another great barrier to include these microextraction procedures to a routine laboratory. Therefore, one great challenge in analytical chemistry is for these efficient membrane-based sample preparation techniques to become routine analysis. It is necessary to investigate ways to adapt the microextraction procedures to be more easily operated with less manual labor associated with it; therefore, the possibility of automation of the membrane-based techniques is an issue to be investigated. A very promising tool which can provide the achievement of interesting results for routine analysis and efficient automation in these procedures is the use of the commercial available 96-well plates. This apparatus allows the simultaneous extraction of 96 samples and it has been
used successfully in recent works with different configurations, for example, a promising configuration called PALME (Parallel Artificial Liquid Membrane Extraction) [60]. A new configuration to the EME has been introduced, called Parallel Eletromembrane Extraction (Pa-EME). In this approach a multiwall plate apparatus to perform multiple microextractions in a single assay is also used [85]. The 96-well plate was also successfully used in a TFME approach [46, 47] with very promising results. Summarizing, the main perspectives in membrane-based microextraction techniques are the search for fully automated and, at same time, efficient procedures to be very attractive and applicable to routine laboratory activities, with special concern to reduce the sample volume mainly for application in biological samples. Another important point is the possibility of modification in some membranes used to these sample preparation procedures, this issue has also been evaluated by a recent review [110].
Acknowledgements The authors are grateful to the Brazilian Government Agency Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) for the financial support which made this research possible.
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two endocrine disrupting compounds (EDCs), n-octylphenol and n-nonylphenol, in environmental waters, Sci Total Environ, 443 (2013) 1-6. [135] H.J. Zhang, Z.X. Du, Y. Ji, M. Mei, Simultaneous trace determination of acidic non-steroidal anti-inflammatory drugs in purified water, tap water, juice, soda and energy drink by hollow fiber-based liquid-phase microextraction and ultra-high pressure liquid chromatography coupled to tandem mass spectrometry, Talanta, 109 (2013) 177-184. [136] M. Hadjmohammadi, H. Karimiyan, V. Sharifi, Hollow fibre-based liquid phase microextraction combined with high-performance liquid chromatography for the analysis of flavonoids in Echinophora platyloba DC. and Mentha piperita, Food Chem, 141 (2013) 731-735. [137] F. Moreno, T. Garcia-Barrera, J.L. Gomez-Ariza, Simultaneous speciation and preconcentration of ultra trace concentrations of mercury and selenium species in environmental and biological samples by hollow fiber liquid phase microextraction prior to high performance liquid chromatography coupled to inductively coupled plasma mass spectrometry, J Chromatogr A, 1300 (2013) 43-50. [138] B.B. Chen, Y.L. Huang, M. He, B. Hu, Hollow fiber liquid-liquid-liquid microextraction combined with high performance liquid chromatographyultraviolet detection for the determination of various environmental estrogens in environmental and biological samples, J Chromatogr A, 1305 (2013) 17-26. [139] A. Saleh, E. Larsson, Y. Yamini, J.A. Jonsson, Hollow fiber liquid phase microextraction as a preconcentration and clean-up step after pressurized hot water extraction for the determination of non-steroidal anti-inflammatory drugs in sewage sludge, J Chromatogr A, 1218 (2011) 1331-1339. [140] C. Zhang, L. Ye, L. Xu, Orthogonal array design for the optimization of hollow fiber protected liquid-phase microextraction of salicylates from environmental waters, Anal Chim Acta, 689 (2011) 219-225. [141] H. Ebrahimzadeh, A.A. Asgharinezhad, H. Abedi, F. Kamarei, Optimization of carrier-mediated three-phase hollow fiber microextraction combined with HPLC-UV for determination of propylthiouracil in biological samples, Talanta, 85 (2011) 1043-1049. [142] P.J. Li, B. Hu, Sensitive determination of phenylarsenic compounds based on a dual preconcentration method with capillary electrophoresis/UV detection, J Chromatogr A, 1218 (2011) 4779-4787.
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Figures And Tables: Figure 1. Three basic extraction modes in SPME: a) DI-SPME; B) HS-SPME; and c) Membrane-protected SPME (reproduced from [16] with permission). Figure 2. Extraction apparatus used in HFM-SPME, adapted from Basheer and Lee (reproduced from [14] with permission). Figure 3. Scheme of the membrane-protected SPME used by Musteata and Pawliszyn (reproduced from [36] with permission). Figure 4. Scheme of the experimental set-up used to Thin-Film Microextraction used by Pawliszyn and co-workers. (A) TFME procecure in headspace mode (B) Scheme of membrane after the microextractions and before introduction into the chromatographic injector. 1 - stainless steel rod, 2 – flat sheet membrane, 3 - aqueous sample, 4 – magnetic stirrer, 5 – rolled membrane (reproduced from [39] with permission). Figure 5. Scheme of microextraction modes used in HF-LPME. (A) three-phase system; and (B) two-phase system (reproduced from [53] with permission). Figure 6. Diagram of experimental set-up used in the first study involving HFLPME (reproduced from [17] with permission). Figure 7. Scheme of experimental set-up used to EME procedure proposed by Pedersen-Bjergaard and Rasmussen (reproduced from [68] with permission).
Figure 8. Scheme of HFRLM procedure, (reproduced, with modifications, from [89] with permission). Figure 9. Representation of the HFRLM apparatus (reproduced from [89] with permission). Figure 10.Scheme of HFRLM used for the extraction of Cd (II) from environmental samples. Table 1: Application of membrane-based methods as sample preparation techniques.
bovine milk
herbicides
gabapentin
tetrandrine and
HF(3)-LPME
HF(3)-LPME
fangchinoline
organomercury
enantiomers
mianserin
drugs
antidepressant
Ni and Pb
antitussive drugs
antihistamines and
haloacetic acids
pesticides
organochlorine
plasma samples
biological samples
samples
environmental water
seafood and
human plasma
biological fluids
biological samples
environmental and
human plasma
aqueous samples
aqueous samples
aqueous samples
environmental samples
Cd (II)
fungicides
honey samples
Matrix
sulfonamides
Analyte
HF(3)-LPME
HF(3)-LPME
HF(3)-LPME
HF(2)-LPME
HF(3)-LPME
HF(2)-LPME
HF(2)-LPME
HF(2)-LPME
MP-SPME
HFRLM
HFRLM
technique
Extraction
HPLC-UV
HPLC-UV
HPLC-UV
CE
HPLC-UV
ET AAS
HPLC-UV
GC-ECD
GC-ECD
GC-ECD
GC-MS
F AAS
LC-MS/MS
technique
Determination
3 and 2
0.2
0.3 – 3.8
3 and 4
0.5 – 0.7
0.02 and 0.03
0.003
0.1 - 18
0.013 - 0.059
0.004 - 0.025
0.003 - 0.013
1.5 and 1.3
5.1 – 27.4
-1
LOD (µg L )
N-octanol
Dihexyl ether
Toluene
Di-n-hexhyl ether
N-dodecane
[C6MIM][PF6}
Hexadecane
1-octanol
Toluene
Toluene
-
(60:40 v/v)
acetate:hexane
N-buthyl
Toluene and
pentanol (55:45 v/v)
1-octanol:1-
SLM
Solvent used to
60
45
25
45
45
12 and 15
60
60
30
20
40
40
36 and
40
time (min)
Extraction
[116]
[115]
[114]
]
[56]
[113]
[112]
[111]
[65]]
[64]]
[14]
[20, 94]
[21]
Ref.
S0003-2670(15)00227-5 http://dx.doi.org/doi:10.1016/j.aca.2015.02.049 ACA 233763
To appear in:
Analytica Chimica Acta
Received date: Revised date: Accepted date:
13-12-2014 13-2-2015 17-2-2015
Please cite this article as: Eduardo Carasek, Josias Merib, Membrane-based microextraction techniques in analytical chemistry: a review, Analytica Chimica Acta http://dx.doi.org/10.1016/j.aca.2015.02.049 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.
Membrane-based microextraction techniques in analytical chemistry: a review
Eduardo Carasek*, Josias Merib
Departamento de Química, Universidade Federal de Santa Catarina, Florianópolis 88040-900, SC, Brazil
*Corresponding Author (E. Carasek) E-mail address: [email protected] Fax: +55 48 3721 6850
Highlights
► Sample preparation step is crucial in the development of a large number of
analytical methodologies ► This review describes aspects concerning to the growth in the development and improvement of sample preparation techniques ► Membrane-based microextraction techniques emerge as efficient, simple, low cost and environmentally friendly procedures ► Some critical points about each discussed membrane-based microextraction techniques are presented ►
Table
containing
different
applications
of
each
membrane-based
microextraction technique is presented
Graphical abstractEduardo Carasek received his PhD degree at the
University of Campinas – Brazil in 1997, and concluded postdoctoral research fellow at the University of Waterloo – Canada in 2006, 2010 and 2014 working with Professor Janusz Pawliszyn, where he developed analytical methods based on solid phase microextraction. He works as Associate Analytical Chemistry Professor at the Federal University of Santa Catarina, Florianópolis – Brazil. His research interest is to develop microextraction methods (SPME and LPME) for the determination of organic and inorganic compounds in several matrices and detection by chromatography and spectrometry.
Abstract
The use of membrane-based sample preparation techniques in analytical chemistry has gained growing attention from the scientific community since the development of miniaturized sample preparation procedures in the 1990s. The use of membranes makes the microextraction procedures more stable, allowing the determination of analytes in complex and “dirty” samples. This review describes some characteristics of classical membrane-based microextraction techniques (membrane-protected solid-phase microextraction, hollow-fiber liquid-phase microextraction and hollow-fiber renewal liquid membrane) as well as some alternative configurations (thin film and electromembrane extraction) used successfully for the determination of different analytes in a large variety of matrices, some critical points regarding each technique are highlighted.
Keywords:
solid-phase
microextraction;
hollow-fiber
liquid-phase
microextraction; hollow-fiber renewal liquid membrane; sample preparation; membrane-based techniques.
Summary 1.
Introduction.......................................................................................................................... 4
2.
Membranes used for extraction procedures................................................................... 7
3.
Membrane-Protected Solid-Phase Microextraction (MP-SPME) ................................ 9
4.
Thin Film Microextraction (TFME).................................................................................. 15
5.
Hollow-Fiber Liquid-Phase Microextraction.................................................................. 17 5.1 A general overview ........................................................................................................ 17 5.2 Three-phase HF-LPME................................................................................................. 19 5.3 Two-phase HF-LPME................................................................................................... 24 5.4 Automation of HF-LPME procedure............................................................................ 27
6.
Eletromembrane Extraction (EME) ................................................................................ 28
7.
Hollow-Fiber Renewal Liquid Membrane (HFRLM) .................................................... 31
8.
Main optimization factors in membrane-based microextraction procedures........... 36 8.1
Choice of membrane................................................................................................ 36
8.2
Sample temperature................................................................................................. 36
8.3
pH adjustment ........................................................................................................... 37
8.4
Ionic strength............................................................................................................. 38
8.5
Extraction time .......................................................................................................... 39
8.6
Organic solvent ......................................................................................................... 40
8.7
Sample stirring .......................................................................................................... 41
9.
Critical points regardingto membrane-based microextraction techniques .............. 41
10. Scientific studies involving membrane-based sample preparation techniques reported in the literature .......................................................................................................... 45 11.
Conclusions and future trends.................................................................................... 45
12.
References .................................................................................................................... 47
1. Introduction Sample preparation procedures are usually applied in chemical analysis to overcome difficulties with sample introduction in the analytical equipment, to separate the analytes from the sample matrix and/or to concentrate them for trace analysis. This step is often considered to be the Achilles’ heel in chemical analysis, mainly due to the risk of analyte loss and sample contamination. In addition to these sources of systematic errors, sample preparation is often the most time-consuming step in analytical procedures [1]. The sample preparation step is generally analyte and matrix-dependent, requiring suitable optimization of the different influencing parameters. The sample preparation and analysis methodologies, which originally involved traditional laboratory liquid-liquid, liquid-solid and gaseous extraction are associated with a number of limitations, including the requirement for arduous time-consuming manual labor and/or, in some cases, the use of large quantities of hazardous extracting solvents. The mode of operation in liquid-liquid extractions also gives rise to limited preconcentration factors as a consequence of the limited extractant-to-sample volume ratios employed. Moreover, coalescence and phase separation can be a slow step, especially when emulsions are formed [2, 3]. Over recent decades, sufficient attention has not been paid to the sample preparation step, especially considering the advances achieved in terms of analytical instrumentation, but efforts are currently being focused on its improvement. In this regard, current trends are moving toward its simplification, miniaturization and automation involving also the use of solventfree
and
other
environmentally-friendly
procedures,
while
maintaining
good/acceptable extraction efficiencies [4]. The past 24 years have been very
rich in relation to this issue and of great importance due to the development and improvement microextraction
of
so-called techniques
miniaturized developed
extraction in
this
techniques.
period
are
Notable
solid-phase
microextraction (SPME), developed by Pawliszyn and co-workers [5], and earlier studies which resulted in the development and application of liquid-phase microextraciton (LPME) by Dasgupta`s group [6-11]. These research studies have allowed the introduction of new concepts which have enabled the extraction and determination of different analytes in several matrices with a small volume of extracting solvents and, in the case of SPME, the possibility of a solventless extraction procedure. The use of alternative microextraction techniques for sample preparation reduces the number of errors that commonly result from multi-stage procedures, and limits the negative impact on the environment and the health of those performing the laboratory work. A reduction in the amount of organic solvents employed in the extraction process allows economic benefits and reduces the problems associated with waste treatment [12]. Another important advance in sample preparation techniques is the use of membranes in the microextraction procedures. In general, these approaches have wide applicability to matrices of great complexity or those containing molecules which interfere with the efficiency of the procedure [13]. Notable variants of such sample preparation techniques are the use of a microextraction mode in SPME called membrane-protected SPME, which can be applied to samples containing particulate material which could damage the SPME fiber [14-16]. Another important sample preparation technique that makes use of membranes is hollow-fiber liquid-phase microextraction (HF-LPME) proposed
by Pedersen-Bjergaard and co-workers [17]. This technique allows the analysis of complex samples, including those containing suspended or particulate material. HF-LPME can generally be used applying two different approaches according to the number of phases involved in the procedure. The two-phase approach (HF(2)-LPME) is known as microporous-membrane liquid-phase microextraction (MMLPME) while the three-phase HF-LPME approach (HF(3)LPME) is referred to as liquid-liquid-liquid microextraction (LLLME). In addition, more recently, the use of another variant of the application of membranes in extraction procedures has been developed, called hollow-fiber renewal liquid membrane (HFRLM) extraction [18-21]. This approach has some differences compared with classical HF-LPME procedures, such as the use of one aliquot of extractor solvent applied directly into the sample to allow renewal of the membrane liquid during the extraction procedure. In addition, the development of new configurations for membrane-based microextraction procedures have been proposed and some advances can be pointed out as the development of Thin Film Microextraction (TFME) as well as Electromembrane Extraction (EME). Thus, it can be observed that the use of membranes in analytical procedures has been the object of several studies and many authors have applied these microextraction techniques to a variety of matrices. Also, some reviews have been published [13, 22, 23], evidencing the great importance of these membrane-based procedures in the sample preparation step. Regarding the use of membranes in certain analytical procedures, this review addressed the characteristics, basic theoretical aspects, differences and applications of the membrane-protected-SPME, HF(3)-LPME, MMLLE or HF(2)LPME,and HFRLM techniques, as well as some aspects regarding different
configurations involving TFME and EME are discussed. Also, some highlights of the critical aspects of each procedure are presented. A table containing summarized details of some studies involving these approaches reported in the literature is provided.
2. Membranes used for extraction procedures Following the development and improvement of extraction techniques, several membrane-based methods have been developed as alternatives to the conventional techniques. A large variety of membranes with different structures, transport properties and separation mechanism are available. These distinct membrane characteristics generally originate from dissimilar raw materials or preparation methods. In general, in the microextraction techniques synthetic membranes are applied, both organic (polymeric) and inorganic membranes [24, 25] A membrane is a selective barrier through which different gases, vapors and liquids move at varying rates. The membrane facilitates the two phases coming into contact with each other without direct mixing. Molecules move through membranes via the process of diffusion and are driven by a concentration, pressure or electrical potential gradient. The diffusion-based transport can be expressed by Flick’s first law of diffusion according to equation 1 [25]. j = −D
dc dx
(1)
where the J is the rate of transfer (or flux) (g/cm2 s), D is the diffusion coefficient (cm2/s) and dc/dx is the concentration gradient.
The integration of the above equation gives equation 2. j=
D(Cis − Cil ) L
(2)
where Cis is the concentration of i at the outer membrane surface, cil is the concentration of i in the lumen and L is the membrane thickness. The flux of analytes across the membrane is also affected by temperature since this determines the diffusion coefficient. In the case of liquids, this can best be described by the Stokes–Einstein equation, shown in the equation 3. D=
kT 6παη
(3)
where k is the Boltzmann constant, T corresponds to absolute temperature, π is the pi number, α is the radius of the solute and η is the solution viscosity.
The quantity, size and distribution of pores throughout the membrane structure represent important characteristics of the membrane morphology. Membranes which have no pores in their structure are known as non-porous, while those which possess pores are referred to as porous. The size, shape and distribution of pores in a membrane are largely dependent on the processes through which they are made and play a significant role in their mode of separation. Selected molecules pass through the openings in porous membranes and movement through these membranes involves size exclusion. Therefore, these membranes are useful in applications such as nanofiltration and dialysis. Non-porous membranes are solid (pore-free) structures and the molecules move through them via diffusion, and therefore, their compatibility with the analyte is critical [25].
Concerning the chemical nature and the kind of analyte, membranes can be classified on the basis of their hydrophobic or hydrophilic nature. Cellulose acetate,
regenerated
cellulose,
polysulfone,
polycarbonate,
polyamide,
polyethersulfone and ion exchange membranes are well suited for the isolation of ionic or polar species from aqueous/organic solutions. On the other hand, hydrophobic membranes (e.g., polytetrafluoroethylene, polypropylene, silicone rubber, latex, polyvinylchloride or polyvinylidene difluoride) are commonly exploited for the selective on-line separation of gases and volatile inorganic or organic compounds [26]. The membrane most commonly used in microextraction procedures is Acurel 3/2 Q, comprised of a hollow microporous polypropylene tube (Membrana GmbH, Wuppertal, Germany) with an inner diameter of 600 µm, a wall thickness of 200 µm, a pore size of 0.2 µm and a wall porosity (by volume) of around 70% [27]. Other types of capillary membranes, such as those composed of polysulfone [27] and cellulose [28], have also been used for sample
preparation
purposes.
For
thin-film
microextraction
approach,
membranes composed by polydimethylsiloxane, carboxen/polydimethylsiloxane and polydimethylsiloxane/divinylbenzene have been produced and applied; in this case, the thin polymeric membranes sheets are used not only to sample clean-up but also as extraction phases (preconcentration).
3. Membrane-Protected Solid-Phase Microextraction (MP-SPME) The SPME procedure represents a great advance in the miniaturization of sample preparation techniques. In SPME, a small amount of the extracting phase associated with a solid support is placed in contact with the sample
matrix or in the headspace above the matrix for a predetermined time. If this time is sufficiently long, a concentration equilibrium is established between the sample matrix and the extraction phase. When equilibrium conditions are reached, exposing the fiber for a longer amount of time does not lead to a greater accumulation of analytes [29]. The constant for the distribution between the amount analyte contained in the matrix (A(matrix)) and the amount extracted by the SPME fiber (A(fiber)) can be represented as shown in equation 4. A(matrix) ⇆ A( fiber ) K mf =
Cf Cm
(4)
where K mf represents the matrix – fiber distribution constant; Cf represents the analyte concentration in the SPME fiber and Cm represents the analyte concentration in the matrix.
The total analyte concentration can be described as the sum of the amount of analyte present in the matrix, in the headspace and in the SPME fiber, as described in equation 5. n0 = n f + nhs + nm
(5)
where n0 represents the total amount of analyte; n f represents the amount of analyte in the SPME fiber; nhs represents the amount of analyte in the headspace; nm represents the amount of analyte present in the matrix. Using equation 5 with some mathematical adjustments, the total amount of analyte mass extracted by the SPME fiber can be described by equation 6. nf =
C0 .Vm .V f .K mf Vm + V f .K mf
(6)
where n f represents the total mass of analyte extracted by the SPME fiber; V f represents the fiber coating volume; K mf represents the fiber coating – sample matrix distribution constant;
c0 represents initial concentration; and Vm
represents the matrix volume [29]. In general, this type of microextraction involves the adsorption/absorption of the analytes by a fused silica fiber coated with an adequate stationary phase and its subsequent desorption immediately prior to gas chromatography analysis [30]. Various types of polymeric coating are commercially available, such as polydimethylsiloxane (PDMS), PDMS-divinylbenzene (PDMS/DVB), and DVB/Carboxen/PDMS (DVB/Car/PDMS). The SPME procedure is simple, relatively quick and does not require the use of organic extraction solvents [31]. Traditionally, SPME is used in the headspace mode (HS-SPME) for the analysis of highly volatile compounds and in the direct immersion mode (DI-SPME) for the determination of compounds with lower volatility [32]. Another extraction mode used in SPME is membraneprotected SPME. A scheme showing these three extraction modes used in SPME can be seen in Figure 1.
FIGURE 1
In the membrane-protected SPME mode a membrane is placed around the SPME fiber to protect it. This is a useful precaution when matrices
containing solids in suspension or particulate material, such as soil, milk, urine and blood, are analyzed [16]. In general, the use of SPME in complex matrices (food samples, soil samples, biological fluids) requires sample pretreatment or modification of the sampling protocol in order to simplify the matrix and to prevent damage of the fiber. The complexity of the sample can affect the recovery of the analytes, the analytical method precision, the accuracy, and the sample compatibility with a subsequent chromatographic technique. In a sample which contains nonvolatile and strongly interfering compounds, such as proteins, humic acids and fatty material, analysis using either DI-SPME or HS-SPME is difficult to perform [14, 33-35]. To overcome some problems associated with applying SPME to complex matrices a new approach to SPME has been proposed [28], which enables the analysis of high boiling-point and non-volatile analytes in complex aqueous or other liquid matrices. In this approach, the SPME fiber device is placed inside a hollow cellulose membrane with a molecular weight cut-off (MWCO) of 18000 Da. The membrane, forming a concentric sheath around the fiber, allows the target analytes, which typically have a molecular weight of less than 1000 Da, to diffuse through while excluding interfering compounds of high molecular weight, such as humic acids which have molecular weights up to several million Da. With membrane protection, direct immersion of this protected-SPME fiber can be used successfully for the extraction of heavy PAHs, such as chrysene and perylene, from aqueous samples containing humic acids. In another study [14] it is proposed the use of a porous hollow polypropylene fiber in a membrane-protected solid-phase microextraction
procedure for the determination of triazine herbicides in complex samples with separation/detection by gas GC-MS. The authors called this approach hollowfiber-membrane solid-phase microextraction (HFM-SPME) and bovine milk and sewage sludge were used as matrices. A 65 µm PDMS/DVB SPME fiber was protected by a hollow polypropylene fiber membrane and a scheme of the experimental set-up is described in Figure 2.
FIGURE 2
The extractions were performed by direct immersion of the protectedSPME fiber into the bovine milk samples. The internal diameter of the HFM (polypropylene membrane) of 600 µm was large enough to accommodate the SPME stainless steel protective tubing of the fiber. The SPME fiber assembly was inserted into a 7-cm long HFM (one end sealed using a flame) which completely covered the stainless steel tubing and the polymeric fiber. A bovine milk sample volume of 5 mL was used and an oil bath was used to adjust the sample temperature. After the microextraction procedure, the HFM was discarded and the SPME fiber was subjected to thermal desorption for 5 min. The results obtained in this study presented relative standard deviations ranging from 4.30 to 12.37% and correlation coefficients for the calibration curves of between 0.9799 and 0.9965 for triazines in bovine milk. Regarding the sewage sludge samples only recovery studies with two different spiked concentrations (20 and 100 µg L−1) were performed. The recovery dates varied between 93.33 and 107.78% and the RSDs were lower than 13%.
The same SPME extraction mode was applied successfully [36] for the determination of the free concentration of the medicament placitaxel in liposome formulations with separation/detection by LC-ESI/MS. For the effective direct extraction of low molecular weight compounds from complex liquid samples, a hollow membrane (molecular weight cut-off of 15 kD, for proteins, and 10 nm pore size) was used to form a concentric sheath around a coated SPME fiber. In this case, the best optimized SPME coating was comprised of a Carbowaxtemplated resin (CW/TPR). The end of the membrane was sealed and great care was taken to avoid air entering the space between the fiber and the membrane. The membrane blocked the access of large particles to the coating surface like liposomes, while target analytes with low molecular weight diffused through the membrane and reached the extraction phase. A dialysis membrane was used which inhibited the direct interaction between the SPME extraction phase and the liposome content of the liposome formulations. The set-up for the membrane-protected SPME used in this study is shown in Figure 3.
FIGURE 3
This microextraction mode was applied successfully to the determination of the free paclitaxel in liposome formulations, with good linearity over the range of concentrations of interest, this being a very useful alternative to the application of SPME for complex samples. More recently, a very promising approach involving SPME to overcome problems associated with the complexity of the samples was developed [37, 38]. In this approach the researches proposed the use of an external PDMS
layer over the commercial PDMS/DVB fiber. According to the authors the coating procedure consists of immersing the commercial PDMS/DVB fiber in the PDMS solution and subsequently withdrawing it slowly at a rate of approximately 0.5 mm s-1. Passing it through a micropipette tip of around 350 µm diameter aperture ensured that a thinner layer was formed, with the excess polymer being removed. After the coating process, the coated fiber was placed in a vacuum oven at 50 °C under N2 flow for 12 h. The coating/curing process was repeated twice to ensure complete and uniform coverage. Procedures for the microextraction of triazole pesticides [37] obtained with this new approach presented an extraction capability similar to that of the PDMS/DVB commercial fiber in water samples, evidencing that the presence of the PDMS layer did not negatively affect the extraction efficiency. In addition, the PDMS/DVB/PDMS was successfully applied to complex samples, such as whole grape pulp, for over 100 cycles with no sample pretreatment being required. In another study [38] the same strategy was used for a PDMS/DVB/PDMS coating to determine 10 triazole pesticides in grape and strawberry pulps.
4. Thin Film Microextraction (TFME) Another
important
advance
in
membrane-based
microextraction
techniques has been the development of the Thin-Film Microextraction. This microextraction approach consists basically on the use of a thin sheet of a polymeric membrane with high surface area as the extraction phase [39]. In the earlier studies involving membrane-based sample preparation approaches, the polymeric membranes were most used as a barrier to isolate the analytes from the sample matrix (clean-up). However, in the TFME approach the polymeric
membrane has a preconcentration capacity and it acts as an extraction phase for analyte species before the measurements in an analytical system [40]. Pawliszyn and co-workers [39] proposed the use of a thin PDMS sheet to extract some PAHs from aqueous samples with separation/detection by GCMS; in this experimental set-up a PDMS membrane was attached to a stainless steel rod, this membrane was shaped like a flag with two tested dimensions (1 cm x 1 cm and 1 cm x 2 cm) and placed in a 40 mL vial containing 10 mL of aqueous sample, both direct immersion and headspace modes were applied. After the required extraction time, the membrane was rolled around the rod and placed into the heated chromatographic injector to thermal desorption. This experimental set-up of TFME is presented in the Figure 4 (A and B).
FIGURE 4 (A and B)
Excellent results to the analytical parameters of merit were obtained using this technique for extraction of PAHs from aqueous samples. The limits of detection varied from 2.5 to 19 pg mL-1 for acenaphthene and pyrene, respectively; correlation coefficients above 0.9972 with relative standard deviations lower than 13.6% were obtained. One important factor to be taking into account when the TFME is employed is the achievement of higher extraction rates, this occurs due to larger surface area to extraction-phase volume ratio of the thin film, without sacrificing the sampling time if compared to other microextraction techniques [40], More recently, several studies involving the use of a thin membrane as extraction phase in microextraction procedures have been developed, including
reviews containing theoretical aspects, calibration methods, TFME formats, extraction phases and applications of this approach [40, 41]. Among these works, the development of extraction phases with high extraction capacities has been explored. Mixed extraction phases were introduced to TFME procedures; in this sense, the production of extraction phase formed by divinylbenzene particle-loaded membrane combined with PDMS for trace gas sampling [42], as well
as
the
development
of
carboxen/polydimethylsiloxane
polydimethylsiloxane/divinylbenzene extraction
and
phases for determination of
polar compound in water samples [43] can be highlighted. Also, the use of a cooled membrane for gas sampling was reported [44], this strategy allowed the combination of the advantages from large and cold surface area and the achievement of high sensitivity for volatile compounds. In addition, important works involving the determination of quaternary ammonium compounds from water samples were developed using TFME approach [45, 46], as well as the development of coatings based on thin films combined with automated 96-blade system was successfully developed for determination of benzodiazepines [47] and analytes of wide polarity range from biological fluids [48] .
5. Hollow-Fiber Liquid-Phase Microextraction 5.1 A general overview Sample preparation using membrane-based liquid-phase microextraction techniques is seen as an alternative to common approaches involving solidphase extraction (SPE), solid-phase microextraction (SPME) or traditional liquid-liquid extraction (LLE) [23]. This type of microextraction also represents an important variant of the LPME techniques, mainly regarding single-drop
microextraction (SDME) [7]. SDME is the simplest operational mode of the LPME techniques, in which a single liquid drop is used as the extractor phase. It is based on the principle of the distribution of the analytes between a microdrop of extraction solvent placed at the tip of a micro-syringe and an aqueous phase. Solvent extraction is based on the principle that the equilibrium ratio for the concentrations of solute in the organic and aqueous phases is constant. In SDME, a solvent microdrop is exposed to an aqueous sample, wherein the analyte is extracted by the drop. After extraction, the microdrop is retracted back into the microsyringe and then injected into the respective instruments for further analysis. In this case, high enrichment factors are obtained due to the high ratio of sample volume to organic phase volume with the use of few microliters of organic solvent, representing a great advance in sample preparation techniques [49]. In spite of its simplicity and direct compatibility with chromatographic systems, SDME has gained limited popularity within the analytical community. The major reason is related to the stability of the drop during extraction. In order to speed up extractions, stirring or agitation is required, but the mechanical stability of a single drop suspended at the tip of a microsyringe is relatively poor, and the drop is easily lost in the sample solution. In addition, biological samples, such as plasma, may emulsify substantial amounts of organic solvents, and this may even enhance the instability problem [50]. To overcome the problems associated with the instability of the microdrop of extraction solvent, in 1999 Pedersen-Bjergaard and Rasmussen [17]
proposed
membrane-based
another
important
approach,
microextraction
initially
referred
to
technique as
using the
liquid-liquid-liquid
microextraction (LLLME). In this technique, the analytes are firstly extracted into a supported liquid membrane (SLM) sustained in the pores of a hydrophobic hollow porous fiber, and later into an acceptor phase placed inside the lumen of the fiber. Later, with the publication of further studies involving this technique, this procedure also became known as hollow-fiber liquid-phase microextraction (HF-LPME). This microextraction technique was developed as a promising method of sample preparation owing to its simplicity, efficiency, low cost, negligible volume of solvents used and excellent sample cleanup ability [51]. HF-LPME modes can be classified according to the number of phases involved in the system, with two-phase or three-phase HF-LPME generally being applied [4, 17, 52, 53]. One of these proposed HF-LPME set-ups is shown in Figure 5.
FIGURE 5
According to these schemes it can be observed that the main difference between the two approaches of HF-LPME is the extraction solution contained in the lumen of the hollow membrane: in the three-phase system an aqueous acceptor phase is used and in the case of the two-phase approach an organic phase is used as the acceptor phase. Properly sealed vials and, in the case of the above scheme, small conical tubes are used as guides.
5.2 Three-phase HF-LPME In the first study involving this type of microextraction, HF(3)-LPME was investigated by Pedersen-Bjergaard and Rasmussen in 1999 [17]. The principles of this microextraction are based on the so-called SLMtechnique
which is based on a three-phase (aqueous–organic–aqueous) system, where the organic solvent is held in the pores of a porous membrane supported by capillary forces. The membranes used for microextraction purposes can have the flat format flat or hollow fibers. The SLM is in contact with the two aqueous phases (the donor phase, that is the aqueous sample, and the acceptor phase, usually an aqueous buffer) in the hollow fiber configuration placed in the lumen of the fiber [13]. The hydrophobic polypropylene membranes, such as that cited above, are among the most commonly used to perform this microextraction technique. The experimental procedure involving the HF(3)-LPME configuration is generally composed of an SLM, which is formed in the pores in the wall of the hollow fiber. This may be accomplished by dipping the hollow fiber into an organic solvent of low polarity (like n-octanol, dihexyl ether or toluene) for few seconds. Alternatively, a small quantity of the organic solvent can be injected into the lumen of the hollow fiber and immobilized into the porous of the membrane. After loading the SLM, the lumen of the hollow fiber is filled with the acceptor phase. In HF(3)-LPME the acceptor solution may be an acidic or alkaline aqueous solution resulting in a three-phase extraction system [52]. Equation 4 establishes a relation, in the case of equilibrium, between the analyte concentrations in sample (A sample), in the organic extractor phase (A organic phase) and in the aqueous acceptor phase (A acceptor phase).
A ( sample) ⇆ A (organic phase) ⇆ A (acceptor phase)
(4)
The overall extraction process is affected by the partition coefficients for the partitioning between the organic phase and the donor solution (Korg/d) and between the acceptor phase and the organic phase (Kacc/org), which are defined by equations 5 and 6, respectively. K org / d =
Ceq ,org
(5)
Ceq ,d
K acc / org =
Ceq , acc Ceq ,org
(6)
where Ceq,org is the analyte concentration at equilibrium in the organic phase, Ceq,d is the analyte concentration at equilibrium in the donor solution and Ceq,acc is the analyte concentration at equilibrium in the acceptor phase.
The partition coefficient for the partitioning between the acceptor phase and the donor phase, which may be considered as the overall driving force for the extraction, is calculated as the product of (Korg/d) and (Kacc/org) [22] as shown in equation 7.
Kr / d =
Ceq ,acc Ceq ,d
= K org / d .K acc / org
(7)
The pH is an important parameter which affects the extraction efficiency when working with a system of HF(3)-LPME. The pH of the donor phase (sample) should be adjusted to maintain the analytes in the non-ionized form, while the acceptor phase pH should be adjusted to a value at which the analytes remain ionized. The difference between the pH values for the donor and acceptor phases is one of the key parameters which can promote the
transfer of analytes from the donor phase to the immobilized organic solvent and subsequently to the acceptor phase. Thus, the pH values for the donor and receptor phase selected are slightly lower and higher, respectively, than the pKa value for the analyte [54]. Pedersen-Bjergaard and Rasmussen [17] performed a pioneering study using the three-phase approach to determine methamphetamine concentrations in biological fluids. In this study, methamphetamine was extracted from aqueous samples and biological fluids with a 8-cm porous hollow polypropylene fiber and a three-phase system was employed to perform the microextraction using 25 µL of acidic acceptor phase and an SLM filled with 1-octanol and posterior methamphetamine determination by capillary electrophoresis. Figure 6 shows a diagram of the experimental set-up proposed by the authors (initially referred to as LLLME).
FIGURE 6
This study, which was the first using this configuration to be published, demonstrated the great potential of the technique. In addition, the low cost of the material, simplicity and low solvent consumption can be highlighted as important advantages with regard to the development and improvement of the HF-LPME procedures. Another study using the HF(3)-LPME approach [55] to determine two mianserin enantiomers in plasma samples with capillary electrophoresis was published. In this study, di-n-hexyl ether was impregnated in the pores of the hollow fiber and an acidic solution was used as the acceptor phase. Efficient
sample clean-up and satisfactory results to analytical parameters of merit were achieved. The
HF(3)-LPME
approach
was
applied
to
the
extraction
of
antidepressant drugs [56]. In this case, amitriptyline, imipramine and sertraline in aqueous and biological fluid samples (such as plasma and urine) were determined using chromatographic detection performed by HPLC-UV. The solvent used to impregnate the pores of a polypropylene hollow fiber membrane was n-dodecane and the pH values for the donor phase and acceptor (aqueous) phase were set at 12 and 2.1, respectively. Enrichment factors of up to 300 were achieved and the relative standards deviations were lower than 12%. A three-phase configuration to extract valerenic acid [57] was applied prior to separation/detection by HPLC-UV. To perform this study the researchers used dihexyl ether as an organic extracting solvent in the pores of a hollow fiber and then back extracted them into an aqueous solution with pH 9.5 located inside the lumen of the hollow fiber, the sample pH used for this extraction being 3.5. The HF(3)-LPME approach has been applied not only to the determination of organic compounds but also in studies on metals. This technique was used to determine trace concentrations of mercury in water samples with detection by electrothermal atomic absorption spectrometry [58]. To perform the extraction, the researchers added a solution of 1-(2-pyridylazo)2-naphthol (PAN) to the donor sample at pH 7. The hollow polypropylene fiber membrane was impregnated with toluene and the lumen was filled with 10 µL of ammonium iodide solution.
A miniaturization of HF(3)-LPME has been proposed by Sikanen and coworkers [59]; in this new concept, called droplet-membrane-droplet liquid-phase microextraction, sample volume of 15 µL, acceptor phase of 10 µL and a flat porous polypropylene membrane as SLM were used. The flat membrane was arranged bellow the sample droplet and above the acceptor phase. Another important advance in HF-LPME is called Parallel Artificial Liquid Membrane Extraction (PALME) [60] and consists basically on a system where the sample and acceptor phase are separated by a flat membrane impregnated with the organic solvent. This system is compatible with a 96-well plates device and it has great advantages such as low sample and solvent consumption, as well as the possibility of extraction of multiple samples. This new configuration can be much explored in a near future to investigate new possibilities of automation for the HF-LPME procedure with 96-well plates device.The miniaturization of the microextracion procedures is one of the trends in the membrane-based sample preparation techniques. A microfluidic-chip to liquid phase microextraction was developed and applied to study drug metabolism [61]. This approach consists basically on the introduction of a low sample volume with aid of a pump at 3 – 4 µL min-1, this sample was placed in contact with a SLM and, on the other side of the membrane an acceptor solution was present (pumped at 1 µL min-1). Excellent enrichment factors were obtained with this device, which is emerging as an alternative to limited volume samples.
5.3 Two-phase HF-LPME In HF(2)-LPME, a microsyringe is filled with a few microliters of an organic solvent which is immiscible with water. A small piece of porous hollow
fiber is filled with this organic solvent, subsequently, the piece of hollow fiber is connected to the needle of the microsyringe containing a determined volume of this organic solvent, after this the system is placed into the sample to perform the microextraction of the analytes; the organic solvent in both wall porous and in the lumen of the fiber acts as extraction phase. Equation 7 establishes a relationship, under equilibrium conditions, between the analyte concentration in sample (A sample) and in the organic acceptor phase (A organic acceptor). A ( sample) ⇆ A (organic acceptor )
(7)
In the HF(2)-LPME approach the analytes are extracted by passive diffusion from the aqueous sample directly into the organic acceptor phase. This process is described in equation 8, and is dependent on the partition coefficient (Kacc/d) for the partitioning between the organic acceptor phase and the donor solution (sample). K acc / d =
Ceq ,acc Ceq , d
(8)
where Ceq,acc is the analyte concentration at equilibrium in the organic acceptor phase and Ceq,d is the analyte concentration at equilibrium in the donor solution (sample).
The HF(2)-LPME approach in which the solvent is held within the pores and inside a hollow porous fiber is analogous, in terms of the mass transfer behavior, to solid-phase microextraction. Equation 9 describes the mass of
analyte extracted as a function of time, for short exposure times, during the SPME process [29]. n=
2π Dw .L.Cwt b + δ ln b
(9)
where Dw is the diffusion coefficient of the analyte in the real sample phase (cm2 s-1), L is the length of the fiber (cm), Cw is the analyte concentration in the sample (ng mL-1), b is the outer radius of the fiber (cm) and δ is the diffusion film thickness (cm) [3].
A dynamic configuration to HF(2)-LPME has been reported [22]. In this case, the needle of the syringe and the piece of hollow fiber are placed into an aqueous sample and, during the extraction, small volumes of the aqueous sample are repeatedly pushed and pulled in and out of the hollow fiber using the syringe plunger. During withdrawal of the aqueous sample, a thin film of organic solvent is built up in the hollow fiber and this vigorously extracts the analyte from the sample segment. Dynamic systems have also been reported to HF(3)-LPME [62] and the great advantage of these systems is an improvement of the extraction speed when compared with the static conditions. As in the case of HF(3)-LPME, the approach involving HF(2)-LPME can be applied to the analysis of a large variety of matrices. A method based on HF(2)LPME with 2-octanol impregnated in a hollow polypropylene fiber membrane to extract dichlorophenol isomers in urine samples with separation/determination by gas chromatography-negative chemical ionization mass spectrometry was proposed [63].
A two-phase approach was applied for the determination of six fungicides (chlorothalonil, hexaconazole, penconazole, procymidone, tetraconazole, and vinclozolin) in water samples adjusted to pH 4 [64]. A hollow polypropylene fiber membrane was impregnated with toluene, which was used as the extraction solvent. The researchers obtained enrichment factors ranging from 135 to 213 and recovery tests were between 90.7% and 97.6%. Satisfactory results for the determination of some organochlorine pesticides from environmental matrices with the two-phase approach [65] were obtained performing extractions with a 1.3-cm length of hollow polypropylene fiber membrane fitted into a 10 µL microsyringe and with 5 µL of toluene immobilized in the pores of the hollow membrane.
5.4 Automation of HF-LPME procedure Several sample preparation methods involving microextractions have high extraction efficiencies and at the same time allow a lower consumption of organic solvents, as previously commented in this text. However, these techniques can present some manual labor associated with the handling and transfer of the collected extract to the analytical equipment. These difficulties can lead to the possibility of losses of analytes during the procedure, decreasing the extraction efficiency and, many times, causing problems associated with reproducibility in the analytical measures. In this sense, emerges the possibility of automation of these techniques. One great advance in the field of automation of HF-LPME was the development of a fully automated HF-LPME procedure using a CTC CombiPal autosampler, as well as the use of kinetic calibration for determination of
carbaryl from red wine samples with separation/detection by CG-MS [66]. All steps of the HF-LPME procedure were performed by the autosampler, decreasing significantly the manual labor and improving the reproducibility with using the proposed device. In another work [67] it was proposed the use of a fully automated HF-LPME procedure for determination of flunitrazepan in plasma
and
urine
samples
with
separation/detection
by
GC-MS/MS.
Polyvinylidene difluoride hollow fiber was used in this study because it showed good stability and also presented less adsorption of biomolecules, which is an important factor for analysis in complex biological samples. In addition, the automation of HF-LPME procedure showed great accuracy allowing satisfactory analytical results.
6. Eletromembrane Extraction (EME) The electromembrane extraction is one of the variants of the liquid phase microxtraction that has been gaining great attention of the scientific community in the sample preparation field. Since its development in 2006 [68] the number of scientific publications involving application and improvement of this technique is growing. The basic principle of this technique is the application of a d.c. potential across a SLM as a powerful driving force for migration of charged species toward the electrode of opposite charge in the acceptor phase [69-71]. The apparatus used to the EME is similar to the one used in HF-LPME procedures. However, for the EME is necessary a power supply and two electrodes. A power supply provides d.c. potential (generally 1 – 300 V) to enhance the extraction rate of ionizable analytes from the donor solution (sample) to acceptor phase, which is contained in the lumen of a hollow fiber;
two platinum electrodes are used to perform the migration of the analytes, one of this electrodes is placed into the sample and the other is placed inside the hollow fiber into the acceptor phase. Generally, a polypropylene hollow fiber membrane is used and an organic solvent is immobilized into the porous to create a SLM. To perform the electro-migration of the analytes is necessary that the electrode located into the acceptor phase is charged oppositely to the analytes; for example, to extract cationic analytes the electrode placed into the acceptor phase may be charged negatively (cathode) and the positively charged electrode (anode) may be placed inside the sample; in other hand, to determine anionic analytes, the electrode placed into the acceptor phase may be charged positively (anode) and the negatively charged electrode (cathode) may be placed inside the sample [72]. The EME technique was used for the first time to extract basic drug from aqueous samples [68]; the scheme of this experimental set-up is showed in the Figure 7.
FIGURE 7
Due to the use of d.c. potential to force the migration of the analytes across the SLM, faster extractions generally are obtained with the application of this technique in comparison with traditional HF-LPME procedures. Other advantages such as efficient clean-up of the samples and high preconcentration capacity can also be mentioned, becoming the EME technique a powerful tool to sample preparation in analytical chemistry [73, 74]. The EME technique has been explored by several researches, having recent reviews containing basic principles, theoretical aspects and applications
about this promising technique in the literature [75, 76]; in addition, studies involving flux simulation [77] and some kinetic aspects [78] have also been reported. Different studies regarding improvement of the EME can also be pointed out. Ramos-Payán and co-workers [79] introduced a new hollow fiber polypropylene membrane to EME procedure; in this study, nanometallic particles (silver nanoparticles) were deposited in a polypropylene hollow fibers which were used for extraction of non-steroidal anti-inflammatory drugs with separation by HPLC; these new membranes allowed an increase in the electrokinetic migration across the SLM. Another important modification on membranes used for the EME procedure was the introduction of carbon nanotubes into the membranes [73, 80]. The presence of the nanotubes allowed a larger surface area, and also contributed to increase the overall analyte partition and the transport of the compounds across the membrane. The EME technique has also been used not only for determination of organic compounds, but also for extraction of metallic species in aqueous samples [81]. A study related to the concept of dual-EME procedure for speciation of the metallic species Cr(III) and Cr(VI) in aqueous samples by migration of these species toward electrodes placed into two acceptor phases contained in different hollow fibers was proposed [71]. The separation was performed by HPLC and a complexation step was previously necessary prior to the detection by UV. Following the improvement of the EME technique, Petersen and coworkers [82] developed a miniaturized EME system with a flat membrane using few microliters of aqueous sample and acceptor phase, this approach was called drop-to-drop EME. In this procedure, the researchers performed the
extraction of pethidine, nortriptyline, methadone, haloperidol and loperamide from 10 µL of aqueous sample to 10 µL of acidic acceptor phase using 15 V in a micro-scale EME procedure.. More recently, a new configuration to the EME procedure based on a flat membrane device [83, 84] was proposed. The application of a flat membrane instead of traditional hollow fiber membranes allowed the use of a larger acceptor phase volume, this factor combined with using a higher extraction time leads to the achievement of exhaustive extractions of peptides [83] and basic drugs from plasma samples [84]. In another recent
study, a very promising configuration to the EME,
called Parallel Electromembrane Extraction (Pa-EME) was proposed [85]. In this new configuration, four antidepressant drugs were extracted from human plasma samples. The samples were placed inside a 96-well plates device and 8 microextractions with voltage of 200 V were performed simultaneously, the separation/detection was performed by LC-MS/MS. This configuration emerges as a future alternative to automation of the EME technique.
7. Hollow-Fiber Renewal Liquid Membrane (HFRLM) The HFRLM approach, based on surface renewal theory, was proposed in 2005 [86-88]. The main modification introduced with this extraction technique is the addition of an extra amount extractor solvent injected directly into the sample
simultaneously
with
the
microporous
hollow
fiber
membrane
impregnated with an organic solvent [21]. In the HFRLM procedure the extractor solvent is introduced into the sample, resulting in a solution with a high aqueous/organic solvent ratio, which
is stirred outside of the hollow membrane. Due to the wetting affinity of the organic phase and hydrophobic membrane, a thin organic film of solvent is developed at the interface between the donor phase and the membrane. The shear force due to the sample agitation causes the formation of organic microdroplets on the surface of the liquid membrane layer, which separate from the surface of the liquid membrane. At the same time, the organic microdroplets present in the sample greatly increase the contact area between the extractor solvent and the sample. Simultaneously, these microdroplets are reintroduced into the solvent film renewing the liquid membrane, which can accelerate the mass transfer rate, reducing significantly the mass transfer resistance in the hydrodynamic boundary layer at the donor phase/membrane interface. The additional organic phase in the donor phase is required only for the renewal, and continuously replenishes the loss of membrane liquid due to its solubility and emulsification, to avoid liquid membrane degradation. On the other hand, the resistance of back-extraction in the lumen side of the membrane can be greatly reduced by the chemical reactions [20, 89]. Figure 8 shows a scheme of the HFRLM process proposed by Ren et al. [89].
FIGURE 8
In a classic HFRLM process, the mixture of organic phase and stripping phase flows through the lumen side of the hollow fiber module, the feed phase flowing through the shell side. Zhang et al. [90] performed a study on the extraction of Cu(II) from aqueous samples and determined that the mass transfer can be calculated with the use of equations 10 and 11.
K=
∆C =
(C inf –
Q f .(C inf − C out f )
(10)
n.π .d 0 .L.∆C
D ' out D ' in Cs ) – (C out – Cs ) f D D D ' out (C inf – Cs ) D ln D ' in (C out – Cs ) f D
(11)
where K is the overall mass transfer coefficient (m s-1), Qf is the flux of the feed phase (m3 h-1),
in out C inf , C out are the copper (II) concentrations at the f , Cs and Cs
inlets and outlets of the feed and stripping phases (g m-3), respectively, D and D’ are the distribution coefficients of the extraction and back-extraction respectively, L is the effective length of the shell side, d0 is the inner diameter of the fiber and n is the number of fibers.
Also, the mass transfer flux, J (g m-2 h-1) can be calculated according to equation 12. J=
Q f .(C inf − C out f ) n.π .d 0 .L
(12)
The use of this variant of the membrane-based extraction techniques has been applied successfully in the extraction and isolation of metallic species, such as Cu (II) [91-93] and Co (II) [92], from aqueous samples. In an earlier study [89, 93] was applied this extraction technique to the simultaneous extraction and stripping of Cu (II) from wastewater. A system of CuSO4 + di-ethylhexyl phosphoric acid in kerosene + HCl was used in the HFRLM process and showed good stability in the constant renewal of the liquid
membrane during the process, with direct contact of the organic droplets and a large mass transfer area provided by the aqueous phase. Hollow hydrophobic fibers are used in this procedure, and their pores are filled with the organic phase. The stirred mixture of the organic and feed (or stripping) phases at a high w/o volume ratio was pumped through the lumen side of the module. The flow rates on the two sides were controlled to maintain a positive pressure on the shell side with respect to the lumen side, in order to prevent penetration of the organic phase into the shell side and permit stabilization of the interface between the phases at the hydrophobic membrane pores. A set-up of the apparatus used for HFRLM in a single-pass mode is shown in Figure 9.
FIGURE 9
This procedure was very efficient for the extraction of Cu (II) and presented a high mass transfer rate, compared with the hollow-fiber-supported liquid membrane and hollow-fiber membrane extraction processes. Carasek’s research group adapted the HFRLM technique for use at the micro-scale, in order to extract not only metal species [20, 94] but also organic compounds [95] from different matrices, allowing the HFRLM to be used as a sample preparation technique to clean up and preconcentrate analytes prior to analysis by chromatography or atomic absorption spectrometry. These researchers applied HFRLM to the extraction of Cd (II) from environmental samples, with determination by flame atomic absorption spectrometry [20]. The sample vials were introduced into the temperature-
controlled bath unit at the appropriate temperature. Ammonium O,O diethyl dithiophosphate (DDTP) and a mix of N butyl acetate and hexane (60/40% v/v) were added to the sample. A hollow PDMS fiber was cut into 8-cm lengths. One end of each piece of membrane was connected to a needle attached to a 250 µL microsyringe. A mix of organic solvents was introduced into the sample for the extraction of the target Cd–DDTP complex and to carry it over the PDMS membrane, the walls of which had been previously filled with the same organic solvents. The organic solvents were solubilized inside the PDMS membrane, leading to a homogeneous phase. The complex strips the lumen off the membrane and, at higher pH, the Cd–DDTP complex is broken down and Cd (II) is released into the stripping phase. EDTA was used for the complexation of the Cd (II), helping to trap the analyte in the stripping phase. A scheme of the apparatus used to perform the HFRLM is shown in Figure 10.
FIGURE 10
The methodology employing HFRLM was also applied to the determination
of
sulfonamides
in
honey
samples
with
subsequent
separation/detection by LC-MS/MS [21]. A mixture of 1-octanol:1-pentanol (55:45 v/v) was used as the extracting solvent, which was placed directly onto the sample. It was also used to obtain a three-phase system containing carbonate buffer, at pH 10, as the receptor phase solution. Multivariate analysis was applied to determine the best extraction conditions. Variables such as extraction time, pH (donor and acceptor phases), solution volumes, extraction solvent type and ionic strength of the solution were investigated. Good results
were obtained for the analytical parameters of merit. The repeatability and accuracy were also evaluated and were 15% and 13%, respectively.
8. Main optimization factors in membrane-based microextraction procedures
8.1 Choice of membrane In HF-LPME, EME and HFRLM procedures the membranes of greatest interest are those which have a hydrophobicity which allows interaction with the organic solvent as well as high porosity for the immobilization of this solvent. In general, polypropylene membranes are considered to be the best option, and their specifications have been mentioned above [96]. In membrane-protected SPME the membrane can act as a barrier and thus a flexible and malleable material can be applied to form a concentric cylinder around the SPME fiber. Additionally, the membrane must allow the passage of the target compounds toward to the microextraction fiber and molecules with high molecular weight must not be able to enter the membrane. In more recent configurations to the EME technique, some metallic particles are included into the membranes to facilitate the application of the d.c potential. Researches are being developed to improve the efficiency of the membranes employed, taking into account that the chosen membrane represents an important factor in a membrane-based microextraction procedure.
8.2 Sample temperature
In the SPME technique, increasing the extraction temperature can significantly reduce the equilibration time and speed up the overall procedure. Two effects, one positive and one negative, take place when the extraction temperature is raised: (i) the positive effect is that the headspace capacity and/or analyte diffusion coefficient is increased and thus the extraction rate is enhanced, and (ii) there is a negative effect on the distribution constant [16]. This negative effect of increasing the extraction temperature can be overcome by using a variant of SPME called cold-fiber SPME [97-100]. In generally, for membrane-protected SPME the fiber is placed into the sample and thus an increase in the temperature can reduce the time require to reach equilibrium. For the HF-LPME, EME and HFRLM procedures, for the determination of non-volatile compounds it is generally necessary to raise the sample temperature, which will increase the diffusion coefficient of the target compound and equilibrium will be reached in a shorter time [3, 96]. However, care must be taken regarding this variable since the temperature affects the sample viscosity and the solubility of the extractor solvent in the sample, causing degradation (degeneration) of the liquid membrane in SLM [20].
8.3 pH adjustment In SPME, in most cases, the non-dissociated/neutral species of the analytes are extracted. Full conversion of the analytes into neutral forms by pH adjustment can significantly improve the method sensitivity. Therefore, low pH values will improve the extraction efficiency of acid compounds and high pH values will improve that of basic compounds [16]. To extract polar or even ionic compounds polypyrole coatings have been employed [50, 101].
For HF-LPME, pH adjustment can increase the extraction efficiency and the equilibrium can be affected by the solubility of acidic or basic analytes. In most systems of solvent microextraction using two phases the sample pH must be modified to prevent the ionization of acid or basic analytes. In such cases, the pH should be adjusted to at least 1.5 units lower than the pKa for acidic species and to at least 1.5 units above the pKa for basic compounds. For acid analytes, the sample pH is generally adjusted to between 0.1 and 3.5, while for basic analytes it varies between 10 and 14. For the EME technique the pH adjustment is an important factor for extraction efficiency. The analytes must be charged to the migration of this species until the electrode oppositely charged, so the pH of the sample is adjusted to guarantee the ionization of the analytes. In HF(3)-LPME, to ensure the extraction of the analyte by the receptor phase and prevent its return to the organic phase located in the pores of the membrane, the acceptor phase pH must be adjusted to ensure ionization of the analytes. Thus, basic receptor solutions should be used for acids and acidic analyte acceptor phases should be used for basic analytes [3]. Also, in HFRLM systems the extraction efficiency is dependent on the equilibrium between the analytes from the donor phase and the organic solvent, as well as that between the analytes from the organic solvent and the acceptor phase. In this case, it is important that this equilibrium is shifted to the acceptor phase, to trap the analytes in this phase [21].
8.4 Ionic strength
In some cases, increasing the ionic strength improves the extraction efficiency, especially for volatile analytes. The salting-out effect causes the analyte molecules to pass more rapidly from the sample matrix to the headspace and thus this step can be useful in the HS-SPME procedure. Sodium chloride is most often used to adjust the ionic strength of the samples. In the case of membrane-protected SPME, modifying the ionic strength needs to be carefully studied since the extraction efficiency of the analytes from complex and “dirty” samples can be affected differently by changes in the ionic strength depending on the characteristics of the compounds and the matrices [3]. For HF-LPME and HFRLM, depending on the analyte, the addition of salt and the consequent change in the ionic strength of the sample solution can significantly affect the results obtained with liquid-phase microextraction. The addition of salt can decrease the solubility of the analytes and thus increase the extraction efficiency due to the effect of salting out. Therefore, it is important to verify the influence of this variable for each case in the system under study. On the other hand, in certain situations this variable may not have a significant effect on the efficiency of the microextraction procedure [96]. For the EME technique the presence of ionic substances in the donor solution causes an increase in the ion balance value in the system, which decreases the flux of analytes across the SLM [76]. However, some studies showed that the addition of salt increases the extraction efficiency [102, 103]; therefore the ionic strength is a very important variable to be carefully optimized when the EME procedure is employed.
8.5 Extraction time and extraction temperature Another very important factor is the optimization of the extraction time, considering that the mass transfer process is time-dependent. The extraction time is theoretically defined as the time the system requires to reach equilibrium. Typically, the extraction time is dependent on various analyte characteristics, such as molecular weight and volatility [3, 96]. In most studies, the sample extraction is the time-limiting step of the SPME procedure. Therefore, selection of the optimum extraction time is one of the critical steps in the development of a method for this microextraction technique. The time required to reach equilibrium is independent of the sample concentration, and its selection is always a compromise between the extraction time, sensitivity and repeatability of the analytical method. In some cases, a pre-equilibrium condition is considered when the equilibrium time is very long, making the microextraction impracticable [16]. Regarding the extraction temperature in membrane-based sample preparation techniques with the presence of an organic solvent is most common the use of temperatures below 40°C. Temperatures above this value can cause undesirable effects due to partial degradation of the SLM [76].
8.6 Organic solvent The organic solvent content in the HF-LPME, EME and HFRLM procedures is also a variable of considerable importance. The solvent used must have certain characteristics, such as high selectivity and good extraction efficiency for the compounds of interest, water-immiscible, compatibility with the analytical technique employed (for example, with the mobile phase used in
HPLC), and high purity without contaminants or interferents which could hinder the analysis. The main solvents used in HF-LPME are 1-octanol, cyclohexane and toluene [3]. 8.7 Sample stirring Sample stirring is commonly applied to accelerate the extraction kinetics. Increasing the stirring rate of the donor solution speeds up the extraction and the diffusion of the analytes through the interfacial layer of the hollow fiber membrane [104]. In the case of HF-LPME, the organic solvent is protected and more vigorous agitation, such as rates of 2000 rpm (HF(2)-LPME) and 1500 rpm (HF(3)-LPME), can be employed [3].
9. Critical
points
regardingto
membrane-based
microextraction
techniques Some considerations regarding the membrane-based sample preparation techniques should be mentioned for each of the topics discussed, as can be observed above in relation to the membrane-protected SPME technique. The main advantage of this approach is the possibility of using SPME to analyze complex matrices or matrices containing particulate or suspended material. The polymeric membrane acts as a barrier to compounds of high molecular weight allowing the diffusion of compounds with low molecular weight through it, facilitating the determination of several analytes in complex matrices such as blood, milk and urine. In general, for the analysis of complex matrices SPME in HS mode is used, but this mode can be impracticable for the determination of less volatile compounds. In this regard, membrane-protected SPME mode represents an interesting alternative for overcoming the problems associated
with damage of the fiber by complex samples when the use of the direct immersion mode is necessary without the use of organic solvents. On the other hand, this SPME mode can offer some disadvantages. One is the possibility of damaging the SPME fiber during the placing of the polymeric membrane around it. In many cases the commercial SPME fibers can be easily damaged during handling due to the fragility of the silica rods traditionally used as supports for coatings in SPME [105, 106]. In addition, few authors have published studies in which this SPME mode was investigated. One of the probable reasons for this is the development and improvement of the HF-LPME technique since, in many cases, this procedure can replace membraneprotected SPME for the analysis of complex samples containing analytes of low volatility. The advantages of HF-LPME include its low cost and simplicity of operation and also this is a virtually solventless microextraction technique with the consumption of only a few microliters of organic solvent. An alternative approach to overcoming the difficulties associated with membrane-protected SPME is the application of a PDMS layer over the SPME fiber [37, 38], as described above. In this approach the sample preparation is simple, fast and can be automated. In addition, the fiber life-time is significantly increased even with its immersion in complex samples. Among the membrane-based sample preparation techniques applied in microextraction procedures, HF-LPME is certainly the most commonly used and it has been investigated in a large number of research laboratories. This represents an important advance in liquid-phase microextraction because HFLPME is not only a good sample preconcentration technique but also an excellent sample clean-up procedure, which makes it directly applicable to
“dirty” and complex samples [107]. The disposable nature of the hollow fiber eliminates the possibility of sample carry-over and ensures high reproducibility, and the impregnated pores in the walls of the hollow fiber offer some selectivity by preventing the extraction of high molecular weight materials [49]. Another important advantage of the HF-LPME approach is the low cost of the materials used in this kind of microextraction, as well as the use of a low volume of organic solvents, in fact, it is virtually a solventless microextraction technique. On the other hand, some negative points are associated with the HFLPME procedure, for instance, manual labor is required to prepare the fibers individually [3], the presence of a membrane barrier between the source (sample) phase and receiving (acceptor) phase reduces the extraction rate and increases the extraction time, the appearance of air bubbles on the surface of the HF reduces the transport rate and decreases the reproducibility of the extraction and in real samples (e.g., blood plasma, urine and wastewater), the adsorption of hydrophobic substances onto the fiber surface may block the pores [108, 109]. HFRLM is not as well known or as widespread in the analytical research laboratories as the membrane-based sample preparation technique for microextraction procedures when compared with other procedures such as HFLPME (2 and 3 phase). Thus, few publications can be found in the literature in which this approach is applied as a microextraction technique for sample preparation prior to analytical determinations [20, 94, 95]. Most authors report the use of this technique for the extraction, removal and isolation of metals from aqueous samples in studies related to engineering sciences [89-93].
Among the potential advantages of the HFRLM technique are the intensification of mass transfer, due to the renewal of the membrane liquid, and the high membrane surface area, which leads to high mass transfer rates and high concentration factors. Other important factors which should be mentioned are that the process remains stable over a long period of time, since it is easy to replenish the membrane liquid, no leakage occurs between two phases and there is no secondary pollution during the emulsification due to lateral shear forces. Notable also are the facility with which the operation can be carried out and the low cost of the constituent materials [89]. Thus, further effort should be directed toward gaining a better understanding of this approach to membranebased sample preparation techniques, due to the great potential of the HFRLM technique as discussed herein. The application of TFME emerges as an excellent alternative for membrane-based sample preparation procedure. In this case the membrane acts as extraction phase, which leads to preconcentration capacity associated with this approach. This enables high extraction efficiencies and sensitivities for the analytes due to the applicability of a sheet membrane with high surface area, allowing trace determinations. One advantage is the possibility of determinations without using extraction solvent. On the other hand, there are some difficulties associated with introduction of the sheet membrane into the chromatographic injector system. The EME approach has been used as faster variant of membrane-based sample preparation techniques, this approach has great capacity of sample clean-up with possibility to perform microextractions in very complex matrices, such as biological fluids. The main advantage associated with this approach is
regarding extraction time, generally few minutes are required to the microextraction step if compared with traditional HF-LPME approaches. On the other hand, additional materials are needed to perform the microextraction, such as two platinum electrodes and an external power supply. In addition, the EME technique, in the original experimental set-up, is difficult to be automated and, due to electrical field applied, the appearance of some “bubbles” into the samples can decrease the extraction efficiency. Very recent developments such as PALME and Pa-EME have emerged as very promising approaches toward the automation of the microextraction procedure; in addition, there is the possibility of using a 96-well plates device in the microextraction procedure, which allows the simultaneous extractions from multiple samples. These new approaches follow the same environmental concerns associated to other microextraction techniques, presenting a very low solvent and sample consumption as an important factor. On the other hand, been relatively new approaches, more characteristics and details of the experimental and theoretical considerations have to be explored and few works involving these membrane-based approaches are found in the literature.
10. Scientific
studies
involving
membrane-based
microextraction
techniques reported in the literature Membrane-based microextraction techniques have been applied for the determination of several compounds in many varieties of matrices, as can be seen in Table 1.. Some characteristics of the studies reported in the literature are detailed along with the microextraction technique applied for the determination in each case.
11. Conclusions and future trends Membrane-based sample preparation techniques are an attractive tool for the extraction of a wide range of compounds in complex and ‘dirty’ matrices, such as biological and food samples. Among the compounds determined using membrane-based techniques are drugs, metabolites, alkaloids, pollutants and metals. The number of research groups working with these techniques is growing due to the attractive features they offer, such as ease of use, timesavings, the need for only small amounts of sample and solvent, and low cost compared to conventional and other microextraction techniques. However, drawbacks related to this procedure include the limited number of commerciallyavailable membranes for HF-LPME and difficulties associated with the automation of membrane-based techniques still remains, even though advances on automation of some membrane-based microextraction procedures have been reported [66, 67]. In addition, the need for a large number of analyses per day is another great barrier to include these microextraction procedures to a routine laboratory. Therefore, one great challenge in analytical chemistry is for these efficient membrane-based sample preparation techniques to become routine analysis. It is necessary to investigate ways to adapt the microextraction procedures to be more easily operated with less manual labor associated with it; therefore, the possibility of automation of the membrane-based techniques is an issue to be investigated. A very promising tool which can provide the achievement of interesting results for routine analysis and efficient automation in these procedures is the use of the commercial available 96-well plates. This apparatus allows the simultaneous extraction of 96 samples and it has been
used successfully in recent works with different configurations, for example, a promising configuration called PALME (Parallel Artificial Liquid Membrane Extraction) [60]. A new configuration to the EME has been introduced, called Parallel Eletromembrane Extraction (Pa-EME). In this approach a multiwall plate apparatus to perform multiple microextractions in a single assay is also used [85]. The 96-well plate was also successfully used in a TFME approach [46, 47] with very promising results. Summarizing, the main perspectives in membrane-based microextraction techniques are the search for fully automated and, at same time, efficient procedures to be very attractive and applicable to routine laboratory activities, with special concern to reduce the sample volume mainly for application in biological samples. Another important point is the possibility of modification in some membranes used to these sample preparation procedures, this issue has also been evaluated by a recent review [110].
Acknowledgements The authors are grateful to the Brazilian Government Agency Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) for the financial support which made this research possible.
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Figures And Tables: Figure 1. Three basic extraction modes in SPME: a) DI-SPME; B) HS-SPME; and c) Membrane-protected SPME (reproduced from [16] with permission). Figure 2. Extraction apparatus used in HFM-SPME, adapted from Basheer and Lee (reproduced from [14] with permission). Figure 3. Scheme of the membrane-protected SPME used by Musteata and Pawliszyn (reproduced from [36] with permission). Figure 4. Scheme of the experimental set-up used to Thin-Film Microextraction used by Pawliszyn and co-workers. (A) TFME procecure in headspace mode (B) Scheme of membrane after the microextractions and before introduction into the chromatographic injector. 1 - stainless steel rod, 2 – flat sheet membrane, 3 - aqueous sample, 4 – magnetic stirrer, 5 – rolled membrane (reproduced from [39] with permission). Figure 5. Scheme of microextraction modes used in HF-LPME. (A) three-phase system; and (B) two-phase system (reproduced from [53] with permission). Figure 6. Diagram of experimental set-up used in the first study involving HFLPME (reproduced from [17] with permission). Figure 7. Scheme of experimental set-up used to EME procedure proposed by Pedersen-Bjergaard and Rasmussen (reproduced from [68] with permission).
Figure 8. Scheme of HFRLM procedure, (reproduced, with modifications, from [89] with permission). Figure 9. Representation of the HFRLM apparatus (reproduced from [89] with permission). Figure 10.Scheme of HFRLM used for the extraction of Cd (II) from environmental samples. Table 1: Application of membrane-based methods as sample preparation techniques.
bovine milk
herbicides
gabapentin
tetrandrine and
HF(3)-LPME
HF(3)-LPME
fangchinoline
organomercury
enantiomers
mianserin
drugs
antidepressant
Ni and Pb
antitussive drugs
antihistamines and
haloacetic acids
pesticides
organochlorine
plasma samples
biological samples
samples
environmental water
seafood and
human plasma
biological fluids
biological samples
environmental and
human plasma
aqueous samples
aqueous samples
aqueous samples
environmental samples
Cd (II)
fungicides
honey samples
Matrix
sulfonamides
Analyte
HF(3)-LPME
HF(3)-LPME
HF(3)-LPME
HF(2)-LPME
HF(3)-LPME
HF(2)-LPME
HF(2)-LPME
HF(2)-LPME
MP-SPME
HFRLM
HFRLM
technique
Extraction
HPLC-UV
HPLC-UV
HPLC-UV
CE
HPLC-UV
ET AAS
HPLC-UV
GC-ECD
GC-ECD
GC-ECD
GC-MS
F AAS
LC-MS/MS
technique
Determination
3 and 2
0.2
0.3 – 3.8
3 and 4
0.5 – 0.7
0.02 and 0.03
0.003
0.1 - 18
0.013 - 0.059
0.004 - 0.025
0.003 - 0.013
1.5 and 1.3
5.1 – 27.4
-1
LOD (µg L )
N-octanol
Dihexyl ether
Toluene
Di-n-hexhyl ether
N-dodecane
[C6MIM][PF6}
Hexadecane
1-octanol
Toluene
Toluene
-
(60:40 v/v)
acetate:hexane
N-buthyl
Toluene and
pentanol (55:45 v/v)
1-octanol:1-
SLM
Solvent used to
60
45
25
45
45
12 and 15
60
60
30
20
40
40
36 and
40
time (min)
Extraction
[116]
[115]
[114]
]
[56]
[113]
[112]
[111]
[65]]
[64]]
[14]
[20, 94]
[21]
Ref.
