Talanta xx (xxxx) xxxx–xxxx

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Talanta
journal homepage: www.elsevier.com/locate/talanta

Recent progress, challenges and trends in trace determination of drug

analysis using molecularly imprinted solid-phase microextraction
technology
⁎
Saeedeh Ansaria, , Majid Karimib
a
Department of Chemistry, Saveh Branch, Islamic Azad University, Saveh, Iran
b
Department of Materials Science and Engineering, K.N. Toosi University of Technology, Tehran, Iran

A R T I C L E I N F O A BS T RAC T

Keywords: The quantification of drugs in biological samples is a significant task for determination of the physiological
Drug analysis efficiency in evaluated drugs in the drug discovery. To analysis of the chemical compounds at the trace and
In-tube MIP-SPME fiber ultratrace levels, adequate analytical procedures should be applied. Therefore, sample preparation method
Molecularly imprinted polymer undoubtedly is the most important stage in the trace determination process. In spite of the great growth of
Monolithic MIP-SPME fiber
analytical instrumentation during the recent years, sample preparation is still nowadays considered the impasse
Sol-gel MIP-coated SPME fiber
of the all analytical procedure, especially in drugs analysis. Because of the low concentration level of drugs in
Solid-phase microextraction
blood, plasma, and the diversity of the metabolites, the chosen extraction technique should be almost perfect.
Solid-phase microextraction (SPME) is a powerful, simple, fast and an equilibrium-based sample preparation
method that permits integration of sampling, sample clean-up, and pre-concentration in a single solvent-free
step for chemical analysis. Molecularly imprinted polymers (MIPs) that provided by the presence of a template
during their synthesis are the stable polymers with molecular recognition abilities and excellent materials which
provide selectivity to sample preparation. Because of its characteristics such as easy preparation, high
selectivity, and chemical stability, MIP is widely utilized in many analytical fields. Accordingly, the molecular
imprinting and SPME methods combination would prepare a strong analytical instrumentation which
comprises simplicity, flexibility, and the selectivity characteristics of both methods. This review focuses on
the application of solid-phase microextraction method coupled with molecularly imprinted polymers, namely
molecularly imprinted solid-phase microextraction (MISPME), for trace determination in drug analysis.

1. Introduction the picograms or below levels, can be accomplished by the analytical

instrumentations. However, if an inappropriate sample preparation
Nowadays, a high-resolution separation and low detection limits, in method has been used before the injection, the all of the advanced

Abbreviations: AA, Ascorbic Acid; AAS, Anabolic steroids; ABA, Abacavir; BPA, Bisphenol A; CCD, Central composite design; CE, Capillary electrophoresis; CGA, Chlorogenic
acid; CGC, Capillary gas chromatography; CMIP, Conducting molecularly-imprinted polymer; CNT, Carbon nanotube; CW-DVB, Carbowax and polydivinylbenzene; DA, Dopamine;
DFC, Diclofenac; DMF, Dimethylformamide; DMSO, Dimethyl sulfoxide; DPASV, Differential pulse anodic stripping voltammetry; DPCSV, Differential pulse cathodic stripping
voltammetry; DVB, Divinylbenzene; EE-SPME, Electrochemical solid-phase micro extraction; EGDMA, Ethylene glycol dimethacrylate; FA, Folic acid; FID, Flame ionization
detector; FQ, Fluoroquinolone antibiotic; GC, Gas chromatography; GC-MS, Gas chromatography-mass spectrometry; HF-LPME, Hollow fibers liquid phase microextraction; HPLC,
High-performance liquid chromatography; HPLC/FD, High-performance liquid chromatography analysis with fluorescence detection; HPLC/PAD, High-performance liquid
chromatography with photodiode-array detector; HPLC/UV, High performance liquid chromatography analysis with UV detection; HPTLC, High performance thin layer
chromatography; In-tube SPME, In-tube solid-phase microextraction; LC-MS, Liquid chromatography-mass spectrometry; LLE, Liquid–liquid extraction; LOD, Limit of detection;
LOQ, Limit of quantification; LPME, Liquid phase microextraction; MAA, Methacrylic acid; MAMP, Methamphetamine; MEPS, microextraction packed sorbent; MIMSPE,
Molecularly-imprinted micro-solid-phase extraction; MIP, Molecularly-imprinted polymer; MIPMME, Molecularly imprinted polymer monolith microextraction; MISPME,
Molecularly Imprinted Solid-Phase Microextraction; MTMOS, Methyltrime-thoxysilane; MWCNTs, Multi-walled carbon nanotubes; OFL, Ofloxacin; OPPy, Overoxidized polypyrrole;
PA, Polyacrylate; PAD, Photodiode array detector; PDMS, Polydimethylsiloxane; PDMS-DVB, Polydimethylsiloxane and poly(divinylbenzene); PEEK, polyetheretherketone;
PMMA, Polymethyl methacrylic acid; ppb, Parts per billion; PPPY, Poly-N-phenylpyrrole; PPy, Polypyrrole; PVC, Poly (vinylchloride); RSM, Response surface methodology; SA,
Salicylate; SBSE, stir-bar sorptive extraction; SEMs, Scanning electron micrographs; SLM, Supported liquid membrane; SMO, Sulfamethoxazole; SMT, Sulfamethazine; SPE, Solid-
phase extraction; SPME, Solid-phase microextraction; SSF, Stainless steel fiber; TAOS, Tetraalkoxysilane; TAP, Thiamphenicol; TBZ, Thiabendazole; TCs, Tetracyclines; TRIM,
Trimethacrylate; UV, Ultraviolet-visible spectroscopy
⁎
Corresponding author.
E-mail address: ansarisaeedeh@gmail.com (S. Ansari).

http://dx.doi.org/10.1016/j.talanta.2016.11.007
Received 29 September 2016; Received in revised form 3 November 2016; Accepted 4 November 2016
Available online xxxx
0039-9140/ © 2016 Elsevier B.V. All rights reserved.

Please cite this article as: Ansari, S., Talanta (2016), http://dx.doi.org/10.1016/j.talanta.2016.11.007
S. Ansari, M. Karimi
analytical processes can be impaired. So, sample preparation acts a
crucially important role in the analytical procedures especially in drugs
analysis which is the theme of our discussion. The sample preparation
has many different roles such as the elimination of interferences and
preconcentration of the analyte, converting the analytes to appropriate
form for separation and detection. Because of the low concentration
levels of drugs in plasma and the variety of the metabolites, the selected
extraction technique should be virtually exhaustive [1].
Till now, several methods for the quantification of drugs in
pharmaceutical preparations [2,3] and in biological samples [4,5] have
been described utilizing HPLC with UV detection [6,7], fluorescence
detection [8], liquid chromatography-mass spectrometry [9,10],
HPTLC [11], spectrofluorometric [8] and densitometric methods
[11]. In the complex matrices, a sample pretreatment process requires
for determination of organic pollutants that presenting at trace levels.
Solid-phase extraction (SPE) [12] and liquid-liquid extraction (LLE)
[13] were often applied historically for the separation of analytes from
aqueous matrices. However, some defects are coupled with LLE such as
generally labor-intensive, time-consuming, and needs large quantities
of expensive, toxic and environmentally unfriendly organic solvents
which often combined with environmental and health risks. Also, SPE
requires less solvent but still needs multiple steps and additionally, the
enrichment performance of SPE is comparatively low. Accordingly,
these methods cannot be used in low concentration levels of analytes
and complex matrices [14,15]. Nowadays, novel sample-preparation
procedures are likely to play a significant role in sample pretreatment
of analytical chemistry which has many advantages compare to
conventional methods such as removing of additional sample clean-
up and concentration stages before chromatographic analysis, reduc-
tion in organic-solvent consumption and in sample degradation, and
enhancement in extraction performance and selectivity. Usually, a
favored sample pretreatment process includes three main purposes:
1. Sample matrix simplification;
2. Analyte enhancement or concentration; and,
3. Sample clean-up [16].
Therefore, because of using either no or very little amounts of toxic
organic solvents, the simplification and miniaturization of sample
preparation methods are recommended. In recent years, the solid
phase microextraction (SPME) technique is one of the most favorite
and applicable techniques for sample preparation in the green analy-
tical chemistry. Since its introduction by Arthur and Pawliszyn in 1990
[17], many researchers worldwide has been utilized and performed this
technique regarding its rapid development, basic understanding,
development of instruments and novel applications. Hence SPME
becomes widely used in many various fields such as environmental
analysis [18,19], food analysis [20–22], bioanalysis [23–25], drug
monitoring [26], pharmaceutical samples [27,28] and toxicology [29].
Also, SPME has been used in coupled with various instrumental
analytical procedures, especially high-performance liquid chromato-
graphy (HPLC) and gas chromatography (GC) to determine trace levels
of analytes from samples. This popularity of SPME can be due to its
enormous advantages such as solvent-free nature, possibility of full
automation, operation simplicity, relatively short extraction time, and
easy coupling with chromatography (such as GC), all of which reduce
contamination of the original sample and loss of analytes [16].
The SPME procedure is based on the partitioning of the analytes
among the sample and the coating. The coating that uses in the SPME
is fixed on the surface of a metal wire or a fused silica fiber. So, to
obtain high extraction performance, an excellent material for coating
acts a very important role. Until now, several SPME coating materials
have been commercially used, including polydimethylsiloxane (PDMS),
carboxen/PDMS, PDMS/divinylbenzene (DVB), polyacrylate (PA),
carbowax/DVB and carbowax/templated resin [30]. In addition, sev-
eral new laboratory techniques such as physical and vapor deposition
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technology, sol-gel technology, and electrochemical procedure, have
been investigated to made applicable SPME fibers. In some applica-
tions of real sample analysis, these laboratory-made coated fibers have
been successfully exerted which is because of their high extraction
capacity and good analytical precision. However, with all of these
mentioned advantages, the lack of selectivity of these laboratory-made
coated fibers is the initial drawback associated during the extraction of
target analytes. Due to their unsatisfactory selectivity, these traditional
coatings usually cannot efficiently extract analytes in complex biologi-
cal or environmental samples [15].
Based on recent studies, molecularly imprinted polymers (MIPs)
have many prominent advantages such as stability, recognition ability,
simplicity and low cost of preparation and also potential application to
a wide range of target molecules. Due to their practical features, MIPs
have possessed much consideration in the separation and extraction
field of analytical chemistry. The selectivity of MIPs has been used in
several applications, such as sensors [31,32], capillary electrochroma-
tography [33,34], enantiomeric separations [35], SPE [36–38] and
catalysis [39,40]. One of the most promising technical applications
which is a very advanced methodology that solves the drawback of
selectivity of the coatings [41,42] and is used many recently, has been
molecularly imprinted solid-phase microextraction (MISPME). Thus
far to our knowledge, the MISPME technology with all of these
mentioned advantages has not been reviewed especially in the drugs
analysis.
In this article, we review several configurations of MISPME
techniques that were applied in drugs and pharmaceutical sample
analysis, which can be improved the analysis process more sensitive,
more selective, and more environment-friendly. These techniques
include MIPs as SPME-fiber coatings (MIP-coated SPME fiber), MIPs
and in-tube SPME (MIP in-tube SPME), monolithic MIP fiber for
SPME (monolithic MIP-SPME fiber), sol-gel MIP and SPME (sol-gel
MIP-SPME fiber), membrane MIPs and SPME and Other MIP-SPME
techniques that used for drug analysis. These methods were accoun-
table for extracting the most of the analytes from the sample matrix
before the analysis based on the partition or adsorption of analytes. We
are discussed on brief descriptions of advantages and capabilities of
each modern extraction technique, and how these techniques could
improve the absorption and extraction for a variety of analytes.
2. Molecularly-imprinted polymers
MIPs are the newly synthesized polymers that can be used for the
selective extraction of selected molecules. These new synthetic poly-
meric materials, display high selectivity and binding capacity toward a
target molecule that purposely participates in the synthesis process.
They have high chemical, mechanical, and thermal stabilities. Because
of these applicable advantages, MIPs are used for the separation or
detection of many compounds in different applications in the analytical
chemistry. They are also applied in catalysis and organic synthesis.
However, MIPs have a great potential in the drug delivery, where they
could be used as new and selective drug dosage forms [43].
Applications of the MIPs in sample preparation techniques are
illustrated in Fig. 1.
2.1. Synthesis of MIPs
The primary polymerized materials in the production of a MIP
included the functional monomer, the cross-linking agent, and the
template molecule. Because of its task in the pendent of the functional
groups to the functional monomers, the template molecule acts an
important role in all molecular imprinting processes. So, the subse-
quent properties of the binding sites are dependent on the structure
and functionalities of this molecule. The ability criteria of the template
molecule to interact strongly with monomers was defined when
candidate molecule features comprises its cost, availability, and the
S. Ansari, M. Karimi
Fig. 1. Applications of molecularly imprinted polymers (MIPs) in sample preparation methods. Reprinted from Handbook of Molecularly Imprinted Polymers, chapter 3, Molecularly
Imprinted Polymers for Sample Preparation, A.M. Carro-Diaz and R.A. Lorenzo-Ferreira, Fig. 3.1, page 89.
chemical functionalities to be considered. To obtain the highest
efficiency of the MIPs toward the target analyte in the analysis, precise
selection of the functional monomers utilized in the MIP production is
very important. There are many various commercially available func-
tional monomers such as methacrylic acid (MAA) and 4-vinylpyridine
(4-VP) that have been most widely used in the different polymerization
techniques. The third component in the in the synthesis of a MIP is the
cross-linking agent that has significant tasks in the polymerization
techniques such as stabilize the molecular recognition site, deliver
mechanical stability, and control the porosity of the polymer. Many of
commercially available cross-linkers are compatible with molecular
imprinting and also a few of which simultaneously have ability to
complexing with the template, so play the functional monomers role. In
the many polymerization techniques, ethylene glycol dimethacrylate
(EGDMA) and trimethylolpropane trimethacrylate (TRIM) are the
most widely used materials as a cross-linking agent.
The synthesis of MIPs includes three main steps. In the first step, a
prepolymerization complex creates between a template molecule (an
imprinted compound) and a selected functional monomer(s). Then, in
the next step, the prepolymerization complex is crosslinked with a
compatible cross-linking agent during the polymerization process, and
in the last stage, the template is removed from the polymeric matrix
with leaving the well-defined three dimensional cavities [44]. The
selective uptake of analyte in the sample was allowed when the
template molecules removed by chemical reaction or extraction pro-
cess, and the created binding sites in size, shape and position of the
functional groups are supplementary similar to the template. The
scheme of the imprinting process is shown in Fig. 2.
2.2. Polymerization techniques
The molecular imprinting process allows the creation of selective
and specific binding sites that are similar to a goal template in chemical
and steric properties. The MIP can be recognized the template or a
derivative thereof as a target. MIPs can be synthesized using three
various imprinting processes (Fig. 2): the “covalent”, the “non-cova-
lent” and “semi-covalent” approaches.
1. The covalent procedure needs the formation of covalent bonds
among the template and the functional monomer before the poly-
merization process. The elimination step of the template from the
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polymer matrix after synthesis comprises with the covalent bonds
cleavage. In the last step, the synthesized polymer treated with
reagents in solution or is refluxed in a Soxhlet extraction.
2. The non-covalent protocol, which is the most widely used due to
relatively simple practically and complexation step during the
synthesis, is obtained by mixing the template with an suitable
functional monomer(s), in an appropriate porogen solvent. The
template molecules are depleted from the synthesized polymer
matrix by a washing solvent or a mixture of solvents. Then, the
rebinding process of the template was performed by non-covalent
interactions.
3. The semi-covalent technique is a mixture of the two prior methods.
So, before polymerization, the interactions among the template and
the functional monomers are established with the covalent bonds,
and after the removing step of the template from the polymer
matrix, the subsequent re-binding of the analyte to the MIP exploits
non-covalent interactions, as the non-covalent imprinting protocol.
The main drawback of the covalent bond is in the fact that the
template and the monomers in the molecular imprinting process must
be easy to form and break by a reversible reaction. Unfortunately, there
are not many reactions with this specific property to satisfy this
purpose. This is why a second approach has been used which is proper
to the association between functional monomers and template via non-
covalent interactions such as hydrogen bonding, ionic interactions, van
der Waals forces, π-π stacking, and metal coordination. Compared to
the covalent approach, non-covalent imprinting is more versatile and
enables the imprinting of a wider range of compounds, although the
weaker interactions involved, based mostly on equilibria, are respon-
sible for a more heterogeneous distribution of binding site structures
and affinities [45]. Also, some important advantages of both mentioned
techniques such as the high stability of the template and functional
monomers during the imprinting process and the fast interactions
creation during the recognition of the target are achieved in the “semi-
covalent” approach.
3. Solid-phase microextraction technique
SPME is one of the most widely-used sorptive-based extraction and
sample-preparation techniques for liquid and gas samples. In this
procedure the sample is placed in contact with an appropriate material
S. Ansari, M. Karimi
Fig. 2. A scheme for synthesis and imprinting process of molecularly imprinted polymer. Reproduced with permission [45].
and in this condition, various materials availability to perform the
extraction process is very vital. Usually, in this method, a thin polymer
film coating on a fiber or metal wire utilizes to extract analytes from
gaseous or aqueous samples. In spite the other separation techniques,
several procedure steps such as sampling, preconcentration, extraction,
and sample introduction in SPME can merge all in a single step which
is a great advantage. Also, the SPME technique has many other
advantages such as simplicity, solvent-free, inexpensive, fast, easily
automated and reliable which also can be applied with good selectivity
and excellent sensitivity for both direct aqueous and headspace sample
analysis. Nowadays, because of the fast development of new practical
configurations, improvement of instrumentation and automatic de-
vices, and also innovation and introduction of new polymeric fibers, the
SPME technique undoubtedly can be used in many different fields of
chemical analysis. The type and the thickness of the stationary phase
and also other parameters of the process such as fiber exposure time,
sample volume and temperature, sample stirring, and extraction vial
volume determine the efficiency of the preconcentration. Also, many
different and applicable materials for the coating fibers has been used
include polydimethylsiloxane (PDMS), polyacrylate (PA), also mixtures
of polydimethylsiloxane and poly (divinylbenzene) (PDMS-DVB),
Carbowax and polydivinylbenzene (CW-DVB), Carbowax and molecu-
larly-imprinted resin (CW-TPR) [30,46]. The first polymer that used
for SPME was the non-polar PDMS and till now this coating is most
applied for the extracting only non-polar analytes very well. Usually,
with the consideration of this fact that “like dissolving like”, can be said
those polar coatings such as CW-DVB or PA most probably extract the
polar compounds. But sometimes there are some drawbacks such as
the CW-DVB fiber is forcefully polar coating and its maximum
temperature is only 265 °C, which limits the application range.
Moreover, silica fibers are fragile and must be handled with great care,
so more robust SPME fibers with long life and relatively low cost are
highly desirable [47]. In the two past decades, different separation
methods such as capillary gas chromatography (CGC) [48,49], GC/GC-
MS [50,51], LC/LC-MS [52,53], GC-ICP-MS [54], and a combined
HPLC-UV and HPLC-MS method [55,56] have been coupled with the
SPME as a sample preparation technique for drug analysis.
3.1. Principle of SPME
In SPME procedure, to concentrate and isolate analytes into a range
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of coating materials, the coated fibers are utilized. After extraction
process, by the help of the syringe-like handling instrument, the fibers
are transmitted to the analytical devices for the quantification and
separation of the target analytes. The sample collecting procedure is
illustrated in Fig. 3. The establishment of equilibrium among the
sample matrix and the analyte and a partition mechanism are the
principals of the SPME. The distribution constant, K, for equilibrium
[57] is defined by:
K = C f /Cs (1)
In the above equation, Cf and CS are the equilibrium concentrations
of the analyte in the fiber and the sample, respectively. Eq. (1) explains
that the extracted quantity is constant within the limits of experimental
error after the establishment of equilibrium. Also, with a finite volume
of the sample, Eq. (1) can be represented as:
KVf VC
s 0
n=
KVf + Vs (2)
where n, C0, Vf, and VS are the analyte extracted quantity, the primary
concentration of given analyte in the sample, the volume of the fiber
coating and the sample volume, respectively. A proportional relation-
ship among the analyte concentration in the sample and the quantity
extracted using the coated fiber has been shown in the Eq. (2), which is
the foundation for analyte determination. When the distribution
constant is very large, i.e., KVf ≫ VS, the equation can be expressed as:
n = VC
s 0 (3)
Eq. (3) illustrates that the adsorbed analyte quantity is directly
related to the volume of the sample and the initial concentration of the
analyte with finite sample volume. In the field sampling, the sample
volume is very large and VS ≫ KVf. Therefore, n can be written as:
n = KVf C 0 (4)
Eq. (4) demonstrates that the extracted quantity by fiber is directly
dependent on the volume of the coating fiber and also the concentra-
tion of the analyte, but is not related to the volume of the sample. So,
the analyte concentration in the sample matrix will effect directly on
the extracted amount.
S. Ansari, M. Karimi
Fig. 3. Procedure for collecting the sample using SPME. Reproduced with permission [15].
3.2. Preparation of SPME coating
Since its presentation in the early 1990s, SPME has been widely
investigated and has found many applications. This is due to the large
variety and availability of the sorbents and coatings and also because of
the SPME solventless nature. For a predetermined amount of time, a
small quantity of extracting phase is placed in contact with the sample
matrix or headspace above it in common SPME techniques.
Accordingly, a stationary phase extracts the analyte(s) from a gaseous,
aqueous, or headspace in the solid or liquid sample conditions. The
stationary phases are usually coated on various surfaces or mostly can
be packed geometrically inside the different instruments such as tubes,
needles or syringe tips. While the flexibility of the SPME instrument
geometry has an intrinsic task in the diverse applications of this
method, the extraction of analytes is the coating type of the SPME
fibers responsibility. Therefore, various coating methods have been
used to development coating kinds in the reproducible and commer-
cially appropriate SPME instruments. There are several options as
coating techniques based on the sorbent kind such as sol-gel technol-
ogy, electrochemical processes, dipping and physical deposition tech-
niques, chemical grafting, liquid-phase deposition (LPD), electrospin-
ning, and hydrothermal method. Some of these methods were ex-
plained in the following.
3.2.1. Sol-gel technology
Sol-gel technology is one the best SPME fiber coating preparation
method because of its intrinsic efficiency and advantages such as
material homogeneity at the molecular level, high solvent and thermal
stability, single-step manufacturing procedure, chemical bonding
among the fused-silica surface and the sorbent, and the porous
structure of the mixed material. To improve the performance of
traditional fibers, Chong et al. [58] introduced the first sol-gel-based
SPME fibers. For preparing the chemically bonded PDMS fiber, they
applied methyltrime-thoxysilane (MTMOS) as a precursor. The expla-
nation of that the originating of the sol-gel network was from an alkyl
derivative of tetraalkoxysilane (TAOS) precursor possesses with a more
open structure which can effectively minimize the stress during drying
and cracking, introduced by Mark [59]. Since then, sol-gel technology
as a fast developing field is used to prepare SPME fibers and so many
researchers [60,61] has been researched on the preparation of un-
breakable sol-gel fibers. In 2006, Azenha and co-workers [62] fabri-
cated the first unbreakable SPME fiber. With the usage of a new,
unbreakable titanium wire as a substrate, they demonstrated that Ti-O-
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Si bonds can be formed by the hydrosilanes can alkoxysilanes under
appropriate conditions. In recent years, to obtain fibers with different
characteristics, several studies were performed using different coating
modifiers and polymers [63–65].
3.2.2. Electrochemical procedure
Another way that can be an alternative to deposit coatings on SPME
fibers is electrochemical procedures. In this technique, the main idea is
the coating the metal fiber as an SPME instrument a conducting
polymer, and cyclic voltammetry (CV) or potentiometry which usually
use for this purpose. The reduced or oxidized forms of the fiber
coatings can be obtained from these inexpensive techniques. The first
study on the electrochemical procedures was performed by Wu et al.
[66]. The SPME fiber coating on platinum was performed with the
poly-N-phenylpyrrole (PPPY) and the prepared polypyrrole (PPy) films
by this group. Since then, PPy and its derivatives have attracted great
interest in the development of these procedures [66–68]. Nowadays,
with the consideration of these applicable results, the matrix separation
and the preconcentration of anionic [69], cationic [70] and neutral
analytes [71] are carried normally out by these electrochemically
controlled SPME fibers.
3.2.3. Physical deposition
In spite other techniques, immerse the fiber into a polymer
solution, and then stabilize it with conditioning or heating, is one of
the simplest and quickest processes to coating an SPME fiber that is
called physical deposition. An alumina-based SPME fiber using poly
(vinylchloride) (PVC) and alumina powder at the optimum ratio of
97:3, constructed by Farajzadeh and Rahmani [72]. Subsequently, the
first multi-walled carbon nanotubes (MWCNTs) as SPME fiber coating,
was prepared by Wang et al. [73]. They dispersed the MWCNTs in
dimethylformamide (DMF) as suspension and then dipped the fiber
into the suspension and in the last step heated at 1608 °C to remove the
solvent. Recently, a novel graphene (G)-based SPME fiber prepared by
Chen et al. [74] and the synthesized G coated on a stainless steel wire
by immobilizing, which successfully used to the determination of
pyrethroids.
4. MISPME procedures
4.1. MIPs as SPME-fiber coatings
As mentioned, the extraction phases applied to SPME fibers have
S. Ansari, M. Karimi Talanta xx (xxxx) xxxx–xxxx

first report on the manufacturing of an SPME fiber obtained through

photo-polymerization [under ultraviolet (UV) irradiation] of a pre-
polymer solution on the surface of the silylated anodized aluminum
wire, to achieve a chemically bonded coating with ametryn-imprinted
polymer introduced by Djozan et al. [77]. For this target, the pre-
polymer MIP solution was sprayed by laboratory-made pneumatic
sprayer onto the surface of anodized-silylated aluminum wires to
coating them with MIPs. A porous Al2O3 layer with the high surface
area which changes to hydroxyl groups with sodium hydroxide created
using the anodizing technique. These groups have the substitution
reaction capability with methoxy which leads to fabrication of more
Fig. 4. Schematic representation of MIP-coated fiber of MISPME. Reproduced with
stable and effective fiber. Then, a GC and GC-MS injection port can
permission [15].
directly determine the results and also photochemical polymerization
carried out under UV irradiation. In the selectivity study of the
the most considerable influence on extraction performance. Hence,
prepared aluminum coated fiber, high selectivity for triazine com-
many various applications can be executable for SPME using changing
pounds obtained but for unrelated compounds, these parameters was
the extraction phase. Because of many drawbacks such as cost,
very low. Also, real samples such as spiked tap water, maize, rice, and
challenges in synthesizing fibers, chemical or thermal instability, and
onion used to the reliability of the fabricated fiber evaluation. Finally,
inappropriate analytes selectivity from using commercial SPME fibers,
for investigated analytes (i.e. simazine, atrazine, propazine, prometryn,
the advent of MIP-SPME fibers solved many of these problems. MIP-
terbutryn, ametryn, and cyanazine), high extraction performance with
SPME fibers are usually synthesized easily with low cost, but they are
high quantities of recoveries and low detection limits obtained by using
rigid and perform selectively towards the specific analyte. In this
this method.
strategy, MIP particles placed on a thin fused silica fiber using coating
Subsequently, the lack of selective recognition of target analytes in
process and the MIP-coated fiber is performed as an SPME fiber to use
aqueous samples was one of the well-known drawbacks of MISPME
in a sample pretreatment technique. Schematic representation of MIP-
procedure which Barahona et al. [78] introduced an organic supported
coated fiber in MISPME procedure is shown in Fig. 4.
liquid membrane (SLM)-protected MISPME technique. In this work,
Hu et al. [75] obtained a MIP-coated SPME fiber with tetracycline
the prepared MIP-coated fibers placed inside a polypropylene hollow
(TCs) as a template using multiple co-polymerization method to
capillary and preserved by immobilizing an organic solvent as a thin
development of the applicability and the selectivity of the SPME
SLM in the capillary wall holes. MIPs demean as a sorbent of reversed-
technique. In this study, a MIP-coated SPME method coupled with
phase and therefore both some of the matrix components and target
HPLC was developed for the fluorimetric determination of four TCs.
analytes can be maintained trough non-specific interactions. So, a
The prepared fibers had many advantages such as porous, highly
washing solvent able to eliminate matrix components and to re-
crosslinked, homogeneous, and were appropriate for the simultaneous
distribute non-specifically bound analytes to the selective imprints
multi-analytes analysis of trace tetracycline, oxytetracycline, doxycy-
utilized. However, the success of such a technique was not always
cline, and chlortetracycline in complex samples. The stability of the
guaranteed. The extraction technique includes two concurrent pro-
extraction quality even after more than 100 experiments was one of the
cesses: liquid phase microextraction (LPME) using polypropylene
most important and applicable advantages of this prepared fiber
hollow fibers (HF-LPME) of the analytes from the sample to an organic
coating. These results illustrated that tetracycline MIP-coated fibers
acceptor solution through an SLM; and SPME procedure of the
attracted the specific selectivity to TCs samples and the used MIP-
analytes from the organic acceptor solution to a MIP-coated fiber
coated SPME-HPLC method could be developed successfully the
inside the polypropylene capillary.
sensitivities of TCs determination. Another significant advantage of
In consideration of the prior investigation results and to develop the
this proposed method was the quickly adsorption and desorption
selectivity and extraction performance of MISPME fibers with using
process of TCs with the introduced MIP-coated fiber. The optimized
molecularly imprinted PPy and its derivatives as conductive polymers
extraction circumstances such as desorption and extraction solvent and
for the extraction phase, Ameli and Alizadeh [79] improved over-
the stirring speed were also studied.
oxidized polypyrrole (OPPy) films templated with salicylate (SA) as an
To selective extraction and analysis of anabolic steroids with a
electrochemically controlled MISPME called CMIPs for SPME. This
testosterone-imprinted polymer and a selective, physically and chemi-
group introduced the electrodes, which were electrochemically coated
cally robust SPME fiber, Qiu and Liu [76] developed a simple way using
with OPPy films of salicylate-MIP. The prepared CMIP film good
a thermal radical co-polymerization technique which directly coupled
selectivity and extraction ability were due to its supplementary
with gas chromatography-mass spectrometry (GC-MS). The author
structure of the cavities which made during over oxidation. The
group evaluated the parameters of the method extraction efficiency
proposed EC-SPME and the OPPy film as the SPME absorbent was
which obtained via MIP-coated SPME fibers such as extraction ability
useful in constructing simple instruments for the quantification and
and selectivity towards anabolic steroids by electrostatic forces in polar
selective cleanup of salicylate in the physiological samples such as
solvents. In this study, similar to the previous research, the prepared
human serum and urine, probably because of the applicable advantages
fiber was porous, homogeneous, and chemically and physically stable
such as easy preparation and very simple instrumentation.
which the proposed MIP-coated SPME-GC-MS procedure could be
Over time, because of the sufficient enough, rapid, and reproducible
developed the sensitivity of anabolic steroids determination. In addi-
features in simultaneous preconcentration and clean-up of biological
tion, the accuracy of mentioned method in the extraction recoveries of
fluids, the application of MIPs as a sorbent for the MIP-coated SPME
the anabolic steroids analysis in spiked human urine samples and also
procedure became one of the significant tasks of the MIP particles. So,
in the intra-day experiments were much acceptable. Fig. 5A show the
by templated linezolid molecule, Szultka et al. [80] prepared molecu-
SEM image of prepared MIP-coated SPME fiber.
larly imprinted polymer coated fibers for solid-phase microextraction.
In considering to significant drawbacks such as fragility and short
The electrochemical polymerization process used to the preparation of
lifetime of the fused silica fibers that used as the support material, the
the poly-(3-methylthiophene), polythiophene, and polypyrrole coat-
enhancement of MISPME procedures could be restricted; but using of
ings. This group applied the molecularly imprinted coatings with a
metal wires via high mechanical stability as fiber supports, makes this
reproducible and stable response to biological samples analysis. The
technique more robust and more applicable for different analysis. The
experimental outcomes about prepared molecularly imprinted SPME

6
S. Ansari, M. Karimi
Fig. 5. SEMs of several MIP-SPME fibers prepared by: (A) Qiu et al. [76] with MIP-coated SPME method; (B) Hu et al. [87] with in-tube MIP-SPME method; (C) Hashemi-Moghaddam
et al. [95] with monolithic MIP-SPME method; (D) Saraji et al. [98] with sol-gel MIP-coated SPME method.
coatings showed a high selectivity toward linezolid. Also, the MIP-
coated SPME methodology followed by HPLC with UV and MS was
easy and had many advantages such as reliability and sensitivity at the
trace level, which also requiring a low sample volume, and seems to be
a good analytical alternative to routine quality control for biomedical
analysis. The biological samples that were used in this study for
preconcentration and isolation investigation included new types of
biological samples such as acellular and protein-free simulated body
fluid and also human plasma samples. The results showed that for the
selective extraction of antibiotic drugs in the new types of biological
samples, the SPME MIP-coated fibers were appropriate.
Subsequently, in the similar work, Amiri Pebdani et al. [81] used
successfully molecularly imprinted polymer sorbent in the hollow fiber
in a simple MIP-HF-SPME procedure coupled with the fiber optic-
linear array spectrophotometer for the quantification and extraction of
diclofenac in the different types of biological and environmental
samples such as water, urine, and plasma. Also, the accuracy of this
method examined by this group through the recovery experiments.
Many important and applicable features such as simplicity, selectivity,
and high extraction recovery created by the combination of the HF-
SPME technique and prepared molecularly imprinted sorbent.
Recently, a new type of temperature-sensitive MIP particles
synthesized for the SPME coating using ofloxacin (OFL) as template
molecules. With the temperature-sensitive MIP particles, using differ-
ent temperatures, both of the adsorption and desorption steps could be
faster. Zhao et al. [82] used Dopamine for self-polymerize on stainless
steel fiber (SSF) as the SPME support followed by silanization. Then,
with using of methacrylic acid as functional monomer and N-isopropyl
acrylamide as temperature sensitive monomer, MIP particles synthe-
sized as SPME coating on the modified SSF in a capillary. The synthesis
could be well repeated with multiple capillaries putting in the same
reaction solution. Finally, the prepared MIP fiber applied to extract
OFL from milk with satisfied recoveries.
Mirzajani and Kardani [83] developed the thermal stability of the
MIP-coated SPME fibers. The author’s group prepared a novel MIP
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fiber coating on stainless steel wire templated by ciprofloxacin mole-
cules which had excellent thermal and mechanical stability and also
long lifetime. The prepared fiber used MISPME-HPLC/UV technique
for extraction of fluoroquinolones (FQs) from pharmaceutical and
biological fluids samples. The fabricated fibers in this investigation
had many significant advantages such as high thermal stability (up to
300 °C), long lifespan, good reproducibility, great extraction perfor-
mance, and high selectivity for FQs in biological samples; also these
newly introduced fibers were inexpensive and stable, and nevertheless,
the repeatability of these fibers without decreasing in the extraction
recoveries was satisfactorily high and they were easily prepared. Other
applicable advantages of the proposed method were using a small
volume of sample (only 0.25 mL of serum or plasma was enough for
one analysis), by reducing the quantity of blood collected and mini-
mizing difficulties with some types of patients, such as children.
Additionally, for the expected analyte levels, the values of LOD,
precision, and extraction yields were appropriate and satisfactory.
The experimental results illustrated that compared with the direct
HPLC analysis, the matrix interference removed significantly and the
sensitivities of FQs detection greatly increased in the spiked sample
solutions with the MIP-coated fiber SPME-HPLC technique. Also, the
MIP-coated SPME-HPLC technique could be used for the sensitive and
selective monitoring of trace levels of ofloxacin, norflorxacin, ciproflox-
acin, and levofloxacin in the biological samples, due to the specific
recognition of MIP coating to template molecule and its structural
similarity.
The adsorption behavior and fitting equilibrium data of MIP-SPME
fibers also were studied using different models such as Langmuir,
Freundlich, and Langmuir-Freundlich. In this regard, Terzopoulou
et al. [84] synthesized a MIP-SPME fiber and used for the selective
extraction of the abacavir (ABA) as an antiviral drug. So, they evaluated
the effects of the adsorption behavior procedure factors and the
equilibrium data fitted by the different isotherm models. Finally, the
SPME methodology combined with the liquid desorption and liquid
chromatography with mass spectrometry (LC-MS) applied for the
S. Ansari, M. Karimi
quantification of the target analyte in the biological and environmental
samples such as urine, wastewaters, and surface waters samples. Also,
the central composite design (CCD) and response surface methodology
(RSM) used for the optimization of the process parameters such as
extraction time, stirring speed, and salt content that influences on the
extraction recovery. Overall, the proposed procedure was reliable, easy
to handle, sensitive, minimized desorption solvent volume, and requir-
ing a low sample. Hence, this new MIP-SPME showed the great outlook
for selective extraction and enrichment of ABA in the complex aqueous
samples and demonstrated the convenience for daily operation.
4.2. MIPs and in-tube SPME
The in-tube SPME method is used as the SPME instrument which is
an open tubular fused-silica capillary with an internal surface coating.
Since 1997s which Eisert and Pawliszyn [85] introduced in-tube SPME
technique, many researchers has been used this method in them works.
This procedure is simple and can be combined easily on-line with
HPLC and GC analysis. In-tube SPME technique helps appropriate
automation of the extraction procedure to reduces the analysis time
and also in compare to the manual off-line techniques that mentioned
by Kataoka [26,27], the present method has better sensitivity and
precision. As one of the pioneer groups in this field, Mullett et al. [86]
used an on-line automated MIP in-tube SPME technique for propra-
nolol quantification in biological fluids samples which to our knowl-
edge, this was the first work on the automated application of a MIP
particles for in-tube SPME procedure. The applicable mentioned
advantages such as inherent selectivity, chemical, and physical robust-
ness of the MIP particles demonstrated these molecularly imprinted
polymers as an effective stationary-phase material for in-tube SPME
process. The chromatographic separation, the simplicity of the sample
preparation, and improved selectivity for analytes were some of the
other advantages of the MIP in-tube SPME technique. In the following,
some of the studies in this field are provided in the summary.
The MIP-based in-tube SPME process has mostly been applied for
bioanalysis and biosamples determination. In one of these studies, for
animal-producing food samples analysis, Hu et al. [87] introduced an
on-line in-tube SPME method by packing MIP fibers longitudinally into
a polyetheretherketone (PEEK) tube as the on-line extraction unit. The
obtained instrument possesses rapid kinetics for its longitudinal
channels, reduced back-pressure, and also had improved extraction
capacity compared with the customary SPME devices. Additionally,
using molecularly imprinted coatings provides specific extraction
which largely decreased the interference of sample matrix. The using
of this technique not only had the high selectivity of MIPs but also
provided the excellent fluid dynamics of the fiber-in-tube procedure. In
proposed method, for the analysis and determination of the four FQs
residues as the antibiotic drug in the animal-producing food samples,
the PEEK tube firstly packed with multiple ofloxacin imprinted fibers
(OFL-MIP-fibers) to evaluate the new strategy. By using a capillary as
the reaction chamber, the author’s group could minimize the utilization
of the synthetic agents. This technique used successfully to determina-
tion and analysis of the FQs in the chicken and pork liver samples with
good repeatability. To the development of the method and to simulta-
neous extraction assessment of different categories of antibiotic drugs,
the PEEK tube packed with two different fibers imprinted using
ofloxacin and sulfamethazine respectively. The primary outcomes
illustrated that simultaneously enrich the target analytes from compli-
cated samples obtained from the hybrid packing strategy. Then, the
pork liver samples spiked with sulfonamides and FQs considered to the
possibility of using the procedure. The scanning electron microscope
(SEM) photograph of the OFL-MIP-fibers was illustrated in Fig. 5B.
In other investigation, Chaves and Queiroz [88] developed this
method by the synthesis of MIPs particles as a stationary phase for in-
tube SPME procedure. They templated a protein (biopharmaceutical)
with a non-covalent imprinting process using protease for MIP-SPME
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of interferon alpha 2a from plasma samples which coupled by HPLC
analysis with fluorescence detection (HPLC-FD). The prepared MIP
showed high selectivity for the analyte in a complex matrix and also a
small sample volume (50 µL) required for the extraction process. In
consideration of the analytical validation outcomes, the proposed
method (MIP in-tube SPME-HPLC/FD) can be an applicable tool to
determine interferon alpha 2a in plasma samples from patients
receiving therapeutic dosages.
Subsequently, for the improvement of the extraction performance
and also obtain more convenient manipulation of the various features
of the extraction system and instrumentation comprising clean-up,
rate, selectivity, and efficiency, can applying an electrical potential in
the method. Asiabia et al. [89] were one of the groups that used from
this potential in them study. For the preconcentration and selective
extraction of indomethacin as a target analyte in biological samples,
they introduced an automated on-line electrochemically controlled in-
tube solid-phase microextraction (EC-in-tube SPME) technique
coupled with HPLC/UV analysis. With the aim of the increase applic-
ability and selectivity of this method, a novel molecularly imprinted
polymer coated tube created and used for selective extraction of
indomethacin. For this purpose, on the inner surface of a stainless-
steel tube, nanostructured copolymer coating including polypyrrole
doped with ethylene glycol dimethacrylate prepared by an electroche-
mical synthesis. The prepared MIP coating was highly cross-linked,
homogeneous, and porous with a high specific surface area. These
advantages caused to the enhancement of the extraction performance
of the fiber and also considerable extraction selectivity during analysis
obtained by the using MIPs as sorbents for sample preparation.
Moreover, reproducible and stable responses obtained by this proposed
method but also these responses were without being significantly
impressed by interferences which commonly existing in the biological
samples. Overall, with the important advantages and results of this
method, compare with the conventional in-tube SPME methods, can
possibly control different parameters of an extraction system such as
selectivity, rate, clean-up, and extraction efficiency and also success-
fully used for selective extraction of indomethacin in biological
samples.
4.3. Monolithic MIP fiber for SPME
The stability and the selectivity of the SPME fibers act the very
important role in the analysis results. Hence, the finding newly
techniques that promote these parameters in the procedure have been
considerable. One of the techniques that can improve these features is
monolithic MIP fiber preparation which is extensively used in the
SPME process. In this strategy, for the preparation of imprinted fibers,
is illustrated a completely various and much simpler approach. This
approach performs with the direct synthesis of molecularly imprinted
polymeric fibers (monoliths) using capillaries as molds, which are
etched away after polymerization.
In order to resolve the inherent problems such as lacking porosity,
poor stability, fragility, low capacity, MIP crippling, low chemical, and
matrix interferences associated with MISPME fibers, Prasad et al. [90]
prepared a MIP fiber (monolith) sensor to serum folic acid (FA) at
ultratrace levels. In this approach, using a free-radical thermal-poly-
merization method as a hybrid molecularly imprinted micro SPE
(MIMSPE) fiber (without any solid support being used in SPME), the
MIP system for FA analysis prepared from a new monomer, 2,4,6-
trisacrylamido-1,3,5-triazine (TAT), ethylene glycol dimethacrylate
(EGDMA) and dimethyl sulfoxide (DMSO) as the cross-linker and
porogen, respectively. The human serum samples considered to the
direct determination of FA by this Sensor without special treatments
(just dilution). Also, for the direct electronic conduction, the conductive
carbon particles with an orderly “carbon strip” arrange immobilized on
the MIP sensor with the same polymer as is applied in the MIMSPE
fiber.
S. Ansari, M. Karimi
In another study, a MIP fiber fabricated with many applicable
advantages such as high selectivity and stability, durability, easy
fabrication, better repeatability and very low cost in comparison with
the commercial fibers such as PDMS fiber. Based on a MIP, Djozan
et al. [91] prepared a monolithic SPME fiber for pre-concentration,
extraction, and quantification of methamphetamine (MAMP) from a
model aqueous solution. In this approach, a gas chromatography-flame
ionization detector analysis applied for the determination of MAMP
from the human saliva samples. The results revealed that high
extraction efficiency can be achieved in a low detection limit and also
this type of monolithic MIP fiber had good compatibility for the
biological samples analysis, especially for the saliva samples.
Some of the previous works used hazardous materials (e.g. HF) that
cause to environmental and health risks. For solving this drawback,
Deng et al. [92] produced MIP fibers in batch reproducibly which in
this condition a large number of these fibers can be produced rapidly
and conveniently without applying hazardous materials (e.g. HF). This
group developed the monolithic MIP fiber and SPME process for
extracting ephedrine and pseudoephedrine in biological samples such
as urine and serum samples by the capillary electrophoresis (CE)
analysis. The produced MIP fibers in the batch reproducibly, polymer-
ized with in situ method using a silica capillary mold and templated
with ephedrine molecules which in this case each fabricated fiber can
be used for 50 extraction cycles without significant reduction in the
extraction capability. With this methodology, using the prepared fibers,
the handling throughput of the samples can be improved and also the
samples can be pretreated in the batch mode. In addition to the
advantages of easy preparation and low cost, the results illustrated that
when a cross-contamination condition occurs in the determination of
different complex samples, using these fibers can avoid this problem.
Finally, the preliminary using of this technique for urine and serum
samples showed satisfactory recoveries and reproducibility in the
extraction and clean-up of the ephedrine and pseudoephedrine from
the complex sample matrix.
In 2012s, for the first time, a novel, durable sulfamethoxazole
(SMO)-MIP monolith in a micropipette tip synthesized coupled with
HPLC and PAD detection and also used to determination of SMO as a
selective and sensitive analytical procedure. Subsequently, Sun et al.
[93] developed this method as a MIP monolith fiber sorbent for the
selective extraction of the antibiotic SMO in the milk sample. They
synthesized the monolith with templated SMO and a mixture of
acrylamide and 4-vinylpyridine as the co-functional monomers. The
prepared monolith placed in the tip of a micropipette and connected to
syringes in various sizes so applied without any other treatment and
demonstrated high enrichment ability and selectivity for the SMO in
the milk samples.
One of the major traditional drawbacks related to the MIPs is
residual template bleeding. In other newly work, Ma et al. [94]
developed and characterized a MIP monolith templated using thiam-
phenicol (TAP) to avoid this problem and also applied for the
determination of TAP in the milk samples coupled with HPLC-
photodiodes array detector. In order to avoid any other treatment
and simple perform of the solid-phase microextraction technique, the
synthesized MIP monolith placed in a micropipette tip and connected
with syringes in different sizes. The results showed the high selectivity
and enrichment ability for TAP using the molecularly imprinted
polymer monolith microextraction (MIPMME) method and also the
efficiencies of the method in the TAP analysis of the milk samples were
satisfactory.
Determination of some cancer biomarkers can be very vital and has
great importance for the human health. Accordingly, Hashemi-
Moghaddam and Hagigatgoo [95] investigated on the development of
a simple method based on MIPs and SPME procedure for selective
extraction of nonderivatized sarcosine, as a prostate cancer biomarker,
from the complex matrix by GC analysis. Therefore, a Monolithic,
flexible, and stable SPME fiber produced based on MIP particles. The
9
Talanta xx (xxxx) xxxx–xxxx
SPME technique needs fibers with vital characteristics such as porous,
homogeneous, firm, selective, inexpensive, chemically and physically
stable which the fabricated monolithic MIP fibers satisfactorily had
these features and could be directly inserted into the GC injection port.
Due to the lower boiling point of sarcosine compared with other amino
acids, GC analysis of sarcosine performed without derivatization. The
selectivity of the produced fiber in comparison to analog compound
also evaluated. The hybrid procedure of MIP and SPME proposed a
powerful sample preparation tool which successfully used for the
extraction of sarcosine from urine samples, combined by gas chroma-
tography flame ionization detector (GC/FID) analysis. In addition, the
miniaturization and automation of the system carried out. The
morphological structure of the sarcosine-imprinted monolithic SPME
fibers is illustrated in Fig. 5C, which shows SEM image of monolithic
SPME fiber at ×50,000 magnifications.
4.4. Sol-gel MIP and SPME
The supplying of the monolithic MIP fibers needs careful selection
of the cross-linker ratio and even fabricated MIP based fibers operate
weakly in the aqueous solutions; hence, the simple sol-gel technique
solved some of the problems and difficulties with MIP fibers. The sol-
gel materials are prepared based on acid- or base-catalyzed hydrolysis
of silanes and polycondensation of silanols into a polysiloxane network
[47]. However, despite the rapid growth of this methodology, the fibers
are fragile, lacking porosity and thereby provide poor accessibility of
the target analyte to binding sites. Therefore, the low capacity and the
stability of such fibers demand major enhancements. Prasad et al. [96]
prepared ascorbic acid (AA) molecularly imprinted polymer (MIP)-
coated SPME fiber that could be coupled to a complementary MIP
sensor using silylated polymethyl methacrylic acid (PMMA) fibers as
material supported by sol-gel technology. In this condition, the
organic-inorganic-organic interpenetrating matrix is due to the sol-
gel adhesion among the fiber surface and the MIP film layer which
expected to supply an enhanced surface area and high level of porosity
of SPME fiber. For a better signal amplification to achieve an accurate
limit of detection in biological, highly diluted aqueous and pharma-
ceutical samples, both of the extraction yields of AA with the MIP-
coated fiber and a supplementary MIP sensor combined together
without any matrix influence or cross-reactivity.
For the first time, Tiwari and Prasad [97] prepared molecularly
imprinted micro-solid phase extraction fiber by improving molecularly
imprinted polymer film on the surface of silica fiber probing “grafting
via surface attached monomer” (method I) and “grafting via sol-gel”
(method II) techniques. The second approach was inferior to the
determination of insulin and had low detection sensitivity. Notably,
both of the molecularly imprinted micro-solid phase extraction or
supplementary sensor techniques were inefficient to explore the
accurate level of insulin in the real samples. However, for the obtaining
the high detection sensitivity in ultra-trace levels of the insulin in
human blood serum and Huminsulin injection, without any non-
specific (false-positives) assistances, the coupling of these approaches
could be quite appropriate. The proposed hyphenated instrument could
use as a possible marker for hazard of the developing type 2 diabetes
mellitus and diabetic coma due to insulin resistance in human beings.
In another study, influences of the nanofibers on the extraction
performance evaluated. Saraji and Mehrafza [98], for the extraction of
simazine, introduced a novel molecularly imprinted sol-gel material
based on polysiloxane nanofiber as an SPME coating on a stainless
steel wire. The nanostructured molecularly imprinted fiber templated
via simazine and fabricated using methyltriethoxysilane as the sol-gel
precursor by a simple single step process at the room temperature. So,
the prepared fiber used for the simazine extraction in the various water
samples coupled with the GC and MS detection. Also, other triazine
compounds such as terbuthylazine, ametryn, cyanazine, and desmetryn
could cross-selectivity via this proposed approach. Then, the commer-
S. Ansari, M. Karimi
cial fibers (PDMS and PA) and non-imprinted fiber evaluated in
comparison to the prepared nanofiber which showed the high surface
area of these nanofibers caused high extraction efficiency (8 ng) and
also a satisfactory selectivity for simazine and its analogous compounds
obtained. At the same time, a short equilibrium time obtained that was
due to the low thickness of the fiber. The detection limit of the method
was below the allowed quantity of simazine in the European
Community. The SEM image of the constructed stainless steel wire
coated with molecularly imprinted nanofibers is shown in Fig. 5D.
4.5. Membrane MIPs and SPME
Sometimes MIP fibers are produced by a membrane. Different types
of the membrane such as propylene HFs and glass fibers are utilized in
these conditions. In one study, for extraction of the chlorogenic acid
(CGA) in medicinal plants, Golsefidi et al. [99] introduced a simple
preparation method with propylene HF as a membrane which devel-
oped modified bisphenol A (BPA) molecularly imprinted polymer
sorbent fiber solid phase microextraction (MIP-HF-SPME). Briefly,
the acrylate-based MIP synthesized utilizing the following approach: in
the first step, organic-inorganic hybrid solution (sol-gel solution)
combined with carbon nanotubes (CNTs); then, 12 µL of this solution
injected into parts of polypropylene HF; in the next step, the top and
the end of the segments closed, then permitted to form the gel network
(72 h), and, after eliminating entrapped molecules of the template and
drying with air, the fiber was ready to use in SPME procedure. The
author group also optimized the important parameters that influenced
the synthesis process of organic-inorganic hybrid MIPs and the
microextraction procedure. Finally, a powerful sample preparation tool
obtained using a combination of the molecular imprinting and HF-
SPME techniques which had many significant advantages such as
selectivity, simplicity, high porosity, chemical stability, and flexibility.
So, it can be concluded that the MIP-HF-SPME method had the control
polymer-sorbent without the addition of template, stronger affinity to
the template molecule, and high extraction performance.
4.6. Other MIP-SPME techniques
In addition to the mentioned studies, sometimes researchers
introduce individual approaches that can be considered. One of these
studies performed by Prasad et al. [100] for preconcentration, isola-
tion, and analysis of dopamine (DA) at ultratrace levels in highly dilute
aqueous samples. They applied a combination approach in SPME,
using a molecularly imprinted polymer-brush coating on an optical
fiber coupled with a supplementary molecularly imprinted polymer
sensor. The clinical diagnosis needs appropriate stringent detection
limit for the several neurodegenerative diseases analysis which this
combination method enabled this feature for the analyte and also
illustrated the unique versatility of the MIP film grafted as a polymer
brush on the sol-gel surface of a homemade SPME fiber for analysis of
DA. This proposed technique used for the DA analysis in the real
samples without false-positive results by the precise and accurate
SPME ultratrace determination with many suitable advantages such
as the protein-resistant zwitterionic nature of the binding sites, the
‘induced-fit’ mutual polarization of the MIP and DA and the dual
preconcentration by the MIP sensor.
In another work, using microbeads of a MIP, Chen et al. [101]
introduced and developed a selective, rapid, and applicable approach to
dispersive solid-phase microextraction (DSPME). This proposed meth-
od enabled the sample clean-up and preconcentration of sulfametha-
zine (SMZ) by the capillary electrophoresis analysis with UV detection.
The MIP microbeads synthesized by precipitation and suspension
polymerization with using methacrylic acid, ethylene glycol dimetha-
crylate, and SMZ as functional monomer, cross-linking monomer, and
template, respectively. The mentioned particles achieved highly dis-
persive and homogeneous material and also demonstrated a fast rate to
10
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achieve adsorption equilibration. Therefore, the proposed MIP-
DSPME-CE-UV technique had the potential of a sensitive, selective,
convenient, and fast analysis of the trace SMZ in the milk and other
complicated matrices such as wastewater and chicken samples.
Moreover, with these wonderful advantages, the MIP-DSPME-CE-UV
methodology provided a conceivable approach to determining different
compounds in complex matrix samples.
Subsequently, the electrochemistry technique combined with the
SPME process that derived a new electrochemically controlled solid-
phase microextraction (EC-SPME) approach to the sample preparation
and cleanup applications. This modified EC-SPME technique with
solid-phase electrodes used for the detecting the ions, cations, and
anions of the metals. A conducting molecularly imprinted polymer
(CMIP) film using the polypyrrole, electrosynthesized by Ameli and
Alizadeh [102] for the selective extraction and adsorption/desorption
of the naproxen. For the preparation of the film, using the cyclic
voltammetric method, a template anion (naproxen) inserted into a
platinum electrode during the electropolymerization of pyrrole. The
OPPy films applied as a potential-induced selective recognition element
in the solid-phase sorbent process. Also, the important procedure
parameters which control the efficiency of the CMIP film evaluated
utilizing fluorescence spectroscopy. It can be concluded that, during
adsorption/desorption processes of naproxen, the extraction enhanced
by using suitable electrochemical potentials and also applying electro-
chemical control was useful in the removing interferences.
5. Conclusion
The Sample preparation is one of the crucial parameters in drug
analysis. The role of the sample preparation is to eliminate interfer-
ences in the analyte, converting the analytes to appropriate form for
separation, preconcentration, and detection. Usually, we encounter
with the biological samples include the low concentration levels of
drugs and because of this important feature, the selected extraction
technique and sorbent should be virtually suitable. Also, there are
several factors such as suitable selectivity, stability, fast response, and
high sensitivity that should be considered. The selection a sorbent that
enabled all of these features is somewhat unachievable and, almost
always, we are compelled to victim some aspects in favor of others. One
of the sample preparation techniques with many inherent advantages
such as low solvent consumption, high selectivity and sensitivity,
simple operation, and increasing reliability compared to the conven-
tional methods, is SPME. This powerful approach has been widely
applied in the analysis of organic and inorganic compounds in complex
samples and also can be combined with the various analysis instru-
ments such as HPLC, GC, GC-MS, LC-MS, UV, UPLC, and UPLC-MS.
The application of the MIPs as a sorbent for SPME technique also
presented many significant advantages in the clean-up and preconcen-
tration of the biological sample analysis. So, the combination of the
both SPME and MIP techniques could fabricate the fibers with high
mechanical and thermal stability to use the different solutions and
temperatures. Therefore, future developments and studies on the
MISPME procedure will be followed the two categories; (1) producing
new MISPME coating fibers as sorbent with higher selectivity to
develop the application range of this procedure; (2) the performance
of the introduced MISPME techniques will be improved, which will
help to the execution of the MISPME process in the analytical
laboratories.
In this review, the application of MIPs in SPME, comprising MIP-
coated SPME fiber, MIP in-tube SPME, monolithic MIP-SPME fiber,
sol-gel MIP-SPME fiber, CMIPs and membrane MIPs and SPME and
MIP-SPME as a sensor, in drug analysis have been demonstrated and
illustrated. So, the results showed that the MISPME, because of its
applicable advantages, successfully applied as a microextraction tech-
nique to achieve low analyte LODs in the different real samples,
especially drug analysis. Table 1 provides a summary of the studies
S. Ansari, M. Karimi Talanta xx (xxxx) xxxx–xxxx

Table 1
Summary of studies on the application of MISPME method in drug analysis.

Drug Disease Sample preparation Sample Analytical method Analytical parameters Ref.
method

Propranolol Hypertension, heart rhythm In-tube MIP-SPME fiber Biological fluids UV RSDs: < 5% [86]
disorders LOD:0.32 µg/mL
Ascorbic Acid (AA) Water soluble vitamin Sol-gel MIP-coated Human blood serum and Polarographic analyzer RSD:2.3% [96]
SPME fiber pharmaceutical samples LOD:0.0396 ng/mL
Tetracyclines (TCs) Antibiotic in acute diseases MIP-coated SPME fiber Chicken feed, chicken HPLC equipped with a Recoveries:71.6–93.7% [75]
muscle and milk fluorometric detector RSD:6.7%
LODs:1.0–2.3 µg/L
Dopamine (DA) Heart attack, trauma, kidney MIP-Brush-Coated Human blood serum and DPCSV Recoveries:99.7–101.3% [100]
failure SPME film cerebrospinal fluid RSD: < 2.1%
LOD:0.018 ng/mL
Anabolic Steroids (AAS) Increase protein within cells MIP-coated SPME fiber Spiked water and spiked GC-MS Recoveries:80.1–108.4% [76]
human urine RSDs:4.2–14.7%
LODs:0.008–0.02 ng/
mL
Triazines Anticonvulsants MIP-coated SPME fiber Water, rice, maize and GC and GC-MS Recoveries: 0.85% [77]
onion RSDs: < 10%
LODs: 9–85 ng/mL
Folic Acid (FA) Folic acid deficiency, anemia Monolithic MIP-SPME Human blood serum DPCSV Recoveries:99.1–101.5% [90]
fiber RSD:0.13%
LOD:0.0036 ng/mL
Thiabendazole (TBZ) Fungal diseases SLM-protected MIP- Orange juice HPLC equipped with a Recoveries:6.9–7.0% [78]
coated fluorometric detector RSDs:6.6–9.7%
SPME fiber LOD:4 µg/L
Salicylate (SA) Curing fever and headache, MIP-coated SPME fiber Urine and serum Fluorescence Recoveries:96–108% [79]
alzheimer, cardiovascular, spectrometer RSDs:2.3–3.8%
−8
cancer LOD:4×10 mol/L
Methamphetamine Obesity, ADHD Monolithic MIP-SPME Human saliva samples GC-FID RSDs: < 5.5% [91]
(MAMP) fiber LOD:14 ng/mL
LOQ:45 ng/mL
Chlorogenic Acid (CGA) Anti-bacterial, phlogistic, MIP-HF-SPME fiber Medicinal plant HPLC-UV Recoveries:84.8–97.2% [99]
mutagenic RSD:0.38%
LOD:0.08 ng/mL
Sulfamethazine (SMT) Infectious diseases MIP-DSPME fiber Milk CE-UV Recoveries:89–110% [101]
RSD:4.2%
LOD:1.1 mg/L
Antibiotic Drugs Bacterial infections In-tube MIP-SPME fiber Animal-producing food HPLC-UV Recoveries:83.7–112.3% [87]
samples RSDs: < 7.2%
LODs:0.016–0.11 µg/L
Linezolid Bacterial infections MIP-coated SPME fiber Human plasma HPLC-UV-MS RSDs: < 7.5% [80]
LOD:0.029 µg/mL
Sulfamethoxazole (SMO) Infectious diseases Monolithic MIP-SPME Milk HPLC with PAD Recoveries:93.6–101.7% [93]
fiber detection RSDs: < 6.1%
LOD:1 µg/L
Thiamphenicol (TAP) Respiratory infections, Monolithic MIP-SPME Milk HPLC with PAD Recoveries:93.5–93.8% [94]
bacterial prostatitis, venereal fiber detection RSDs: < 6.3%
diseases LOD:0.005 µg/g
Ephedrine Asthma Monolithic MIP-SPME Serum and urine CE Recoveries:91–104% [92]
fiber RSDs: < 9.1%
LOD:0.00096 µg/mL
Naproxen Arthritis, ankylosing CMIP-EC-SPME film Serum and tablet Fluorescence RSD: < 7.4% [102]
spondylitis, bursitis spectroscopy LOD:1×10−8 mol/mL
Interferon Alpha 2a Antiviral drug In-tube MIP-SPME fiber Plasma HPLC equipped with a RSDs: < 10% [88]
fluorometric detector LOQ:8 ng/mL
Insulin Diabetes, insulinoma, Sol-gel MIP-coated Human blood DPASV detection Recoveries:99.1–102% [97]
polycystic ovary syndrome SPME fiber RSDs:1.21%
LOD:0.009 ng/mL
Diclofenac (DFC) Rheumatoid arthritis, MIP-HF-SPME fiber Water, urine and plasma PDA Recoveries:95.5–104.2% [81]
osteoarthritis, sport injuries RSDs: < 5%
LOD:0.7 µg/L
Sarcosine Prostate cancer Monolithic MIP-SPME Human urine GC-FID Recoveries:97–110% [95]
fiber RSDs:6.4%
LOD:0.37 mg/L
Ofloxacin (OFL) Bronchitis, pneumonia, MIP-coated SPME fiber Milk HPLC-UV Recoveries:89.7–103.4% [82]
infections of the skin and RSDs: < 7.2%
bladder LOQ:0.04 μg/mL
Indomethacin Relieve pain and swelling, In-tube MIP-SPME fiber Urine, plasma, blood HPLC-UV Recoveries:92.6–108.3% [89]
gout RSDs: < 8.4%
LODs:0.07–2 μg/L
Ciprofloxacin Bacterial infections MIP-coated SPME fiber Human plasma and HPLC-UV Recoveries:97–102% [83]
serum, tablet RSDs: < 6.7%
LODs:0.023–0.033 μg/
L
Abacavir (ABA) Antiviral drug, HIV MIP-coated SPME fiber Surface waters, LC-MS Recoveries:88–99% [84]
(continued on next page)

11
S. Ansari, M. Karimi Talanta xx (xxxx) xxxx–xxxx

Table 1 (continued)

Drug Disease Sample preparation Sample Analytical method Analytical parameters Ref.
method

wastewaters, urine Qmax:149 mg/g

LODs:10.1–13.6 ng/L
Simazine Weeds control Sol-gel MIP-coated Water samples GC-MS Recoveries:94–97% [98]
SPME nanofiber RSDs: < 7.6%
LOD:0.005 µg/L

Table 2
Comparison of MISPME approaches which used for several drug determinations. Note: low (*), medium (**), high (***).

MISPME Advantages Disadvantages Range of Detection Stability Selectivity Repeatability Simplicity

technique analytes limit

MIP-coated 1) High porosity 1) Fragility and short lifetime of ** ** *** ** *** ***
SPME 2) Highly crosslinked the fused silica fibers
3) Homogeneous 2) Low selective recognition of
4) Quickly adsorption and target analytes in aqueous
desorption process samples
In-tube MIP- 1) High sensitivity and *** ** *** *** *** **
SPME selectivity
2) Low hazardous solvents
using, (green approach)
3) Low analysis time
4) Cost-effective
5) Easily on-line combination
with HPLC and GC
analysis
Monolithic MIP- 1) High selectivity and 1) Needs careful selection of the ** * *** *** *** **
SPME stability, durability cross-linker ratio
2) Easy fabrication 2) MIP based fibers operate
3) Very low cost weakly in the aqueous
4) High repeatability solutions
Sol-gel MIP- 1) Very high extraction *** *** *** *** *** ***
coated SPME capacity
2) High solvent and thermal
stability
3) Fast adsorption-
desorption kinetics
Membrane MIP- 1) Low cost 1) Environmental and health * ** ** ** *** **
SPME 2) Low carry-over effect risks
3) Low organic-solvent
consumption
4) Good sample enrichment

on the application of MISPME method on drug analysis. Also,
comparison of the different MISPME approaches which are used for
drug determinations was illustrated in Table 2.
Acknowledgment
The authors would like to appreciate Islamic Azad University, Saveh
Branch, for their valuable assistance. The authors also declare that
there is no conflict of interests.
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