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The repeatability and extraction recoveries of parallel electromembrane extraction (Pa-EME) was thoroughly investigated in the present project. Amitriptyline, fluoxetine, and haloperidol were isolated from eight samples of pure water, undiluted human plasma, and undiluted human urine, respectively; in total 24 samples were processed in parallel. The repeatability was found to be independent of the different sample matrices (pure water samples, human plasma, and water) processed in parallel, although the respective samples contained different matrix components. In another experiment seven of the 24 wells were perforated. Even though the perforation caused the total current level in the Pa-EME setup to increase, the intact circuits were unaffected by the collapse in seven of the circuits. In another approach, exhaustive extraction of amitriptyline, fluoxetine, and haloperidol was demonstrated from pure water samples. Amitriptyline and haloperidol were also isolated exhaustively from undiluted human plasma samples; the extraction recovery of fluoxetine from undiluted human plasma was 81%. Finally, the sample throughput was increased with the Pa-EME configuration. The extraction recoveries were investigated by processing 1, 8, 68, or 96 samples in parallel in 10min; neither the extraction recoveries nor the repeatability was affected by the total numbers of samples. Eventually, the Pa-EME was combined with ultra performance liquid chromatography (UPLC) to combine high-throughput sample preparation with high-throughput analytical instrumentation. The aim of the present investigation was to demonstrate the potential of electromembrane extraction as a high throughput sample preparation platform; and hopefully to increase the interest for EME in the bioanalytical field to solve exisiting and novel analytical challenges., (Copyright © 2014 Elsevier B.V. All rights reserved.)

In this paper, extraction kinetics was investigated experimentally and theoretically in hollow fiber liquid-phase microextraction (HF-LPME) and electromembrane extraction (EME) with the basic drugs droperidol, haloperidol, nortriptyline, clomipramine, and clemastine as model analytes. In HF-LPME, the analytes were extracted by passive diffusion from an alkaline sample, through a (organic) supported liquid membrane (SLM) and into an acidic acceptor solution. In EME, the analytes were extracted by electrokinetic migration from an acidic sample, through the SLM, and into an acidic acceptor solution by application of an electrical potential across the SLM. In both HF-LPME and EME, the sample (donor solution) was found to be rapidly depleted for analyte. In HF-LPME, the mass transfer across the SLM was slow, and this was found to be the rate limiting step of HF-LPME. This finding is in contrast to earlier discussions in the literature suggesting that mass transfer across the boundary layer at the donor-SLM interface is the rate limiting step of HF-LPME. In EME, mass transfer across the SLM was much more rapid due to electrokinetic migration. Nevertheless, mass transfer across the SLM was rate limiting even in EME. Theoretical models were developed to describe the kinetics in HF-LPME, in agreement with the experimental findings. In HF-LPME, the extraction efficiency was found to be maintained even if pH in the donor solution was lowered from 10 to 7-8, which was below the pK(a)-value for several of the analytes. Similarly, in EME, the extraction efficiency was found to be maintained even if pH in the donor solution increased from 4 to 11, which was above the pK(a)-value for several of the analytes. The two latter experiments suggested that both techniques may be used to effectively extract analytes from samples in a broader pH range as compared to the pH range recommended in the literature., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Electromembrane extraction (EME) at low voltage (0-15 V) of 29 different basic model drug substances was investigated. The drug substances with logP<2.3 were not extracted at voltages less than 15 V. Extraction of drug substances with logP≥2.3 and with two basic groups were also effectively suppressed by the SLM at voltages less than 15 V. Drug substances with logP≥2.3 and with one basic group were all extracted at low voltages and with a strong compound selectivity which appeared to have some influence from the polar surface area of the compound. For this group of substances, recoveries varied between 0 and 23% at 5 V, whereas, recoveries varied between 5.5 and 51% at 15 V. Based on mass transfer differences related to charge, polarity, and polar surface, highly selective extractions of drug substances were demonstrated from human plasma, urine, and breast milk. An initial evaluation at low voltage (5 V) was compared with similar extractions at a more normal voltage level (50 V), and this supported that reliable data can be obtained under these low-voltage (mild) conditions by EME., (Copyright © 2012 Elsevier B.V. All rights reserved.)

For the first time, electromembrane extraction (EME) of six basic drugs of abuse from undiluted whole blood and post mortem blood in a totally stagnant system is reported. Cathinone, methamphetamine, 3,4-methylenedioxy-amphetamine (MDA), 3,4-methylenedioxy-methamphet-amine (MDMA), ketamine and 2,5-dimethoxy-4-iodoamphetamine (DOI) were extracted from the whole blood sample, through a supported liquid membrane (SLM) consisting of 1-ethyl-2-nitrobenzene (ENB) immobilized in the pores of a hollow fiber, and into an aqueous acceptor solution inside the lumen of the hollow fiber. The SLM acts as a barrier with efficient exclusion of all macromolecules and acidic substances in the sample. Due to the application of the electrical field, only the cationic compounds of interest are extracted efficiently across the membrane, thus providing extremely clean extracts for analysis with liquid chromatography-mass spectrometry, LC-MS. Recoveries in the range 10-30% were obtained from 80 μl whole blood within 5 min extraction time and an applied voltage of 15V across the SLM. The optimized technique was tested on real forensic whole blood samples taken from three forensic autopsy cases and on five forensic whole blood samples from living persons. The results were in agreement with the analysis using standard sample preparation methods (liquid-liquid extraction) performed on the same samples by Norwegian Institute of Public Health (NIPH), Division of Forensic Toxicology and Drug Abuse Research. Evaluation data were acceptable, with limit of detections (LODs) in the range 40-2610 pg/mL, well below concentrations associated with drug abuse; linearites in the range between 10 and 250 ng/mL with r(2) values above 0.9939, and with repeatability (RSD) of 7-32%., (Copyright © 2011 Elsevier B.V. All rights reserved.)

For the first time, haloacetic acids and aromatic acetic acids were extracted from wastewater samples using electromembrane extraction (EME). A thin layer of toluene immobilized on the walls of a polypropylene membrane envelope served as an artificial supported liquid membrane (SLM). The haloacetic acids (HAAs) (chloroacetic acid, dichloroacetic acid, and trifluoroacetic acid) and aromatic acetic acids (phenylacetic acid and p-hydroxyphenylacetic acid) were extracted through the SLM and into an alkalized aqueous buffer solution. The buffer solution was located inside the membrane envelope. The electrical potential difference sustained over the membrane acted as the driving force for the transport of haloacetic acids into the membrane by electrokinetic migration. After extraction, the extracts were analyzed by high-performance liquid chromatography-ultraviolet detection. The detection limits were between 0.072 and 40.3 ng L(-1). The calibration plot linearity was in the range of 5 and 200 μg L(-1) while the correlation coefficients for the analytes ranged from 0.9932 to 0.9967. Relative recoveries were in the range of 87-106%. The extraction efficiency was found to be comparable to that of solid-phase extraction., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Attenuated cardiac vagal regulation indicates an increased risk of cardiac events, but the reasons for this impaired regulation are not well known. Cardiac vagal regulation was measured in 5.408 subjects (2627 men and 2781 women) who underwent short term (100s) ECG recordings during controlled deep respiration (0.1Hz). Under these conditions, the power in the low frequency (LF) spectral band (0.05 to 0.15Hz) predominantly reflects cardiac vagal outflow. There was a strong inverse relationship between LF power and age in both genders (β=-0.033 in men and -0.035 in women; P<0.0005). There was a more rapid decline in women in the second and third decade in which LF power was significantly lower than in men (P=0.004). In both genders, there was an association between impaired cardiac vagal outflow and fibrinogen level. Altogether, the factors studied explained nearly 20% of the interindividual variation of LF power. In conclusion, in a general population, impaired cardiac vagal regulation is associated with many cardiovascular risk factors, including fibrinogen. Women have a more rapid decline of vagal regulation in the second and third decades., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The simultaneous extraction of acidic and basic analytes from a particular sample is a challenging task. In this work, electromembrane extraction (EME) of acidic non-steroidal anti-inflammatory drugs and basic β-blockers in a single step was carried out for the first time. It was shown that by designing an appropriate compartmentalized membrane envelope, the two classes of drugs could be electrokinetically extracted by a 300 V direct current electrical potential. This method required only a very short 10-min extraction time from a pH-neutral sample, with a small amount (50 μL) of organic solvent (1-octanol) as the acceptor phase. Analysis was carried out using gas chromatography-mass spectrometry after derivatization of the analytes. Extraction parameters such as extraction time, applied voltage, pH range, and concentration of salt added were optimized. The proposed EME technique provided good linearity with correlation coefficients from 0.982 to 0.997 over a concentration range of 1-200 μg L⁻¹. Detection limits of the drugs ranged between 0.0081 and 0.26 μg L⁻¹, while reproducibility ranged from 6 to 13% (n=6). Finally, the application of the new method to wastewater samples was demonstrated., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Amitriptyline, citalopram, fluoxetine, and fluvoxamine were isolated by electro membrane extraction (EME) from 70microl of untreated plasma (pH 7.4), through a supported liquid membrane (SLM) of 1-ethyl-2-nitrobenzene immobilized in the pores of a porous polypropylene hollow fiber, and into 30microl of 10mM HCOOH as acceptor solution inside the lumen of the hollow fiber. The driving force of the extraction was a 9V potential sustained over the SLM with a common battery, with the positive electrode placed in the plasma sample and the negative electrode placed in the acceptor solution. Extractions were performed under totally stagnant conditions with a very simple device for 1min (kinetic regime), and subsequently the acceptor solution was analyzed directly by liquid chromatography-mass spectrometry (LC-MS). Recoveries were 12, 13, 22, and 17% for fluoxetine, amitriptyline, citalopram, and fluvoxamine, respectively. Sample clean-up was comparable to reversed-phase solid-phase extraction (SPE), but EME required substantially less time than SPE. The time advantage of EME was further improved by parallel extraction of three samples (for 1min) with the same 9V battery. EME from plasma combined with LC-MS provided limits of quantification (S/N=10) in the range 0.4-2.3ng/ml, linearity in the range 1-1000ng/ml with r(2)-values of 0.998-0.999, and repeatability in the range 3.2-8.9% RSD in the mid-therapeutic window (100ng/ml).

Liquid-phase microextraction (LPME) based on polypropylene hollow fibers was evaluated for the extraction of the post-harvest fungicides thiabendazole (TBZ), carbendazim (CBZ) and imazalil (IMZ) from orange juices. Direct LPME was performed without any sample pretreatment prior to the extraction, using a simple home-built equipment. A volume of 500 microL of 840 mM NaOH was added to 3 mL of orange juice in order to compensate the acidity of the samples and to adjust pH into the alkaline region. Analytes were extracted in their neutral state through a supported liquid membrane (SLM) of 2-octanone into 20 microL of a stagnant aqueous solution of 10 mM HCl inside the lumen of the hollow fiber. Subsequently, the acceptor solution was directly subjected to analysis. Capillary electrophoresis (CE) was used during the optimization of the extraction procedure. Working under the optimized extraction conditions, LPME effectively extracted the analytes from different orange juices, regardless of different pH or solid material (pulp) present in the sample, with recoveries that ranged between 17.0 and 33.7%. The analytical performance of the method was evaluated by liquid chromatography coupled with mass spectrometry (LC/MS). This technique provided better sensitivity than CE and permitted the detection below the microg L(-1) level. The relative standard deviations of the recoveries (RSDs) ranged between 3.4 and 10.6%, which are acceptable values for a manual microextraction technique without any previous sample treatment, using a home-built equipment and working under non-equilibrium conditions (30 min extraction). Linearity was obtained in the range 0.1-10.0 microg L(-1), with r=0.999 and 0.998 for TBZ and IMZ, respectively. Limits of detection were below 0.1 microg L(-1) and are consistent with the maximum residue levels permitted for pesticides in drinking water, which is the most restrictive regulation applicable for these kinds of samples. It has been demonstrated the suitability of three-phase LPME for the extraction of pesticides from citrus juices, suppressing any pretreatment step such as filtration or removal of the solid material from the sample, that may potentially involve a loss of analyte., (2010 Elsevier B.V. All rights reserved.)

In the current work, droplet-membrane-droplet liquid-phase microextraction (LPME) under totally stagnant conditions was presented for the first time. Subsequently, implementation of this concept on a microchip was demonstrated as a miniaturized, on-line sample preparation method. The performance level of the lab-on-a-chip system with integrated microextraction, capillary electrophoresis (CE) and laser-induced fluorescence (LIF) detection in a single miniaturized device was preliminarily investigated and characterized. Extractions under stagnant conditions were performed from 3.5 to 15 microL sample droplets, through a supported liquid membrane (SLM) sustained in the pores of a small piece of a flat polypropylene membrane, and into 3.5-15 microL of acceptor droplet. The basic model analytes pethidine, nortriptyline, methadone, haloperidol, and loperamide were extracted from alkaline sample droplets (pH 12), through 1-octanol as SLM, and into acidified acceptor droplets (pH 2) with recoveries ranging between 13 and 66% after 5 min of operation. For the acidic model analytes Bodipy FL C(5) and Oregon Green 488, the pH conditions were reversed, utilizing an acidic sample droplet and an alkaline acceptor droplet, and 1-octanol as SLM. As a result, recoveries for Bodipy FL C(5) and Oregon Green 488 from human urine were 15 and 25%, respectively., (Copyright 2009 Elsevier B.V. All rights reserved.)

Electromembrane extraction (EME) of basic drugs from 10 microL sample volumes was performed through an organic solvent (2-nitrophenyl octyl ether) immobilized as a supported liquid membrane (SLM) in the pores of a flat polypropylene membrane (25 microm thickness), and into 10 microL 10 mM HCl as the acceptor solution. The driving force for the extractions was 3-20 V d.c. potential sustained over the SLM. The influence of the membrane thickness, extraction time, and voltage was investigated, and a theory for the extraction kinetics is proposed. Pethidine, nortriptyline, methadone, haloperidol, and loperamide were extracted from pure water samples with recoveries ranging between 33% and 47% after only 5 min of operation under totally stagnant conditions. The extraction system was compatible with human urine and plasma samples and provided very efficient sample pretreatment, as acidic, neutral, and polar substances with no distribution into the organic SLM were not extracted across the membrane. Evaluation was performed for human urine, providing linearity in the range 1-20 microg/mL, and repeatability (RSD) in average within 12%.

In hollow fiber membrane liquid-phase microextraction (LPME), target analytes are extracted from aqueous samples and into a supported liquid membrane (SLM) sustained in the pores in the wall of a small porous hollow fiber, and further into an acceptor phase present inside the lumen of the hollow fiber. The acceptor phase can be organic, providing a two-phase extraction system compatible with capillary gas chromatography, or the acceptor phase can be aqueous resulting in a three-phase system compatible with high-performance liquid chromatography or capillary electrophoresis. Due to high enrichment, efficient sample clean-up, and the low consumption of organic solvent, substantial interest has been devoted to LPME in recent years. This paper reviews important applications of LPME with special focus on bioanalytical and environmental chemistry, and also covers a new possible direction for LPME namely electromembrane extraction, where analytes are extracted through the SLM and into the acceptor phase by the application of electrical potentials.

Since 1999, substantial research has been devoted to the development of liquid-phase microextraction (LPME) based on porous hollow fibers. With this technology, target analytes are extracted from aqueous samples, through a thin supported liquid membrane (SLM) sustained in the pores in the wall of a porous hollow fiber, and further into a microL volume of acceptor solution placed inside the lumen of the hollow fiber. After extraction, the acceptor solution is directly subjected to a final chemical analysis by liquid chromatography (HPLC), gas chromatography (GC), capillary electrophoresis (CE), or mass spectrometry (MS). In this review, LPME will be discussed with focus on extraction principles, historical development, fundamental theory, and performance. Also, major applications have been compiled, and recent forefront developments will be discussed.

The present work has for the first time demonstrated electromembrane extraction (EME) at voltages obtainable by common batteries. Five basic drugs were extracted from acidified aqueous sample solutions, across a supported liquid membrane (SLM) consisting of 1-isopropyl-4-nitrobenzene impregnated in the walls of a hollow fiber, and into an acidified aqueous acceptor solution present inside the lumen of the hollow fiber with potential differences of 1-10 V applied over the SLM. Extractions from 1 ml standard solutions prepared in 10mM HCl for 5 min and with a potential of 10 V demonstrated analyte recoveries of 50-93% in 25 microl of 10mM HCl as acceptor solution. This corresponds to enrichment factors of 20-37. Similar results were obtained with a common 9 V battery as power supply. Recoveries from low-voltage EME on human plasma, urine, and breast milk diluted with acetate buffer (pH 4) demonstrated recoveries in the range of 37-55% after 5 min of extraction. Excellent selectivity was demonstrated as no interfering peaks were detected. Standard curves in the range of 0.0625-0.62 5 microg/ml demonstrated correlation coefficients of 0.994-0.999. Extraction recoveries from human plasma, urine or breast milk were not found to be sensitive towards individual variations. The results show that low-voltage EME has a future potential as a simple, selective, and time-efficient sample preparation technique of biological fluids.

The present work has for the first time described and verified a theoretical model of the analytical extraction process electro-membrane extraction (EME), where target analytes are extracted from an aqueous sample, through a thin layer of 2-nitrophenyl octylether immobilized as a supported liquid membrane (SLM) in the pores in the wall of a porous hollow fibre, and into an acceptor solution present inside the lumen of the hollow fibre by the application of an electrical potential difference. The mathematical model was based on the Nernst-Planck equation, and described the flux over the SLM. The model demonstrated that the magnitude of the electrical potential difference, the ion balance of the system, and the absolute temperature influenced the flux of analyte across the SLM. These conclusions were verified by experimental data with five basic drugs. The flux was strongly dependent of the potential difference over the SLM, and increased potential difference resulted in an increase in the flux. The ion balance, defined as the sum of ions in the donor solution divided by the sum of ions in the acceptor solution, was shown to influence the flux, and high ionic concentration in the acceptor solution relative to the sample solution was advantageous for high flux. Different temperatures also led to changes in the flux in the EME system.

The present work has for the first time compared extraction of basic analytes across a supported liquid membrane (SLM) based on (1) passive diffusion in a pH gradient sustained over the SLM and (2) electrokinetic migration in an electrical field sustained over the SLM. For the passive diffusion experiments, performed as liquid-phase microextraction (LPME), five basic drugs were extracted under strong agitation from alkaline samples (10mM NaOH), through 2-nitrophenyl octylether immobilized in the pores of a porous hollow fibre of polypropylene (SLM), and into 25 microl of 10mM HCl as the acceptor solution. The experiments based on electrokinetic migration, performed as electro membrane isolation (EMI), were conducted under strong agitation from acidic samples (10mM HCl), through the same SLM as in LPME, and into 25 microl of 10mM HCl as the acceptor solution. Whereas LPME relied on diffusion and to some extent also convection as the principal mechanisms of mass transfer, mass transfer in EMI also included a strong contribution from electrokinetic migration. Thus, extraction kinetics was improved by a factor between 6 and 17 utilizing EMI instead of LPME. This major difference in terms of speed was especially pronounced from small sample volumes (150 microl), and suggest that EMI may be a very interesting future concept for miniaturized sample preparation. In addition to improved extraction kinetics, extraction rates were strongly compound dependent in EMI, opening the possibility to control the extraction selectivity by the extraction time.

Electrokinetic cross membrane extraction of acidic drugs was demonstrated for the first time. The acidic drugs were extracted from an alkaline aqueous donor solution (300 microl), through a thin supported liquid membrane of 1-heptanol sustained in the pores of the wall of a porous hollow fiber, and into an aqueous alkaline acceptor solution (30 microl) present inside the lumen of the hollow fiber by the application of a d.c. electrical potential. The negative electrode was placed in the donor solution, and the positive electrode was placed in the acceptor solution. Optimal extractions were accomplished with 1-heptanol as the supported liquid membrane, with 50 V as the driving force, and with pH 12.0 in both the donor and acceptor solutions, respectively (NaOH). Equilibrium extraction conditions were obtained after 5 min of operation with the whole assembly agitated at 1200 rpm. Eleven different acidic drugs were extracted with recovery values between 8 and 100%, and initial data supported that electrokinetic cross membrane extraction provided repeatable data and linear response between original donor concentration and final acceptor concentration of the acidic model compounds.

Hollow fiber protected liquid-phase microextraction (LPME) was developed for large sample volume extractions in a single step, with special emphasis on extraction of basic drugs from environmental waters. Five antidepressant drugs were extracted from 1100 or 100 mL water samples, through approximately 50 microL of dihexyl ether immobilized in the pores in the wall of a porous hollow fiber (liquid membrane), and into 20 microL of 10 mM HCl or HCOOH as the acceptor solution. Extractions were performed for 60 or 120 min supported by magnetic stirring at 800 rpm, and hereafter the acceptor solution was directly injected in HPLC-UV or HPLC-MS. Compared with earlier work on LPME from small sample volumes, both closing the hollow fiber and the type of liquid membrane was found to be critical for large volume extractions. The hollow fibers were carefully closed with a small piece of metal wire, dihexyl ether was used as the liquid membrane, and pH in the sample was adjusted to 11.8 with NaOH. Recoveries from 1100 mL samples were in the range 33-49%, and enrichments were in the range 18,000-27,000 after 120 min of extraction. With HPLC-MS, the drugs were detected down to the 5-30 pg L(-1) level. Within-day precision was within 12.4-20.6% R.S.D. (n=6), whereas between-day precision was within 17.6 and 37.2% R.S.D. Linearity was obtained in the range 1-500 ng L(-1) with r2-values between 0.982 and 0.994. The proposed LPME system was utilized to detect the five antidepressants in wastewater from the city of Tromsø in Northern Norway.

Twenty different basic drugs were electrokinetically extracted across a thin artificial organic liquid membrane with a 300 V d.c. electrical potential difference as the driving force. From a 300 microl aqueous sample (acidified corresponding to 10mM HCl), the drugs were extracted for 5 min through a 200 microm artificial liquid membrane of a water immiscible organic solvent immobilized in the pores of a polypropylene hollow fiber, and into a 30 microl aqueous acceptor solution of 10mM HCl inside the lumen of the hollow fiber. Hydrophobic basic drugs (logP>1.7) were effectively isolated utilizing 2-nitrophenyl octyl ether (NPOE) as the artificial liquid membrane, with recoveries up to 83%. For more hydrophilic basic drugs (logP<1.0), a mixture of NPOE and 25% (w/w) di-(2-ethylhexyl) phosphate (DEHP) was required to ensure efficient extraction, resulting in recoveries up to 75%. DEHP was expected to act as an ion-pair reagent ion-pairing the protonated hydrophilic drugs at the interface between the sample and the membrane, resulting in permeation of the interface.

Basic drug substances were transported across a thin artificial organic liquid membrane by the application of 300 V d.c. From a 300 microl aqueous donor compartment (containing 10 mM HCl), the drugs migrated through a 200 microm artificial liquid membrane of 2-nitrophenyl octyl ether immobilized in the pores of a polypropylene hollow fiber, and into a 30 microl aqueous acceptor solution of 10 mM HCl inside the lumen of the hollow fiber. The transport was forced by an electrical potential difference sustained over the liquid membrane, resulting in electrokinetic migration of drug substances from the donor compartment to the acceptor solution. Within 5 min of operation at 300 V, pethidine, nortriptyline, methadone, haloperidol, and loperamide were extracted with recoveries in the range 70-79%, which corresponded to enrichments in the range 7.0-7.9. The chemical composition of the organic liquid membrane strongly affected the permeability, and may serve as an efficient tool for controlling the transport selectivity. Water samples, human plasma, and human urine were successfully processed, and in light of the present report, electrokinetic migration across thin artificial liquid membranes may be an interesting tool for future isolation within chemical analysis.

Recently, we demonstrated for the first time liquid-phase microextraction (LPME) of polar drugs based on carrier mediated transport. In this new extraction technique, selected analytes were extracted as ion-pairs from small volumes of biological samples, through a thin layer of a water immiscible organic solvent immobilised in the pores of a porous hollow fibre (liquid membrane), and into a microl volume of an acidic aqueous acceptor solution placed inside the lumen of the hollow fibre. In the current paper, this new extraction technique was combined with liquid chromatography-mass spectrometry (LC-MS) for the first time. Carrier mediated LPME was evaluated for several new model drugs (0.01

The demand for automation of liquid-liquid extraction (LLE) in drug analysis combined with the demand for reduced sample preparation time has led to the recent development of liquid-phase microextraction (LPME) based on disposable hollow fibres. In LPME, target drugs are extracted from aqueous biological samples, through a thin layer of organic solvent immobilised within the pores of the wall of a porous hollow fibre, and into an microl volume of acceptor solution inside the lumen of the hollow fibre. After extraction, the acceptor solution is subjected directly to a final analysis either by high performance liquid chromatography (HPLC), capillary electrophoresis (CE), mass spectrometry (MS), or capillary gas chromatography (GC) without any further treatments. Hollow fibre-based LPME may provide high enrichment of drugs and excellent sample clean-up, and probably has a broad application potential within the area of drug analysis. This review focuses on the principle of LPME, and recent applications of three-phase, two-phase, and carrier mediated LPME of drugs from plasma, whole blood, urine, and breast milk.

Basic studies on carrier-mediated transport as a mechanism to extract polar drugs by hollow fibre-based liquid-phase microextraction are presented for the first time. Hydrophilic alkaline drugs with log P (octanol/water partition coefficient) values less than 1 were selected as model substances. Sodium octanoate served as carrier and was added to the sample solution at pH 7 to form hydrophobic ion-pair complexes with the analytes. The ion-pair complexes were extracted into octanol as liquid membrane immobilised in the pores of the hollow fibre. Further extraction into an aqueous acceptor phase inside the lumen of the hollow fibre was facilitated by counter transport of protons from the acceptor solution to the sample solution. Protons from the acceptor solution released the analytes at the liquid membrane-acceptor interface and neutralized the carrier. The acceptor phase was analysed by capillary electrophoresis. The studies show that high extraction recoveries of ionic hydrophilic drugs can be obtained at a sample-acceptor volume ratio of 10. Linear calibration graphs and clean electropherograms indicate that carrier-mediated transport is a promising technique in microextraction of polar drugs from biological matrices.

A disposable device for liquid-phase microextraction (LPME) based on porous polypropylene hollow fibres has recently been introduced. In the present paper, LPME was combined with capillary electrophoresis (CE) and the combination was for the first time evaluated for chiral determination of drugs in biological matrices. The chiral antidepressant drug mianserin was selected as model compound. The mianserin enantiomers were extracted from 0.5 ml of plasma added internal standard and made alkaline with 0.25 ml of 2 M NaOH. The unionised analytes were extracted into di-n-hexyl ether impregnated in the pores of the hollow fibre, and into an acidic solution inside the hollow fibre. This resulted in a three-phase system where the extracts were aqueous, and hence directly compatible with the CE system. Efficient sample clean-up was seen and the extraction recovery was 80% for both enantiomers. Discrimination between the enantiomers in the extraction system was not observed. The limit of quantitation (S/N= 10; 12.5 ng/ml for both enantiomers) and the limit of detection (S/N=3; 4 ng/ml for both enantiomers) were below the therapeutic range for mianserin. The method was validated and successfully applied to determine R- and S-mianserin in plasma samples from seven patients treated with mianserin, indicating that LPME-CE is a promising combination for analysis of racemic drugs present in low concentrations in biological matrices.

Mathematical descriptions for extraction recovery and enrichment were applied for liquid-phase microextraction (LPME) and comparison with conventional two- and three-phase liquid-liquid extraction techniques (LLE) was made. The LPME theoretical calculations were verified by experimental determination of actual partition coefficients and by data obtained with LPME in a robust hollow fibre formate. With hollow fibre LPME operated in the two-phase mode, analytes were extracted from 1 to 4 ml aqueous samples into 25-50 microl of an organic solvent present in the pores and in the lumen of the porous hollow fibres. Compared with conventional two-phase LLE, two-phase LPME provided substantially higher enrichments for compounds with relatively large partition coefficients (K(org)/d>500). In contrast, because of the large volume of organic solvent relative to the sample volume, LLE provided high recovery and moderate enrichment even for compounds with relatively low partition coefficients (K(org)/d>5). Thus, two-phase LPME may be used for substantially enhanced extraction selectivity and enrichment of relatively hydrophobic analytes as compared with LLE whereas conventional two-phase LLE is superior for more hydrophilic analytes. Similar results were found for three-phase LPME where analytes where extracted from 1 to 4 ml aqueous samples through approximately 20 microl organic solvent immobilized within the pores of the hollow fibre and into 25 microl of an aqueous acceptor solution inside the lumen of the hollow fibre. The fundamental differences of LPME and LLE were further demonstrated with practical experiments on extraction of the basic drugs promethazine, methadone, and haloperidol from human plasma and urine.