2040 I. Ali et al. J. Sep. Sci.

2008, 31, 2040 – 2053

Imran Ali1 Review

Vinod.K. Gupta2
Hassan Y. Aboul-Enein3
Afzal Hussain1
1
Department of Chemistry, Jamia
Millia Islamia (A Central
University) New Delhi, India
2
Department of Chemistry,
Indian Institute of Technology
Roorkee, India
3
Pharmaceutical and Medicinal
Chemistry Department,
Pharmaceutical and Drug
Industries Research Division,
National Research Centre,
Dokki, Cairo, Egypt
Hyphenation in sample preparation: Advancement
from the micro to the nano world
Analysis at trace levels, an ideal area of application for hyphenated techniques, is
steadily gaining importance. Many sample pre-concentration and clean-up methods
have been hyphenated with core analytical techniques to accomplish the task of
low level detection. The present article describes the state of the art of hyphenation
of various techniques such as solid phase extraction, micro-solid phase extraction,
dialysis, and chromatographic modalities etc. with liquid chromatography, gas chro-
matography, capillary electrophoresis, and spectroscopic methods. Besides,
attempts have been made to address the hyphenation approach in microfluidic devi-
ces.
Keywords: Capillary electrophoresis / Gas chromatography / Liquid chromatography / Micro-flu-
idic devices / Solid phase extraction /
Received: March 4, 2008; revised: March 10, 2008; accepted: March 17, 2008
DOI 10.1002/jssc.200800123

1 Introduction to simplify these complications is the generation of sim-

Normally, many analytes in biological and environmen-
tal samples are present at very low concentrations in the
nano or level ranges, which are beyond the reach of
detection by conventional analytical instruments.
Besides, thousands of impurities also present in biologi-
cal and environmental matrices disturb analyses and,
hence, sample preparation of biological and environ-
mental matrices is essential prior to introduction onto
analytical machines. One of the most important trends
Correspondence: Professor Hassan Y. Aboul-Enein, Pharmaceuti-
cal and Medicinal Chemistry Department, National Research
Centre, Dokki, Cairo 12311, Egypt
E-mail: enein@gawab.com
Fax: +20-2-33370931
Abbreviations: AAS, atomic absorption spectrometry; AES,
atomic emission spectrometry; DMAE, dynamic microwave-as-
sisted extraction; DSAE, dynamic sonication-assisted extraction;
ECD, electron capture detector; EF, enrichment factor; FID,
flame ionization detection; GF, gel filtration; HCH, hexachloro-
cyclohexane; HGAAS, hydride generation atomic absorption
spectroscopy; ICP, inductively coupled plasma spectrometry; IC,
ion chromatography; IDA, iminodiacetic acid; IMAC, immobi-
lized metal affinity chromatography; IPLC, ion pair liquid chro-
matography; ISP-CGC, immunoaffinity sample pretreatment-
capillary gas chromatography system; LLE, liquid – liquid extrac-
tion; MMLLE, microporous membrane liquid – liquid extraction;
NP, normal-phase; OTT, open-tubular trapping; OPPs, organo-
phosphorus pesticides; PAHs, polycyclic aromatic hydrocar-
bons; PHWE, pressurized hot water extraction; PCB, polychlori-
nated biphenyl; lRPLC, micro reverse phase liquid chromatog-
raphy; SFE, supercritical fluid extraction; SLM, stratum lacuno-
sum-moleculare
ple, rapid, and reliable procedures for sample prepara-
tion. Method development and setup requires the use of
material of known compositions, e. g. certified reference
materials. Therefore, spiking experiments have to be per-
formed for method quality control. Integration and auto-
mation of all the steps between sample preparation and
detection significantly reduce the time of analysis,
increasing both reproducibility and accuracy.
In 1995, the seventh symposium on handling environ-
mental and biological samples in chromatography was
held on May 7 – 10, at Lund, Sweden. This symposium
was in continuation of the series started by the late Dr.
Roland Frei, one of the early visionaries in sample prepa-
ration technologies in analytical sciences. A survey of the
papers presented at this symposium indicates that five
points have been highlighted and considered as essential
during sample preparation. First, the need for a continu-
ous search for new technologies was realized, so that the
high cost due to chemicals and experimental labor may
be reduced. Secondly, the need was recognized for
increasing sensitivity with better and more selective con-
centration techniques, which has driven scientists to
examine affinity and immuno-affinity supports that can
selectively remove compound classes for further investi-
gation. Thirdly, the development of multidimensional
chromatographic techniques allowing on-line sample
clean-up, which provides several advantages including
automation, better reproducibility, and closed system
capability was advocated. The fourth point considered
was the development of better sample preparation tech-
niques enabling more effective use of biosensors and

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J. Sep. Sci. 2008, 31, 2040 – 2053
other sensors because exposure to raw matrices can foul
many sensors. The last and the fifth point, which
requires considerable attention from the scientist, was
the quality movement which has found its way into sam-
ple handling. Therefore, extraction, purification, and
pre-concentration of the natural samples are very impor-
tant and essential operations in separation science, but,
of course, involve the use of costly chemicals and time.
Moreover, these techniques are not able to prepare sam-
ples containing analytes at nano levels. In view of this, a
new trend of hyphenation is emerging in which a sample
preparation unit is coupled with an analytical instru-
ment. This hyphenation technology is the latest develop-
ment and future of sample preparation in the present
century. In view of these developments, the present
article discusses state-of-the-art sample preparation
through hyphenation.
2 Sample preparation techniques
Basically, sample preparation is a complex and sensitive
step in analysis, which requires considerable expertise,
especially when dealing with samples containing ana-
lytes at micro or nano level concentrations. Many off-line
methods have been used for sample preparation, includ-
ing solvent extraction (23%), solid phase extraction
(48%), supercritical fluid extraction (11%), immunoaffin-
ity extraction (5%), matrix solid phase dispersion (2%),
automated solid phase extraction (SPE 2%), dialysis (5%),
solid phase micro extraction (3%), and mole mass filtra-
tion (1%). To provide a quick impression and to permit
comparison, these percentages are shown in Fig. 1.
Solvent extraction (liquid – liquid extraction) is a classi-
cal method of sample preparation exploiting unequal
distribution of solutes in two immiscible liquid phases. It
has been used for the extraction of many compounds of
biological and environmental importance [1 – 2]. Extrac-
tion from liquid and solid samples is carried out by using
a variety of solvents such as hexane, acetone, acetic acid,
benzene, toluene, methanol, acetonitrile, petroleum
ether, ethyl ether, iso-octane, pentane, dichloromethane,
etc. This method has certain drawbacks such as high con-
sumption of costly solvents and time. Besides, the dis-
posal of used solvents (environmental hazards) and emul-
sion formation are other problems associated with this
technique. Of course, solid phase extraction (SPE) is a
quite practical method involving the use of reversed
phase (C8, C18, etc. silica gel) adsorption phases in the
form of discs and cartridges, but it also has certain draw-
backs [3]. SPE requires multiple steps and costly solvents,
and is a time-consuming process since the solvent con-
centration should be protected from evaporation. Some-
times, clotting, channelling, and percolation create
problems in sample preparation in this sort of sample
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Sample Preparations 2041
Figure 1. Percentage contribution of different sample prepa-
ration techniques (source Toxline and Current Contents;
years: 1997 – 1998 – 1999).
handling modality. Chromatographic techniques are
also important and effective methods of sample prepara-
tion and include HPLC, GPC, and SFC. However, these are
not affordable in all laboratories due to their costly
instrumentation and running costs [4, 5]. Besides, mem-
brane filtration and dialysis have also been used for sam-
ple preparation but they are also limited to certain appli-
cations [4, 5]. Due to advances in separation science in
the new millennium the demand for analyses is increas-
ing at nano or lower level detection limits and scientists
in academia and industry as well as government agencies
require data at such low limits all over the world [6].
Under such circumstances, the role of sample prepara-
tion becomes crucial, and creates a need for greater focus
on miniaturization and non-exposure of samples during
their preparation. Moreover, rapidity, efficiency, selectiv-
ity, reproducibility, low cost, and low limits of detection
are demanded by today's separation science. A literature
search and our experience indicate that these demands
can be satisfied by hyphenation.
3 Hyphenation technology
Basically, the above-cited methods are used for sample
preparation in biological and environmental matrices.
However, certain drawbacks make these methods less
than ideal since they are not effective in the case of low
amounts of samples and consume costly solvents and
time. Besides, contamination and poor recoveries may
also occur during experiments. The factors underscored
the need for hyphenated techniques. Hyphenation is
nothing but the coupling of a sample preparation unit
with the core analytical instrument. It has been found
more effective than conventional methods in terms of
efficiency, effectiveness, selectivity, high recoveries, suit-
ability for small samples, and for samples containing
components that are difficult to analyze and give rise to
procedural problems. Therefore, some papers have been
published dealing specifically with biological and envi-
ronmental samples. The use of hyphenation has been
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2042 I. Ali et al.
classified on the basis of the core analytical technique, as
discussed in the following sections.
3.1 Hyphenation in liquid chromatography
Basically, liquid chromatography represents a landmark
in the history of separation science and sample prepara-
tion is a key issue in this area. Many workers have
attempted to hyphenate sample preparation units with
liquid chromatographs and some important research
work is discussed herein. Johansen et al. [7] described the
hyphenation of Automated Sequential Trace Enrichment
of Dialysates (ASTED) system with HPLC for analysis of
antidepressant drugs in plasma. In this system the pro-
tein and particles were purified through a semi-perme-
able membrane and collection of the drug molecules on
a trace enrichment column (TEC) was followed by HPLC
analyses on a Supelcosil column (15064.6 mm). The
ASTED system consisted of a cellulose acetate dialysis
membrane and interactions of analytes with the cellu-
lose acetate membrane have been reported for basic
drugs such as the opiate derivative pholcodine, benzodia-
zepines, and the neuroleptic drug clozapine [8 – 10]. Most
of the antidepressant drugs showed ionic and hydropho-
bic interactions with the membrane and were selected as
model substances to investigate more closely the ability
of cationic surfactants to inhibit analyte-membrane
interactions. The author optimized ASTED – HPLC condi-
tions to achieve maximum recoveries by adding cationic
surfactants to the donor solution in the dialyser, by the
effect of chain length and concentration of cationic sur-
factants, pH of the donor solution, and the volume of the
acceptor solution. Furthermore, the authors used a che-
mometric approach via factorial design and response
surface modeling for optimization strategies. The devel-
oped unit was applied successfully for monitoring mian-
serine, imipramine, desimipramine, amitriptyline, and
nortriptyline drugs in human plasma. Dialysis was per-
formed for 12.8 minutes after which the six port valve
was switched to the injection position and the enriched
analytes were loaded onto TEC with HPLC mobile phase
(acetonitrile – methanol – 0.005 M ammonium phosphate
buffer (pH 7.0) (70:15:15 v/v/v)) at a flow rate of 1.5 mL/
min The limits of detection of the reported drugs in
human plasma were in the range of 17 – 39 nM/L with UV
detection.
Cheng et al. [11] studied the biotransformation of D-
aspartic acid into L-aspartic acid with the help of SPE –
HPLC hyphenation. The column used in HPLC was of
ligand exchange type allowing the chiral separation of D-
and L-aspartic acid. The mobile phase used for SPE was
5 mM sodium-1-octanesufonate (pH 2.2) at 0.1 mL/min
flow rate while HPLC eluent was 0.25 mM CuSO4 (pH 3.6)
at a flow rate of 0.5 mL/min. Kema et al. [12] developed an
automated on-line SPE – HPLC method for profiling of
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J. Sep. Sci. 2008, 31, 2040 – 2053
Figure 2. Schematic representation of on-line SPE system
coupled to HPLC with fluorescence detection, on top SPE
with conditioning of the cartridge and sample injection, the
middle panel represents the system during backward-flush
elution of the cartridge and the bottom panel shows the sys-
tem during regeneration of the cartridge [12].
plasma indoles tryptophan, 5-hydoxytryptophan (5-HTP),
serotonin, and 5-hydroxyindoleacetic acid (5-HIAA) com-
pounds for diagnosing of carcinoid tumors in patients.
The SPE cartridge consisted of hydrophobic polystyrene
resin and the analytes were enriched on SPE due to vari-
ous interactions such as hydrogen bonding, van der
Waals forces, steric effects etc. The fluorometric detector
permitted detection of several metabolically related
indole derivatives. HPLC conditions were Inertsil column
(25063 mm) with mobile phase of different ratio of
50 mM potassium dihydrogen phosphate adjusted to
pH 3.3 with phosphoric acid with acetonitrile as eluent.
This set-up is shown in Fig. 2, indicating a coupling of
SPE and HPLC along with its working mechanism. The
SPE cartridge is pre-conditioned with acetonitrile, dipo-
tassium EDTA in water (5g/L), and water at 3 mL/min
flow rate; followed by autosampling of the enriched
ingredients onto the HPLC column. By the time chroma-
tographic separation on the analytical column is com-
plete, the SPE unit has been made ready for the next sam-
ple preparation and injection. The authors advocated
this hyphenation as an emerging technique due to its
direct injection procedure in combination with column
switching that offered the possibility of combining sam-
ple pre-purification, concentration, and analysis simulta-
neously.
Hasselstrom et al. [13] described a fully automated on-
line SPE – HPLC – UV system for quantification of quetia-
pine, an antipsychotic drug, in human serum. SPE was
conducted on a C2 packing and the mobile phase used for
HPLC was MeOH – 20 mM NH4CH3COO (pH 5.0) (99:1, v/v)
at a flow rate of 1.0 mL/min with 257 nm. Similarly, Man-
drioli et al. [14] also studied quetiapine by SPE – HPLC
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J. Sep. Sci. 2008, 31, 2040 – 2053
hyphenated separation. Kato et al. [15] also described an
on-line solid-phase extraction method, coupled with
HPLC – MS-MS for the determination of 16 phthalate
metabolites in human urine. The method employed a
conventional analytical column for the chromato-
graphic separations of these analytes and the mobile
phase used was A (0.1% acetic acid in water) and B (0.1%
acetic acid in acetonitrile) at a flow rate of 0.35 mL/min.
The limits of detection ranged from 0.11 to 0.90 ng/mL. A
similar set-up was described by Kuklenyik et al. [16] for
the extraction and measurement of perfluorinated
organic acids and amine in human serum and milk. A 12-
lL volume of the reconstituted serum or milk extract
was auto-injected on to HPLC at a 300-lL/min flow rate
with 20 mM ammonium acetate (pH 4) in water and
methanol as mobile phase. The HPLC gradient program
(14 min) was started at 60% methanol in the mobile
phase followed by an increase in organic content to 80%
in 0.5 min, which was kept for 9 min. Later on, the
mobile phase organic content was decreased in 0.5 min
to 60% methanol, where it was kept for 3 min to equili-
brate the column. Furthermore, the same group [17]
described an automated on-line hyphenation of SPE with
HPLC – MS for the extraction and measurement of isofla-
vones and lignans in urine. The mobile phases used were
10 mM ammonium acetate (pH 6.5) and methanol – ace-
tonitrile (50:50 v/v) at a flow rate of 0.8 mL/min, respec-
tively. The detection limits were in the range of 0.2 –
0.7 ng/mL. These authors described these hyphenations
as an innovation in separation science.
Koster et al. [18] reported the analysis of lidocaine in
urine by an on-line SPME – LC method. A polydimethylsi-
loxane (PDMS) coated fiber was directly immersed into
buffered urine with optimized contact time, pH, ionic
strength, and temperature. The extraction yields were
22% in about 45 min with a reproducibility of a 5%
expressed as relative standard deviation. The detection
limits were 25 – 1000 ng/mL. Volmer et al. [19] studied the
eleven corticosteroid and two steroid conjugations in a
urine sample by SPME – LC – MS. Several SPME optimiza-
tion factors such as polarity of fibres, extraction time
and effect of ionic strength, were investigated, and their
impact on the SPME/LC/MS technique was studied. The
method was sensitive with detection limits between 4
and 300 ng/mL and precision between 4.9 and 11.1%
RSD. Kim et al. [20]. developed sol-gel titania-based coat-
ing capillary micro extraction (CME) coupled with HPLC
for the extraction and analyses of polycyclic aromatic
hydrocarbons, ketones, and alkylbenzenes at high pH. To
perform CME – HPLC, a so-gel TiO2 – PDMS capillary was
installed in an HPLC injection port as an external sam-
pling loop. HPLC conditions were ODS column
(25064.6 mm) with acetonitrile – water (80:20v/v) as
mobile phase. The target analytes were extracted on-line
by passing the aqueous sample through this sampling
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Sample Preparations 2043
loop. The sol-gel titania – PDMS coated capillaries were
used for on-line extraction and HPLC analysis of poly-
cyclic aromatic hydrocarbons, ketones, alkylbenzenes,
and a wide range of other less volatile or thermally labile
compounds [21] that are not amenable to GC separation.
Hashi et al. [22] described the determination of polycyclic
aromatic hydrocarbons (PAH) in the atmospheric partic-
ulates by using on-line enrichment coupled with fast
high-performance liquid chromatography with fluores-
cence detection. The limits of detection of PAH were in
the range of 0.02 – 0.23 ng/mL with recoveries between
87 and 12% for spiked atmospheric particulate sample.
The mobile phase used was acetonitrile – water (72:28,
v/v) at a flow rate of 1.0 mL/min. Altun et al. [23] developed
and validated a method for local anesthetics in human
plasma through on-line MEPS by using a cation-
exchanger with a flow rate of 0.20 mL/min.
Abdel-Rehim [24] developed and validated a new sensi-
tive, selective, and accurate on-line micro-extraction in
packed syringe (MEPS) technique hyphenated with HPLC
for the determination of lidocaine, prilocaine, ropiva-
caine, and mepivacaine in human plasma. The extrac-
tion recoveries were in the range of 60 – 90%. Veuthey et
al. [25] described on-line solid phase extraction to achieve
nano analysis of drugs in biological samples. In this
hyphenation technique, the single column performs two
functions, i. e. extraction and separation. The column was
connected to a detection system via a switching valve.
The sample was directly injected on to the extraction
support with and after the extraction, the valve was
switched, and analytes were transferred to the detector
with the eluting mobile phase followed by extraction
support re-equilibration. According to the authors, the
method was simple and several applications have been
published for the direct analysis of biofluids. Quintana et
al. [26] described an automated on-line hyphenation of
SPE – HPLC incorporating multi syringe flow injection
analysis (MSFIA), bead injection, and lab-on-valve (BI –
LOV) prior to HPLC. The potential of the novel MSFI – BI –
LOV hyphenation for on-line handling of complex envi-
ronmental and biological samples prior to reversed-
phase chromatographic separations was assessed for the
expeditious determination of five acidic pharmaceutical
residues viz. ketoprofen, naproxen, bezafibrate, diclofe-
nac, and ibuprofen along with one metabolite, i. e. sali-
cylic acid, in surface water, urban wastewater, and urine.
The column used was an Xterra RP-18 (3.96150 mm)
with the mobile phases A: MeOH – water (20:80, v/v) and
B: MeOH – water (95/5, v/v), both containing 0.1% (v/v) for-
mic acid at flow rates of 1.0 mL/min. The detection limit
was 0.02 – 0.67 ng/mL.
Clarkson et al. [27] described hyphenation of solid-
phase extraction with liquid chromatography and
nuclear magnetic resonance: application for identifica-
tion of flavonol glycosides (kaempferol 3-O-(6-O-a-L-rham-
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2044 I. Ali et al.
nopyranosyl)-b-D-glucopyranoside; kaempferol 3-O-(2,6-di-
O-a-L-rhamnopyranosyl)-b-D-glucopyranoside; quercetin
3-O-(2,6-di-O-a-l-rhamnopyranosyl)-b-D-glucopyranoside
(rutin); and isorhamnetin, 3-O-(6-O-a-L-rhamnopyranosyl)-
b-D-glucopyranoside) and three 5-a-cardenolides (coro-
glaucigenin 3-O-6-deoxy-b-D-allopyranoside; coroglaucige-
nin 3-O-(4-O-b-D-glucopyranosyl)-6-deoxy-b-D-glucopyrano-
side; 39-O-acetyl-39-epiafroside) were identified. Zhang et
al. [28] described an automated on-line hyphenation of
SFC – 2-D – HPLC – MS for sample preparation, separation,
detection, and identification of the fruiting bodies of
Ganoderma lucidum, and at least 73 components in the
extract were resolved with a calculated peak capacity of
up to 1643. The SFE and 2-D HPLC systems were fitted
with a Hypersil-CN (5 lm, 1200A, 15064.6 mm id) and
Chromolith Flash columns, respectively. In the first
dimensional separation, the binary mobile phase was
composed of A (water) and B (methanol) with a flow rate
of 0.1 mL/min In the second dimensional separation, the
mobile phase was composed of C (water) and D (acetoni-
trile) with a flow rate of 4 mL/min. The same group
reported a simple SFE – HPLC system for comprehensive
analyses of traditional Chinese medicines [29]. However,
for complex samples, it is impossible to separate all com-
ponents by one-dimensional chromatography. There-
fore, two-dimensional HPLC has been developed and was
regarded as a powerful technique for the separation of
proteins, peptides, polymers, natural products, and
other complex mixtures by different workers [30 – 43].
Taylor et al. [44] established an on-line SFE – HPLC – UV/
ESI-MS technique for the quantitative analysis of Hyper-
forin pertoratum.
Ritter et al. [45] described the hyphenation of an elec-
trolytic on-line eluent generation device with high per-
formance anion-exchange chromatography coupled
with UV detection for the determination of a wide range
of intracellular metabolites from mammalian cells. The
detection wavelength of the UV detector was switched
from 220 to 260 nm and the detection limits were in the
range of mM. Two Dionex AS11 analytical columns
(25062 mm id) were used with 0.35 mL/min as mobile
phase flow rate. Tuytten et al. [46] described an on-line
automated SPE – HPLC – ESI-MS method for targeted
metabolomic analysis of urinary modified nucleoside
levels. The unit comprised a boronate affinity column as
a trapping device, a hydrophilic interaction chromatog-
raphy (HILIC) separation, and information-dependent MS
detection modes. The system was applied to biological
samples, detecting a number of modified nucleosides.
Clarkson et al. [47] described HPLC – SPE – NMR hyphena-
tion for structural elucidation of some natural products.
Lambert et al. [48] described the identification of natural
products by using SPE – HPLC coupling with Cap-NMR.
This coupling was used for identification of sesquiter-
pene lactones and esterified phenylpropanoids present
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J. Sep. Sci. 2008, 31, 2040 – 2053
in an essentially crude plant extract (toluene fraction of
an ethanolic extract of Thapsia garganica fruits).
Lin et al. [49] described hyphenation of in-tube solid-
phase micro-extraction (SPME) and pressure-assisted CEC
(p-CEC) by installing a poly(methacrylic acid-co-ethylene
glycol dimethacrylate) monolithic capillary at a six-port
valve in a CEC system. Theobromine, theophylline, and
caffeine were chosen as model drugs to facilitate compar-
ison with the results obtained by in-tube SPME – HPLC.
The detection limits of these three analytes were
improved more than 100 times when compared with
direct analysis by l-HPLC. Besides the above-cited meth-
ods of sample preparation, some modalities of liquid
chromatography have also been used as sample prepara-
tion methods and hyphenated with HPLC. Only one
article on size exclusion chromatography coupled with
HPLC is cited. Pomazal et al. [50] described analyses of cop-
per, iron, manganese, and zinc in blood samples by
exploiting the hyphenation of SEC with an HPLC – ICP-
AES unit. Besides, this device was also used to monitor
metalloproteins in erythrocytes and blood plasma sam-
ples. Optimization was achieved via parameters like pH,
flow rate, and salt concentration. For optimizing experi-
ments, blood samples from one female subject were used
and the direct determination of the elements was per-
formed by ICP-AES on blood fractions of ten different sub-
jects to obtain the average concentration ranges.
3.2 Gas chromatography
Gas chromatography is considered the best choice for
analysis of volatile compounds, including several agri-
cultural, industrial, and other chemical compounds. Of
course, many xenobiotics are present at trace concentra-
tions and cannot be analyzed directly and this circum-
stance compels scientists to perform sample preparation,
i. e. to adopt pre-concentration and hyphenation
approaches. Many sample preparation methods have
been coupled with GC for analyses of various species and
these include LLE, SPE, membrane, etc.
Membrane extraction is considered to be one of the
best extraction techniques because it has the important
advantage that the sample and the extractant can contin-
uously be kept in contact without physical mixing, thus
providing the basis for a continuous, real-time process
permitting automation and on-line connection to instru-
ments [51]. Consequently, membrane techniques have
advanced during few decades to a stage permitting the
solution of numerous analytical problems. These tech-
niques allow the simultaneous extraction and enrich-
ment of analytes and typically facilitate selective extrac-
tion at trace levels while consuming small amounts of
solvents. Automated on-line liquid – liquid membrane
extraction (LLME) has also been reported for determina-
tion of PCB [52] and of anesthetics in blood [53]. For PCB
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determinations, Barri et al. [52] designed a miniaturized
membrane extraction card (referred to as the ESy card)
connected to a GC injector via an electromechanical
installation which controls pre-treatment and triggers
the GC instrument. The EF (enrichment factor) exhibited
by this hyphenation was between 33 and 40 for PCBs in
river water. Shen et al. [53] used a sample processor sys-
tem consisting of an auto-sampling injector, dilutors,
and a six-port valve connected to a GC injector loop for
achieving EF up to 50 for some local anesthetics in blood
plasma.
Abdel-Rehim [24] developed and validated a sensitive,
selective, and accurate on-line sample preparation tech-
nique for the determination of lidocaine, prilocaine,
ropivacaine, and mepivacaine in human plasma. The on-
line micro-extraction unit was a packed syringe (MEPS;
silica gel C2) coupled with GC – MS. The plasma samples
(50 – 1000 lL) were drawn through the syringe by an
auto-sampler and passed through the solid support,
resulting in their adsorption onto the solid phase. The
solid phase was then washed once with water (50 lL) to
remove proteins and other interfering material. The
MEPS technique differed from commercial solid-phase
extraction (SPE) in the way in which the packing was
inserted directly into the syringe, and not into a separate
column. MEPS was capable of handling sample amounts
from 10 to 1000 lL of plasma, urine, or water in GC appli-
cations. MEPS took only about one minute for each sam-
ple with greater robustness than the SPME technique,
and gave recoveries between 60 and 90%. GC experimen-
tation conditions were 908C column temperature for
3 min followed by an increase up to 2808C at a rate of
508C per min; with helium as carrier gas at 2.0 mL/min
flow rate.
Li et al. [54] described an hyphenation of SPE with pro-
grammable temperature vaporizers – large volume injec-
tion/gas chromatography/mass spectrometry (PTV – LVI/
GC/MS) for on-line sample preparation and separation of
semi-volatile organic compounds (pesticides and herbi-
cides) in a variety of water samples. The authors utilized
this unit for real life samples of chlorinated tap water,
well water, and river water. Furthermore, optimization
achieved minimum limit of detection (0.1 lg/L) with rela-
tive recoveries in the range of 70 – 120% and a relative
standard deviation of less than 15%. The schematic repre-
sentation of an SPE Twin – PAL PTV – LVI/GC/MS system is
shown in Fig. 3. Pawliszyn et al. [55 – 59] developed solid
phase micro extraction (SPME) methods for non-volatile
compounds. A fused silica rod with a polymeric coating
on the surface was employed as the extraction medium
for the adsorption of volatile analytes from aqueous sam-
ple solutions. The SPME fiber was inserted into the GC
injector port for desorption and analyses of the analytes.
Brossa et al. [60] described an automated on-line SPE –
GC – MS set-up for the determination of a group of endo-
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Sample Preparations 2045
Figure 3. Schematic representation of an SPE Twin – PAL-
PTV – LVI/GC/MS system. S1: upper PAL head and syringe,
S2: lower PAL head and syringe, C1: upper PAL control unit,
C2: lower PAL control unit, FC: sample flow cell, W1: wash
station for upper PAL syringe, W2: wash station for lower
PAL syringe, SR: solvent reservoir, SS: standard station,
SV: on-line sample spiking vial, ET: sample extraction tray,
CT: eluate collection tray, ST: standard tray, WS: water sam-
ple source and WW: water waste container [54].
crine disruptors in water samples. The chromatographic
column used was HP-5 MS (28 m6250 lm id) and the
limits of detection of the method were between 0.001
and 0.036 lg/L.
3.3 Hyphenation in capillary electrophoresis
Nowadays, capillary electrophoresis (CE) is valued as a
versatile technique exhibiting high speed, high sensitiv-
ity, lower limits of detection, and low running costs, and
represents a major trend in analytical science; the num-
ber of publications on this technique has increased expo-
nentially [61 – 64]. CE is suitable for samples that may be
difficult to separate by liquid chromatography and gas
chromatography, or at least complements these tech-
niques since the principles of separation are different.
The lower detection limits of CE lead to the possibility of
separating and characterizing very small quantities of
materials, which normally require pre-concentration
and sample preparation strategies, especially in
unknown matrices. Therefore, some on-line methods
have been reported from time to time to achieve the goal
of micro level separation and detection in CE.
Su et al. [65] studied the analysis of riboflavin in beer by
CE – LED coupled with stacking micellar electrokinetic
chromatography (MEKC) as pre-concentration tech-
niques. The detection limit reported was 1.0 ng/mL with
38 000 theoretical plates per meter. Hsieh et al. [66]
hyphenated sweeping-micellar electrokinetic chroma-
tography with CE to analyze trans-resveratrol in red wine.
The CE buffer was methanol – water solution (25:75, v/v)
and the system was operated at 77 kV with detection at a
wavelength of 369 nm; the detection limit was 5 ppb.
Fang et al. [67] described an on-line centrifuge micro-
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2046 I. Ali et al.
Figure 4. Schematic representation of FIC – CE coupling,
(X): cross-sectional view of the FIA – CE interface and (Y):
schematic diagram of the FIA – CE system used for on-line
sample dialysis, (S): sample, (A): acceptor stream, (E): elec-
trolyte, (M): dialysis membrane, (D): UV detector, (V1): injec-
tion valve in filling position, (V2): injection valve in inject posi-
tion, (W): waste, (C): capillary, (Pt): platinum electrodes, and
(HV): high-voltage supply [70].
extraction back-extraction field-amplified sample injec-
tion capillary electrophoresis system (CME – OLBE – FASI-
CE) for determining trace ephedrine derivatives in urine
and serum. CME and OLBE – FASI were two separate con-
centration units. The detection limits of this set-up were
between 0.15 to 0.25 ng/mL on using photodiode array
UV detection at 192 nm. The separations were achieved
on an uncoated fused-silica capillary (50.2 cm650 lm
id). Zhang et al. [68] developed hyphenation of immobi-
lized metal affinity chromatography with capillary elec-
trophoresis (IMAC – CE) for on-line concentration and
analysis of peptides and proteins. The polymer mono-
lithic immobilized metal affinity chromatography
(IMAC) materials were prepared by an iminodiacetic acid
(IDA) type adsorbent covalently bonded with monolithic
rods of macroporous poly(glycidyl methacrylate-co-ethyl-
ene dimethacrylate). Cu(II) was subsequently introduced
into the support via interaction with IDA. Liu et al. [69]
described a microdialysis hollow fiber as a macromole-
cule trap for on-line coupling of solid phase micro-extrac-
tion and capillary electrophoresis for analysis of protein
samples. The detection limit was 3.0610 – 7 M with UV
absorbance detection. Kuban and Karlberg [70] have
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J. Sep. Sci. 2008, 31, 2040 – 2053
reported an on-line dialysis/FIA – CE sample clean-up pro-
cedure for metal ion analysis; with coupling via a spe-
cially designed interface (Fig. 4). Samples were continu-
ously pumped into a dialysis unit and the outgoing
acceptor stream containing the analytes was allowed to
fill a rotary injector in the FIA part of the system. Multi-
ple sample injections were possible in one electropho-
retic run, and the entire analytical procedure could
easily be mechanized. The repeatability of the unit was
in the range of 1.6 – 3.3% (n = 7). This unit was applied in
a wide range of real samples with complicated matrices
like milk, juice, slurry, and liquors from the pulp and
paper industry.
3.4 Hyphenation in spectroscopy
As in case of chromatography and capillary electrophore-
sis, pre-concentration and sample preparation tech-
niques were also hyphenated with spectroscopic instru-
ments leading their capabilities to analyze samples of
low volume or having poor ingredients. Many modalities
of spectroscopy have been reported in the literature of
identification of various inorganic and organic species.
The most important spectroscopic techniques are atomic
absorption spectrometry (AAS), inductively coupled
plasma spectrometry (ICP), nuclear magnetic resonance
spectrometry (NMR), atomic emission spectroscopy (AES),
mass spectrometry (MS), infrared (IR), atomic fluores-
cence spectrometry (AFS) etc. Normally, the detection lim-
its of these techniques ranged from mg to lg and if
applied in biological and environmental samples having
low concentrations of ingredients, the analytical results
become inadequate. Sample pre-concentration and prep-
aration are the tools used by analytical scientist to over-
come such challenging problems. In view of these facts,
some papers have addressed on-line hyphenation of sam-
ple pre-concentration and preparation techniques
hyphenated with spectroscopic techniques. Sometimes,
chelation of metal ions with suitable reagents enhanced
the detection [71 – 73].
Danesi [74] described a simplified model for the car-
rier-facilitated transport of metal ions through hollow
fiber supported liquid membranes. Yang et al. [75]
reported the clean-up, extraction, and enrichment of
numerous metals including Pb, Cu, Cr, La, Ce, Zn, and Co
by HF-SLME and coupled it with AAS and ICP-MS as shown
in Fig. 5. Katarina et al. [76] described an on-line hyphen-
ation of sample preparation method by using a computer
controlled pre-treatment system (Auto-Pret AES) coupled
with ICP-AES for the sample pretreatment and determi-
nation of trace metals in water samples. This system
enabled determination of trace metals at the ppt level.
Fan et al. [77] synthesized diphenylcarbazone-functional-
ized silica gel for SPE able to withstand 1 – 6 mol/L HCL or
H2SO4 as well as common organic solvents. This SPE was
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J. Sep. Sci. 2008, 31, 2040 – 2053
Figure 5. Schematic of hollow fiber column pre-concentra-
tion unit with ICP-AES [75].
used for the extraction of Hg(II) selectively from eight
metal ions with similar characteristics such as Cd(II),
Ni(II), Co(II), Mn(II), Pb(II), Zn(II), Cu(II), and Fe(III). A
micro-column packed with diphenylcarbazone-function-
alized silica gel was coupled with flow-injection (FI) spec-
trophotometry for the selective separation, pre-concen-
tration, and determination of Hg(II) in six different ciga-
rette samples with detection limit of 0.90 ng/mL.
Motomizu et al. [78] described an on-line flow injection
inductively coupled plasma atomic emission spectrome-
ter (FI – ICP-AES) system using anion- and cation-exchange
resin disks for the speciation of chromium species in
fresh water. Two kinds of ion exchange resin disks
packed in line-filters were fixed and serially connected
on the loop of each six-way valve. Five milliliters of a sam-
ple solution (pH 4.5) was introduced into the system.
Anionic chromate ion, Cr(VI), was collected on the anion-
exchange resin disk while cationic chromium ion, Cr(III),
was collected on the cation-exchange resin disk. The col-
lected species were then sequentially eluted by 2 M nitric
acid and nebulized to the plasma of ICP-AES. The detec-
tion limit of Cr(VI) and Cr(III) were 0.04 and 0.02 lg/L
respectively. This method was applied to the speciation
of Cr(III) and Cr(VI) in fresh water samples. Similarly, Jit-
manee et al. [79} reported arsenic speciation in fresh
water by using inductively coupled plasma-atomic emis-
sion spectrometry coupled with pre-concentration sys-
tem containing solid phase anion exchange resin. Two
miniaturized columns with a solid phase anion
exchange resin, placed on two 6-way valves were used for
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Sample Preparations 2047
the solid-phase collection/concentration of arsenic(III)
and arsenic(V), respectively. The limit of detection for
both As(III) and As(V) were 0.1 lg/L. In the same year,
Sumida et al. [80] described on-line pre-concentration spe-
ciation of Cr(III) and Cr(VI) by using dual mini-columns
coupled with plasma-atomic emission spectrometry in
water samples. Cr(III) was collected on the first column
packed with iminodiacetate resin. Cr(VI) in the effluent
from the first column was reduced to Cr(III), which was
collected on the second column packed with iminodiace-
tate resin.
3.5 Hyphenation in microfluidic devices
Microfluidic devices are an innovation in separation sci-
ence as they can be used to analyze samples of low vol-
ume and having low-concentration ingredients. Among
various methods using microfluidic devices, nano-liquid
chromatography (NLC) and nano-capillary electrophore-
sis (NCE) are the two most important techniques, and are
used to achieve separations at nano levels. During a liter-
ature survey we found few papers dealing with on-line
chip-based sample preparation methods in NLC and NCE.
Attempts have been made to discuss these in the follow-
ing paragraphs.
Huynh et al. [81] described the first hyphenation of
micro-dialysis NCE system for monitoring the hydrolysis
of fluorescein mono-b-D-galactopyranoside (FMG) by b-D-
galactosidase. The layout of the microdialysis/microchip
CE device shown in Fig. 6 indicates channel lengths, volt-
age scheme, perfusate (20 mM sodium phosphate buffer,
pH 7.4). Furthermore, the same authors [82] presented an
on-line microdialysis sampling unit coupled with NCE.
The authors used this set-up for amino acid and peptide
analyses. Wilson et al. [83] reported an on-line desalting
of macromolecule (betaine-type amphoteric or zwitter-
ionic surfactant solutions) using a two-layered laminar
flow system due to differential diffusion of analytes.
Wheeler et al. [84] developed an on-line sample prepara-
tion method for MALDI-MS, which depended on an elec-
tro-wetting-on-dielectric-based technique. Ramsey et al.
Figure 6. Schematic representation of on-line
hyphenation of micro-dialysis sample prepara-
tion unit with NCE [81].
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2048 I. Ali et al.
Figure 7. Schematic representation of chip-based solid
phase extraction-MEKC device. (a): Layout of the entire
device and (b): expanded view of the extraction region of the
device. The dotted lines represent the direction of fluid flow
during extraction; the solid line signifies flow during elution/
injection. (Narrow channels are ca. 55 lm wide, the column
chamber is ca. 210 lm wide with all channels ca. 15 lm
deep.) [85].
[85] coupled SPE to micellar electrokinetic chromatogra-
phy to give a system permitting completely automated
extraction, elution, injection, separation, and detection
steps, respectively and separately. The authors reported
fast analysis of rhodamine B yielding pre-concentration
factors of more than 200 in less than 5 min with a
60 femtomolar detection limit. A schematic representa-
tion of this hyphenation is shown in Fig. 7, clearly indi-
cating sample preparation and separation components.
Legendre et al. [86] described a chip-based on-line solid-
phase extraction (SPE) for DNA and polymerase chain
reaction in NLC. The amount injected was 600 nL of
blood sample. Xiao et al. [87] presented a sample prepara-
tion method on a PDMS/glass chip coupled to gas chro-
matography. The authors tested this assembly for anal-
ysis of ephedrine from aqueous solution and reported
good reproducibilities of extraction and analysis.
Sample stacking has recently come to be regarded as
the best pre-concentration technique in capillary electro-
phoresis, and has been tested in the NCE format [88].
Many modifications have been made to sample stacking,
which include field-amplified sample stacking (FASS)
[89 – 91], large-volume sample stacking (LVSS) [92, 93], pH-
mediated stacking [94, 95], and micellar electrokinetic
chromatography (MEKC) stacking [96 – 98]. Some reviews
have been published on sample stacking techniques for a
wide variety of compounds [88, 99 – 108]. Terabe et al.
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
J. Sep. Sci. 2008, 31, 2040 – 2053
Figure 8. Schematic representation of (a): channel design of
the multi-T microfluidic chip and (b): NCE with negative pres-
sure large volume sample injection. SP: Syringe pump, V: 3-
way valve, HV: high-voltage power supply, T: T-shape con-
nector [115].
[109 – 111] developed cation- and anion-selective exhaus-
tive injection-sweeping-micellar electrokinetic chroma-
tography (CSEI-, ASEI-sweeping-MEKC) methods for
increased sensitivity and detection. Britz-McKibbin et al.
[112, 113] designed an on-line focusing method based on
different mobilities of cationic analytes between back-
ground electrolyte (BGE) and sample matrix, which is
called velocity difference-induced focusing (V-DIF). Cong
et al. [114] reported on-line sample pre-concentration
using field amplified stacking injection in NCE. Accord-
ing to the authors, pressure-driven flows into or from the
branch channels, due to bulk velocity, can be used for
liquid transportation in the channels. The detection sen-
sitivity was improved 94-, 108-, and 160-fold for fluores-
cein-5-isothiocyanate, fluorescein disodium, and 5-car-
boxyfluorescein, respectively, relative to a traditional
method. Similarly, Zhang and Yin [115] developed multi-
T microchip integrated field amplified sample stacking
(FASS) coupled with NCE. According to the authors, a
volumetrically defined large sample plug was formed in
one step within 5 s by negative pressure in the headspace
of two sealed sample waste reservoirs. The authors
reported precisions in migration time and RSD as 3.3%
and 1.3% for rhodamine123 (Rh123) and fluorescein
sodium salt, respectively. Schematic representation of
the channel design of a multi-T microfluidic chip and
NCE system with negative pressure large volume sample
injection is shown in Fig. 8.
Jung et al. [116] designed, fabricated, and characterized
a novel field-amplified sample stacking (FASS)-NCE chip
having photo-initiated porous polymer for the analyses
of fluorescein and bodipy. Furthermore, the authors
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Table 1. Applications of hyphenation in sample preparation of different compounds in various matrices.

Compounds Matrices Hyphenation modalities LOD Refs.

Biological matrices
Trazodone Plasma SPE – GC – FID 3 lg/L [118]
Benzodiazepines Plasma SPE – GC – NPD 5 – 25 lg/L [119]
Benzodiazepines Plasma ISP – CGC 0.5 – 2 lg/L [120]
Biogenic amines Cells and culture medium Dialysis – RPLC – fluorescence – 10 fmol/lL [121]
ED
Ciprofloxacin Biological samples Dialysis – RPLC – fluorescence 0.1 nM [122]
Amino acids Beverages and feed stuff Dialysis – RPLC – fluorescence 1 – 278 lg/L [123]
Fluoroquinolones Fortified tissue Dialysis – RPLC – fluorescence 2.5 – 5 ng/g [124]
Sterols Oils and fats LLE – GC – FID 0.04 – 0.08 ng/100 g [125]
Methylenedioxylated amphet- Plasma and serum samples Dialysis – RPLC – fluorescence 10 lL [126]
amines
Clozapine & N-desmethylcloza- Human plasma Dialysis – RPLC – UV 0.050 – 0.055 lmol/L [10]
pine
Verapamil & Norverapamil Human plasma Dialysis – RPLC – fluorescence 5 lg/L [127]
Local anesthetics Plasma SLM – GC 1 lg/L [128]
Ciprofloxacin Biological samples Dialysis – RPLC – fluorescence 0.1 nM [122]
Phenytoin, Carbamazepine & Plasma Dialysis – RPLC – UV 0.1 – 0.8 lg/L [129]
Phenobarbitone
Tramadol Human plasma RAM – MIP – RPLC – fluoresence a10 ng/mL [130]
Arsenic species Urine Dialysis – IC – HGAAS 1.0 – 2.18 lg/L [131]
Ropivacaine & metabolite Plasma Dialysis – lRPLC – MS 0.1 nM [132]
Ropivacaine Urine SLM – IPLC – UV 2 – 18 nM [133]
Phenols Plasma SLM – LC – biosensor 50 lg/L [134]
Meropenem Rat bile Dialysis – lRPLC – UV 0.1 mg/L [135]
Bambuterol Plasma SLM – lRPLC – UV 80 nM [136]
Atrazine mercapturate Urine SPE – RPLC 0.0 5ng/mL [137]
& planar PCBs Biological samples SFE – NPLC – UV a0.3 – 7.4 ng/g [138]
Blood, milk, tissue
N-Methylcarbamates Food PHWE – PRLC – fluorescence 1 lg/mL [139]
Piritramide Human plasma and urine SPE – LC/MS/MS 0.05 ng/mL [140]
Cyproterone acetate Human plasma RAM – RPLC – MS/MS 300 pg/mL [141]
Sugars and organic acids Foods and beverages Dialysis – RPLC – RI 0.6 – 0.41 lg/g [142]
Fluconazole Blood and dermal rat micro- Dialysis – RPLC – UV 0.10 mg/L [143]
dialysates
Bismuth, cadmium & lead Urine SPE – GF – AAS 0.002 – 0.013 ng/mL [144]
Cadmium Biological RM SPE – ICP-AES 0.05 ng/mL [145]

Environmental matrices
Endocrine disruptors Water SPE – GC – MS 0.1 – 20 ng/L [146]
HCH & ethers Water LLE – GC – ECD or FID 20 – 480 pg/L [147]
Organic pollutants Water SPE – GC – ECD 4.1 – 6.3 ng/L [148]
Phenols Water SPE – GC – FID 1 – 27 ng/L [149]
Phenols Water SPE – GC – FID 0.3 – 2 lg/L [150]
OPPs Water SPE – GC – AED 2 – 5 ng/L [151, 152]
Micro contaminants Water SPE – GC – FTIR 100 – 1000 ng/L [153]
Micro contaminants Water SPE – GC – MS 0.2 – 20 ng/L [154, 155]
Pesticides Water LLE – GC – AED 1 – 5 lg/L [156]
Pesticides Water SPE – GC – MS 2 – 20 ng/L [157]
Pesticides Water SPE – GC – MS a1 lg/L [158]
Pesticides Water SPE – RPLC – MS – MS 0.4 – 13 ng/L [159]
Endocrine disruptors Water SPE – GC – MS 0.1 – 20 ng/L [142]
Triazines & OPPs Wastewater SPE – GC – NPD or MS 15 – 25 ng/L (NPD) [160]
1.5 ng/L (MS)
Alkylthio-s-triazineherbicides River water SLM – RPLC – UV 0.03 lg/L [161]
Vinclozolin Water MMLLE – NPLC – UV 1 lg/L [162]
Cationic surfactants Aqueous samples MMLLE – NPLC – UV 0.7 – 5 lg/L [163]
Drugs Water SFE – RPLC – UV – MS 200 ppb [164]
Wine aroma compounds Wine SFE – GC – FID 0.8 – 3.4 lg [165]
Organic compounds Aerosol particles SFE – NPLC – GC – MS 0.02 – 0.04 ng/m3 [166]
Organic acids Aerosol particles SFE – NPLC – GC – MS 0.4 ng/m3 [167]

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2050 I. Ali et al. J. Sep. Sci. 2008, 31, 2040 – 2053

Table 1. Continued

Compounds Matrices Hyphenation modalities LOD Refs.

PAHs Aerosol particles SFE – NPLC – GC – MS 0.02 – 0.04 ng/m3 [168]

PAHs Soil and sediment PHWE – MMLLE – GC – FID 0.65 – 1.66 lg/g [169]
PAHs Soil and sediment PHWE – MMLLE – GC – FID 0.11 – 1.22 lg/g [170]
PAHs Sediment PHWE – NPLC – GC – FID 0.01 lg/g [171]
PAHs Sediment SFE – GC – MS a0.2 lg/g [172]
PAHs Soil SFE – RPLC – UV 0.2 – 4 ng [173]
Brominated flame Sediment PHWE – NPLC – GC – FID 0.70 – 1.41 ng/g [174]
Retardants
Organophosphorus esters Air particulates DMAE – SPE – GC – NPD 90.9 – 186.2 pg/m3 [175]
Organophosphorus Air particulates DSAE – SPE – GC – NPD 0.1 ng/m3 [176]
Esters
Sulfonamide antibiotics & pesti- Natural water SPE – RPLC – MS/MS 0.5 – 5 ng/L [177]
cides
Hexavalent chromium Colourants Dialysis – IC – UV 5 lg/L [178]
Explosives Filters SFE – RPLC – UV 9.5 – 56.8 ng/filter [179]
Selenium Cu alloys, Ni sponge SPE – AAS 0.2 ng/mL [180]
Cadmium SRM river water SPE – GF – AAS 2610 – 4 ng/mL [181]
Cr(III) & Cr(VI) Fresh water SPE – ICP-AES 0.02 – 0.04 ng/mL [78]
As(III) & As(V) Fresh water SPE – ICP-AES 0.1 ng/mL [79]
Cr(III) & Cr(VI) River water SPE – ICP-AES 0.08 – 0.15 ng/mL [80]
Tap water
Wastewater
Cadmium Seawater SPE – ICP-AES 0.05 ng/mL [146]
Trace metal Seawater and river water SPE – ICP-AES 0.001 – 0.2 ng/mL [182]

described a 1000-fold signal increase during detection. 5 References

This polymer material provided a region of high flow
resistance, which allowed electromigration of sample
ions resulting in pre-concentration. Lichtenberg et al.
[117] developed a microchip device for field amplifica-
tion stacking (FAS), which allowed the formation of com-
paratively long, volumetrically defined sample plugs
with a minimal NCE bias. The authors studied fluidic
effects; arising from solutions with mismatched ionic
strengths, in chip-based electrokinetically. Furthermore,
these authors developed a new chip layout for full col-
umn stacking with subsequent sample matrix removal
by polarity switching. Some important hyphenation
examples are given in Table 1.
4 Concluding remarks
In the present scenario of separation science advance-
ment, hyphenation is continuously gaining importance
for the determination of analytes at micro or lower con-
centration levels. This technique is more useful in biolog-
ical samples where the volumes of matrices are low, e. g.
blood of infants, cerebrospinal fluid, DNA, and other hor-
mone and enzyme samples. It has been observed that the
development of hyphenation techniques is not yet com-
plete and is still progressing. Briefly, the art of hyphena-
tion in separation science will be in great demand during
the present century.
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