Chiral Electrochemical Sensors Based On Molecularly Imprinted Polymers With Pharmaceutical Applications

Chapter 17
Chiral Electrochemical Sensors Based on

Molecularly Imprinted Polymers with
Pharmaceutical Applications
Bogdan-Cezar Iacob, Ede Bodoki, and Radu Oprean

Analytical Chemistry Department, “Iuliu Hatieganu”
University of Medicine and Pharmacy, 4 Louis Pasteur St., 400349,
Cluj-Napoca, Romania
bodokie@umfcluj.ro
17.1 Introduction
There is a noticeable increase in the use of biopolymers and
synthetic polymers in medicine and pharmaceutical analysis as
drug delivery systems, therapeutic systems, macromolecular
prodrugs, as biomimetic receptors, and as recognition element and
as stationary phase in chromatographic and chiral separations [1–3].
Because of their appealing extraction capacity, electrochemical
properties, large modiiable surfaces and multiple active sites,
it is easily understandable the focus toward developing sensing
devices based on nanostructured polymeric preconcentration and
recognition elements. A highly selective interface is essential in
creating electrochemical sensors capable of detecting the target
molecule in a complex matrix, even in the presence of close-
related structural analogues of the analyte. Generally, the interface
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588 Chiral Electrochemical Sensors Based on MIPs with Pharmaceutical Applications
is represented by synthetic chemical compounds able to interact

by nonselective chemical bonds with the analyte of interest
but also with chemical compounds that possess same chemical
functionalities as the analyte. An alternative increasingly employed
in electrochemistry is represented by a class of materials whose
selectivity can be directed in the fabrication process toward the
target molecule. These materials, molecularly imprinted polymers
(MIPs), although they were exploited in electrochemistry for
quite some time, only recently have begun to be used as the
recognition element in the electrochemical sensors for the chiral
discrimination of racemic compounds.
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In this chapter, we present the evolution in the development

of MIP-based chiral electrochemical sensors and also discuss the
impediments encountered in the imprinting process of one of
the enantiomers in the polymer. The nature of the polymers and
their electrical properties are also addressed. An important part
of the chapter is dedicated to the analytical applications of these
sensors.
17.2 Molecular Imprinting Approach

Molecular recognition is fundamental to almost every biological
process, such as ligand–receptor binding, substrate-enzyme
reactions, translation and transcription of the genetic code, being
therefore of universal interest for life sciences. Over the past four
decades, researchers have been inspired by nature to produce
biomimetic materials with molecular recognition properties
using various techniques and procedures, following a careful and
rational design rather than by evolution. Although the technique of
molecular imprinting originated since 1949 [4], it gained a
widespread attention only in the last 20 years, becoming shortly a
very versatile and valuable tool in the hands of analytical specialists.
This higher degree of selectivity compared to conventional
materials offers to MIPs an advantage in analytical chemistry.
One of the most important features of molecular imprinting
is to provide a means for creating robust polymeric recognition
materials with predetermined ligand selectivity [5–7]. Thus, the
main application of MIPs turned out to be in the ield of separation
sciences, as stationary phases in (electro)chromatographic analysis
and chiral separations and as selective sorbents in solid phase
Molecular Imprinting Approach 589
extractions. Other important areas in which MIPs have found their

use are: chemical sensors [8], catalysis [9], drug delivery [10],
alternatives to biological antibodies and receptor systems [11, 12].
The process of MIP creation is generally depicted as shown in
Fig. 17.1. MIPs are obtained by adding to a functional monomer’s
solution a template (target) molecule, which in case of chiral analysis
is represented by one of the enantiomers. After polymerization
and extraction of the template, a cavity is left behind in the structure
of the rigid polymer, which is complementary by shape and
functionality to the template molecule. The key to the manufacture
of MIPs with good binding properties resides in the optimization
of synthesis parameters. The nature of functional monomer

possessing appropriate substituents is very important because
their non-covalent molecular interactions with the template are
crucial for the imprinting process. The resulting MIPs can selectively
recognize and rebind the imprint molecule and in some cases
even bind with other closely related molecules. MIPs present
obvious analytical advantages in comparison with macromolecules
of biological origin in terms of their availability, ease of
preparation and ine-tuning of their properties, rigidity of matrix
and low cost.
Figure 17.1 Scheme of molecular imprinting in chiral analysis using the

noncovalent approach.
The versatility of molecular imprinting resides in the fact that

the template may be any substance, ranging from small molecules
such as amino acids, pharmaceutical compounds, metal ions to
larger molecules (proteins) or even cells and viruses. However,
along with the increase in the size of the template, its removal from
the formed three-dimensional polymeric structure is becoming
more and more dificult, with the risk of being permanently stuck
inside the polymer. This steric hindrance also prevents the access
of the target molecule in the imprinted cavities for the rebinding
process [13].
Based on the occurring interactions during the functional
monomer–template complex formation and template rebinding,

three approaches regarding molecular imprinting are reported:
(a) Covalent Imprinting
The covalent approach or the pre-organized approach implies
the formation of a template-functional monomer complex
through reversible covalent bonds prior to polymerization.
After synthesis and removal of the template, in the subsequent
rebinding step, the initial covalent linkage is reconstituted
between the polymer and template. Therefore, only a low
number of non-selective binding sites are expected to be formed
because of the well-deined stoichiometry taking place between
the functional monomer and template. Unfortunately, this
approach is only applicable to a limited number of template
molecules.
(b) Noncovalent Imprinting
Also known as the self-assembly approach, involves weak,
noncovalent interactions in the template-functional monomer
complex formation and also in the subsequent recognition
step, such as hydrogen bonds, electrostatic interactions, dipole-
dipole interactions, van der Waals forces. This complex must be
maintained throughout the polymerization step therefore
a special attention is required regarding the polarity of the
solvent used. Aprotic organic solvents with low polarities
represent the appropriate medium for the stabilization of the
hydrogen and/or electrostatic bonding between the monomer
and template molecule. The protic solvents like alcohols or
water competitively interfere with these interactions; therefore,
they should be avoided. Usually, during the polymerization, a
Molecular Imprinting Approach 591
large excess of functional monomer compared to the template

is required in order to favor the formation of template-
monomer assemblies. In fact, the association between
the monomer and the template is governed by Le Chatelier’s
principle; therefore increasing the concentration of components
shifts the equilibrium toward complex formation. However,
this excess leads also to the formation of non-speciic
binding sites responsible for the heterogeneous binding site
distribution observed in these MIPs.
(c) Semi-covalent Imprinting
The semi-covalent approach combines the advantages of the

previous two methods, employing reversible covalent bonds in
the imprinting step and noncovalent interactions in the
recognition process, after the cleavage of the template from the
polymer.
In the fabrication process of MIPs, the irst step represents the
choice of proper imprinting approach. This selection is performed
depending on the nature of the used template molecule and the
potential linkages that can be established between the functional
groups on the target molecule and on the functional monomer.
The noncovalent approach has the advantages of being applicable
to almost any type of template and from the synthesis point of
view, it is far simpler than the covalent protocol, being the most
widely adopted technique in the MIP preparation. Due to the weak
interactions on which this approach is relying, it allows rapid and
reversible bindings, most needed in chromatographic separations.
Even though the polymers obtained by this approach present
a higher degree of heterogeneity in the binding sites and therefore
higher degree of nonspeciic interactions, the latter being
considered a limiting factor in chiral analysis, nonetheless, because
of its simple and straightforward preparation protocol it was
imported also in the MIP-based sensor development.
Although the practicalities of MIP fabrication are simple
(directly mixing of template with all the other polymerization
mixture components), there are numerous factors inluencing
the process of molecular imprinting that need rigorous control.
A typical polymerization mixture is made up in a solvent in which
four types of substances are dissolved: one or several functional
monomers, template(s), initiator, and cross-linking agent(s). The

nature of these components, as well as their ratio, plays a crucial
role in the imprinting process, along with the initiation type,
temperature, and duration of polymerization. Unfortunately,
the optimization of all these variables most often was achieved
empirically following tedious and frequently ineficient protocols
by keeping one component constant at a time. However, nowadays
having many chemometric optimization tools (design of
experiments) at disposal, they are starting to be employed in the
selection of suitable monomers, as well as for the ine-tuning
of appropriate ratios between the polymerization mixture’s
constituents [14, 15].

Based on their chemical composition, two major types of
polymeric matrices can be distinguished: organic and inorganic
based-MIPs. Although the irst system on which the molecular
imprinting effect was discovered was based on inorganic silica [4],
the polymers of organic nature experienced the largest spread and
popularity: styrene [16] and acrylate [17–22] based-MIPs. The
vast majority of publications deal with the acrylate based-polymers,
employing mostly the same functional monomer, methacrylic
acid (MAA) and the same cross-linker agent, ethylene glycol
dimethacrylate (EDMA) [23–27]. This combination of monomers is
the most popular nowadays in applications involving separation
techniques (capillary electrochromatography, liquid chromatography),
leading to a good imprinting effect, even though other monomers
have been proven their superiority in the imprinting process. This
particular type of monomer combination was transferred also to
the fabrication of MIP-based electrochemical sensors, although
acrylate polymers present no electrical properties. Thus, it appears
that researchers, as an act of convenience, prefer to broaden the
range of applications of a previously described functional polymer
composition, rather than to test other (novel) structural and
functional monomers.
On the other hand, to obtain and maintain the memory of the
template in the polymeric network, a high degree of cross-linking
is needed, resulting in a rigid organic matrix. Unfortunately,
only 15% of the cavities can rebind the template and the
remaining 85% are collapsing after the elimination of template,
never returning to their initial state [28]. In order to favor a facile
elution and rebinding of the template in the cavities, a high level
Chiral Electrochemical Sensors 593
of polymer lexibility is required. Thus, for the synthesis of MIPs

with high imprinting factor and maximum eficiency a well-chosen
balance between polymer rigidity–lexibility has to be achieved.
17.3 Chiral Electrochemical Sensors

Chirality is a major concern in the modern pharmaceutical industry.
The human body is highly chiral selective, in which optically active
endogenous (bio)molecules are usually present in only one of
their chiral forms, which represents also the basis of one theory
regarding the origin of life [29]. For example, human proteins are
built exclusively by L-amino acids, whereas glucose, having ive
asymmetric carbon atoms, occurs biologically in only one of its
chiral isomer. This quintessential nature of life is a consequence of
the fact that the enzymes that synthesize these chiral biomolecules
are also chiral. Furthermore, enantiomers of pharmaceutically
active compounds, entering the body are metabolized by separate
pathways to produce different pharmacological activities. This
is largely attributed to the current awareness that enantiomers
of a racemic drug placed in a chiral environment such as a living
organism act as completely different molecules, frequently
manifesting different pharmacological activities, as well as
different pharmacokinetic and pharmacodynamic effects. It is also
worth mentioning their economic impact, since nowadays chiral
drugs comprise more than half the drugs approved for therapy
worldwide, including many of the top-selling ones. In 2008, from
the total drugs approved by FDA, 63% were single enantiomers,
32% achiral drugs and only 5% racemates [30]. Single enantiomer
drugs had sales of $225 billion in 2005, representing 37% of the
total pharmaceutical market of $602 billion based on estimates
from Technology Catalysts International and IMS Health [31]. As
a result of advances in chemical technologies associated with the
synthesis, separation and analysis of the individual enantiomers
of a racemate, seconded by recent international regulatory
requirements in the pharmaceutical ield, the number of chiral drugs
marketed as single enantiomers is continuously growing, leading
to an entire process called the “chiral switch” [32, 33].
Thus, chiral analysis is progressively becoming an organic part
of the pharmaceutical analysis, where MIPs may play an important
part.
One of the alternatives to chromatographic methods in chiral

analysis, due to the simpler design, manufacturing, and maintenance,
is the use of chiral electrochemical sensors. The enantioselectivity
of these sensors can be based on various principles of molecular
recognition of the target analytes on a chiral sensing interface.
They may include the use of quasi-chiral multiwalled carbon
nanotubes (MWCNT)/ionic liquids composites [34], chiral
ionophores [35], natural biochemical recognition mechanisms
(e.g., chiral enzymatic biosensors or immunosensors) [36], or they
can employ biomimicking mechanisms with synthetic selectors (e.g.,
chiral sensors based on MIPs) [37]. Generally, the electrochemical
discrimination between enantiomers is based on the difference

in stability constants of diastereoisomeric complexes formed
with the chiral sensing interface. The basic difference and in the
meantime the biggest challenge in chiral sensing in comparison
with chiral separations comes from the fact that in case of the direct
chiral sensing devices there is only one single unitary process
of separation that corresponds to one theoretical plate in
chromatographic separations [38]. Nevertheless, electrochemical
sensors became increasingly employed for detecting different
ionic and/or molecular species because of the possibility of their
reproducible and low cost mass production, with great potential
for single use analysis, avoiding cross-contamination especially in
case of biological samples.
17.4 Chiral Electrochemical MIP-Based Sensors

Nature always amazed researchers related to its power of
molecular recognition, so they endeavored to mimic it. Thus,
molecular imprinting emerged as a technique that it is capable
of creating synthetic receptors with comparable recognition
properties to the biological systems [39], but with an excellent
chemical and thermal stability. MIPs present also obvious
advantages over recognition biomolecules, such as antibodies,
natural receptors and enzymes, in terms of their availability, ease
of preparation and ine-tuning of their properties, rigidity of
matrix and low cost.
Although molecular imprinting has more than six decades
of history [4], MIPs were introduced in electrochemistry only in
Chiral Electrochemical MIP-Based Sensors 595
1990s by Mosbach and coworkers [40, 41]. Since then, important

progress was made in the ield of MIP-based electrochemical
sensors. However, even today, the use of MIPs in the electroanalytical
methods is still very limited, and only a very small number
of publications deal with the preparation of enantioselective
electrochemical sensors, leaving plenty of room for novelty and
innovation in a fairly immature high-tech ield. Moreover, amongst
the small number of papers reporting MIP-based enantioselective
electrochemical sensors, the vast majority of them deals with the
analysis of chiral amino-acids [42–45] or monosaccharides [46].
Yet, the situation is different in most of the cases of chiral sensors
developed for pharmaceutically active compounds in which the

chiral center is located more inwards of the molecule and the
functional groups that are involved in the functional monomer-
template complexes are not directly bound to the asymmetric
carbon. In such electrochemical applications, a certain degree of
selectivity toward the template enantiomer was observed, but
absolute enantioselectivity was never achieved [47, 48]. Using
MIPs as (pseudo)stationary phases in separation techniques
(like high performance liquid chromatography, capillary
electrochromatography), where up to several hundred thousand
theoretical plates are achieved, enantioselectivity is hardly an
issue, and the chiral separation of such molecules is easily
accomplished most often with very high resolutions.
17.4.1 MIP Anchoring Onto the Transducer

In order to be incorporated into an electrochemical sensor
as the chiral recognition element, MIPs must be intimately
integrated with a physicochemical transducer (i.e., the surface of
the electrode). In this case, the role of the MIP is to speciically bind
the target molecule from the sample, whereas the signal generated
by the oxidation or reduction of analytes at the MIP-modiied
electrode is converted by the transducer into a quantiiable signal.
Probably the most important obstacle in the MIP expansion
in electrochemical ield is the unestablished methodology for
transducing speciic binding events into electric signals [49].
One convenient MIP integration strategy into an electro-
chemical sensor is by incorporating small MIP particles into
a conductive material (e.g., carbon paste). MIP particles are
prepared in advance, mostly by bulk polymerization, resulting

in blocks of polymers that are grounded and sieved into particles
of desired size. This method gives particles of irregular size and
shape and leads to an excessive loss of material. In order to obtain
small and spherical particles, other methods were developed, like
suspension polymerization, core–shell emulsion polymerization
and dispersion/precipitation polymerization techniques. This
type of MIP-based electrochemical sensors employed acrylate-
based polymers exclusively for the non-chiral recognition and
determination of different analytes [21, 22, 24, 50]. Although these
sensors present the advantage of a facile renewal of the active

surface just by polishing it on a white clean paper, they suffer
from a poor homogeneity of MIP distribution in the conductive
matrix and thus a low inter-assay reproducibility. Moreover, the
majority of the MIP particles are found embedded in the matrix and
only a small number are exposed at the surface of the electrode,
rendering available only a few speciic recognition sites. Furthermore,
problems such as bleeding or strong nonspeciic adsorption
interactions were observed when employing MIP particles as
chemical receptors.
A more reproducible sensor modiication that offers a larger
coverage and a more intimate contact of the polymer with the
electroactive area is achieved by grafting the MIP onto the surface
of the solid electrode. By introducing a previously silanized indium-
tin oxide (ITO) glass in the polymerization mixture, followed by a
thermal initiation (60°C), a polymer block surrounding the ITO
glass was obtained. After breaking the resulting polymer and the
ultrasonication of the modiied glass, a nanometer range thin layer
[51] of acrylate-based MIP with chiral discrimination properties
was obtained [49]. A more intimate contact between the polymeric
recognition element and the electrode’s electroactive surface is
achieved by immobilizing the iniferter (initiator-transfer agent-
terminator) onto the sensor’s surface, also known as the “grafting
from” method. The polymerization mixture is then uniformly
dispersed over the initiator-modiied surface by spin coating,
followed by an UV [52] or temperature (60°C) [45] initiated free-
radical polymerization. This approach allows a polymer ilm
growth of nanometer-range controlled thickness due to the fact
that polymerization takes place only at the surface of the electrode.
Compared to the “grafting to” approach, the “grafting from” method

presents an evident superiority, offering a more homogenous
MIP coverage of the sensor’s surface with a larger number of
cavities and a 100-fold faster diffusion of analyte [45]. However,
the initiator’s immobilization directly onto the surface is usually
complex and chemically not tenable [53].
The low degree of attachment because of the steric hindrance
offered by the “grafting to” technique was overcame by covalently
bonding the chiral MIP ilm onto the sensor’s surface through
a vinyl functionalized ormosil (organically modiied silica)
monolayer [53]. A silver working electrode was used on the
surface of which a silane self-assembled monolayer (SAM) was

irst attached through a thiol functional group, followed by
functionalization of SAM with a vinyl silane. Three MIP layers were
thermally cross-linked onto the sensor’s modiied surface after
the spin coating of the prepolymerization mixture. The electrode-
to-electrode reproducibility is questionable because of the
numerous modiication steps involved in the chiral sensor’s
fabrication, even though authors claim a RSD of 1.2% for three
different electrodes used for the analysis of thyroxine in blood
serum samples.
The problem related to MIP-transducer integration is
eliminated preparing a chiral MIP monolithic composite by the
polymerization of a MIP pre-polymerization mixture in which
carbon particles were added, resulting a conductive MIP iber used
as a working electrode [37]. This approach involves a straight-
forward sensor fabrication methodology, in which all components
are mixed together in a solvent and the resulting mixture is poured
into glass capillaries followed by thermal polymerization. The
rather odd thing is that the majority of carbon particles were
arranged as a strip along the entire length of the iber and yet
the composite showed very good electro-conductive properties.
An alternative to the carbon powder addition, in order to induce
electrical features to the MIP composite, is to employ conducting
MIP polymers. Thus, a cylindrical electrode based on conductive
stationary phase was fabricated using overoxidized polypyrrole
(PPy) [54]. The polymerization and overoxidation of PPy were
realized in the presence of the template, allowing the creation of
complementary cavities to the template. The conductive poly(aniline-
co-m-aminophenol) copolymer was also tested as a stationary
phase illed into a porous ceramic column for enantioselective

recognition [55].
Nevertheless, probably the most direct way of binding the
chiral MIP to the electrode’s surface is through electropolymerization
[56]. Electropolymerization implies polymer formation on the
electroactive surface upon oxidation or reduction of certain organic
compounds. This procedure is also the most often used method in
the fabrication of chiral MIP-based sensors due to the facile
preparation of the MIP-ilm and the possibility of controlling
polymer thickness and deposition density by easily changing the
polymerization conditions (e.g., applied range of voltage and scan
rate, number of voltammetric cycles, concentration of monomer,

etc.). The most common type of electrochemical MIP formation is
by means of cyclic voltammetry, which allows the growth of ultra-
thin polymer ilms on the surface of the electrode; thus, a good
adherence to the transducer surface is achieved in a simple and
quick manner.
A L-histidine (His)-imprinted sol solution, consisting of
tetraethylorthosilicate (TEOS), phenyltrimethoxysilane (PTMOS),
and methyltrimethoxysilane (MTMOS), was electrodeposited
onto a MWCNT-modiied ITO glass by using cyclic voltammetry
in the range of –0.8 V to +0.9 V [57]. This technique allowed the
formation of a thin, uniform MIP ilm distributed regularly on the
MWCNT-modiied electrode surface. Electropolymerization was
also employed in the preparation of chiral imprinted organic
membranes onto gold electrodes or gold-coated quartz crystal
electrodes [58]. They were achieved by cycling the potential between
–0.4 and –1.4 V in an aqueous solution containing acrylamide,
N,N′-methylenebisacrylamide, NaNO3, Na2S2O8, and L- or D-
histidine. The electropolymerization of acrylamide in solution
is possible only if electrolytes such as tartaric acid, zinc salts,
perchlorate, and nitrate [59] are used.
Another type of chiral MIP sensor using conducting imprinted
polymer, poly(indole-3-acetic acid) (PI3AA), was electrogenerated
in phosphate buffer, in the presence of L- or D-aspartic acid, acting
as template, on a MWCNT-coated pencil graphite electrode (PGE)
by cycling the potential 12 times on a large interval, from –1.6 V to
+1.6 V vs. Ag/AgCl (Fig. 17.2) [60]. A nano-MIP ilm of controlled
thickness was achieved on the modiied pencil tip, which was
subsequently over-oxidized using a more anodic potential, up to
+2.0 V. During over-oxidation, dopant molecules (L- or D-aspartic

acid) were de-doped from the polymeric network. Benzidine was
Figure 17.2 MIP deposition by electropolymerization using cyclic

voltammetry: (a) MI-PI3AA-asp-adduct/MWCNTs-PGE [inset
(1) reduction peak of monomer, inset (2) oxidation peak of
aspartic acid, and inset (3) oxidation peak of monomer], (b)
NI-PI3AA/MWCNTs-PGE, and (c) over-oxidized MI-PI3AA/
MWCNTs-PGE [electropolymerization conditions; 0.05 mM
l-asp, 0.1 mM PI3AA, 0.01 M phosphate buffer (supporting
electrolyte pH 5.0), no. of scan cycles 12, potential range −1.6
to +1.6 V vs. Ag/AgCl, over-oxidation potential range −1.6 to
+2.0 V, scan rate 100 mV s−1)]. Reproduced with permission
from [60].
also used as an electro-active monomer in the electrochemical

fabrication of an ultra-thin nanoilm of MIP for the chiral
discrimination of methionine (MET) [61]. The electropolymerization
was effectuated in an aqueous solution (pH = 2.3) over three
consecutive cyclic voltammetric scans in the potential range of
–1.0 and +1.0 V vs. Ag/AgCl. The resulted polymeric membrane
showed good adhesion onto the carboxylated MWCNT- modiied
PGE surface. The PGE was also employed in the electropolymerization
of copper(II)–5-methyl-thiophene–2-carboxylic acid complex,
in the presence of D- or L-pyroglutamic acid, giving forth of a
molecularly imprinted metallo-polymer [62].
One of the most utilized conducting polymers in

electrochemistry for direct electrochemical polymerization is PPy.
It was also adopted in the MIP fabrication due to its particular
electrical properties and the various moieties with which the
pyrrole ring could be functionalized and eventually could bring
certain favorable features. With the over-oxidation of PPy, the
positive charges from its structure are removed, along with the
introduction of oxygen containing functionalities, i.e., carbonyl
group [63]. Thin ilms of PPy were created in the presence of
L-tryptophan (Trp) (template molecule) on a Pt working electrode
by electrodeposition at a constant potential of +0.8 V vs. SCE [64].
The complementary cavities were accomplished by over-oxidizing
the formed PPy ilm applying a constant potential of +1.0 V. The
polymeric ilm consisted of uniformly sized particles of about
1–2 μm. PPy chiral MIPs were also achieved by a galvanostatic
method in which a constant current of 0.3 mA was applied in
an aqueous solution of Py and template [65]. The as-prepared
PPy nanowires had an average diameter of ca. 100 nm and few
micrometers in length, offering a higher active surface area and
thus more enantiospeciic sites compared to PPy ilms.
The acrylate polymers are well known for their electrical
insulating properties, which limit the eficiency of the signal
transduction, fact that restricted their use as active components
of electrochemical sensors. However, there is a wide selection
of acrylic monomers containing a variety of functional groups
that eventually could improve the resulting polymer’s electric
properties. Moreover, these polymers were intensely studied and
the underlying imprinting process is well known. On the other
hand, conductive MIP polymers offer a good signal transduction
process, reproducibility and a more controllable growth of the

polymer [66]. As a downside, they have a more compact and rigid
structure [67], features that may interfere with the imprinting
effect. The advantages of these two approaches can be combined
by assembling the conducting polymers with the conventional
imprinted polymers into one MIP sensor. Thus, a chiral hybrid
MIP sensor for the analysis of L-Phe was prepared by the
electropolymerization of a polymer precursor, poly [2-(N-
carbazolyl)ethyl-methacrylate-co-meth-acrylic acid] [66]. The
insulating polymethacrylic acid played the role of functional
monomer while the conducting polycarbazole was used as “cross-
linker agent” offering a better grafting on the electrode surface.

Another hybrid MIP example is represented by the
copolymerization of phenol with a covalently constructed complex
between 3-hydroxyphenyl boronic acid (functional monomer) and
monosaccharide (template). The copolymer was deposited on a
gold electrode by cyclic voltammetry using two successive scans
[46]. The obtained polymer presented an irregular morphology
with an average thickness of 36 nm.
17.4.2 Chiral MIP Applications

Although the use of polymers in electrochemistry attracted a
remarkable interest, scientists experienced some reluctance in
employing imprinted polymers as sensing element in sensor
development. Several drawbacks seem to be the limiting factor in
the MIP expanding, like the low density of imprinted cavities, the
electro-insulating properties of traditional MIPs and the slow
diffusion of analyte. In case of chiral MIP-based sensors, the situation
is even more austere. Because of the identical physicochemical
properties of the two enantiomers, differing only in the three-
dimensional geometry, a more speciic receptor has to be developed
in order to achieve chiral discrimination.
17.4.2.1 Amino acids

Various publications have already described MIP-modiied
sensors, which showed good chiral recognition toward the
enantiomers of different amino acids. The feasibility of achieving
electrosynthesized polyacrylamide membranes imprinted with
L- or D-His was explored by using AC impedance spectroscopy and
piezoelectric quartz crystal technique [58]. It was observed that

the electron-transfer between the electrode and the K3[Fe(CN)6]/
K4[Fe(CN)6] (1:1) redox probe was facilitated after the interaction
of MIP with both enantiomers of His due to the swelling of the
polyacrylamide membrane. However, in the case of template
enantiomer, the electron-transfer resistance decreased in a larger
extent compared to the other enantiomer, with 72% and 40%,
respectively. A more considerable difference was noticed in the
case of Au-coated quartz crystals modiied with L- or D-His. The
modiied crystals were also tested for the interference of other
amino acids, such as tyrosine, arginine and phenylalanine, showing
only a limited afinity toward these molecules. An inorganic MIP-

based sensor was also constructed for the chiral analysis of His
and was evaluated by amperometric measurements [57]. When a
solution of L-His was added, the sharpest increase in the current
was observed for the MIP/sol/MWCNTs/Si-ITO electrode, followed
by the MIP/sol/Si-ITO electrode and the lowest current value was
for the non-imprinted polymer/sol/MWCNTs/Si-ITO electrode.
However, by this protocol, the authors fail to evaluate the effect of
D-His on the pristine MIP systematically presenting only the
addition of L-His followed by the addition of D-His. With the addition
of D-His in the case of all three electrodes, the current slightly
decreases, proving a saturation of the binding sites previously
occupied with L-His. Two MIP-based chiral sensors were proposed
by Prasad et al. [52, 68] for trace analysis of His, claiming an absolute
enantiodiscrimination. First sensor was based on the modiication
of hanging mercury drop electrode with the copolymerized poly
(ethylenediamine tetraacetic acid-co-chloranil) imprinted polymer.
Interestingly, the chiral sensor exhibited two different linear
relationships between the differential pulse cathodic stripping
voltammetry (DPCSV) peak currents and target enantiomer
concentration: from 0.0005 to 0.03946 μg mL−1 and from 4.95 to
90.16 μg mL−1, respectively. A remarkable limit of detection of
0.128 ng mL–1 was obtained for the template enantiomer and a
negligible cross-reactivity for the twelve studied interferents was
reported. The proposed MIP-sensor was applied for the L-His
determination in human blood serum samples, and due to their
high dilution, no distortion of peak current or sorption of proteins
was observed. The second sensor was developed by “metal-ion
mediated imprinting” approach, in which Cu2+ ions are able to form
a complex with template (L-His) and acryl phosphate functional

monomer, as shown in Fig. 17.3. The presence of Cu2+ offered an
electroconductive feature of the ilm during rebinding. The MIP-
modiied PGE was tested using differential pulse anodic stripping
voltammetry (DPASV) for L-His detection in blood serum samples
and pharmaceuticals with no matrix effect and cross-reactivity.
Both chiral MIP-based sensors showed an excellent recoveries
and reproducibility.
Figure 17.3 Preparation of L-His imprinted sensor. Reproduced with

permission from [52].
For the enantioselective analysis of D- or L-Asp Prasad et al.

[45, 60] described two novel chiral electrochemical sensors. In
the irst one [60], a molecularly imprinted polymeric ilm of about
2 nm thickness was electro-generated onto a MWCNT-modiied
PGE surface. During the polymerization, a polymeric backbone
with positively charged indole rings was formed, on which Asp
anions as dopant were bound. The resulting electrodes were
characterized by DPASV on the linear range of 0.15–8.9 μM, with a
LOD of 0.016 μM. Recently, a second MIP-based sensor was
developed via surface-initiated activators regenerated by electron
transfer for atom transfer radical polymerization approach over
the matrix of TiO2 nanoparticles/MWCNTs [45]. TiO2 nanoparticles
and MWCNTs were introduced for the enhancement of electron
conductivity and sensitivity. Interestingly, both Asp imprinted

chiral sensors showed noteworthy detection ability without any
cross-reactivity and an extraordinary reproducibility and stability.
Moreover, they were tested in aqueous, pharmaceutical and
biological samples, without any false-positive response.
A thin ilm of overoxidized PPy was imprinted with L-Trp and
its enantioselectivity was characterized by stripping voltammetry
and quartz crystal microbalance (QCM) [64]. The imprinting
effect was greatly affected by the synthesis parameters, such as
overoxidation potential and time and the thickness of PPy ilm.
However, only a partial enantiodiscrimination was obtained due
to the strong MIP surface adsorption of the interfering enantiomer.

PPy was also employed in the fabrication of L-Trp imprinted
cylindrical electrode tested by the potential-induced technique
in which the ejection–rebinding steps are controlled by the
applied potential on the electrode [54]. The resulted polymer
presented a re-binding ratio of L-Trp and D-Trp of 52.6% and
17.3%, respectively. The enantioselectivity of the L-Trp imprinted
PPy was also tested by differential pulse voltammetry on glassy
carbon working electrode and by QCM technique on Au-coated
quartz crystals. Similar selectivities were obtained in both cases,
proving the formation of imprinted cavities for the template
enantiomer during the overoxidation process of PPy. Absolute chiral
discrimination ability toward Trp enantiomers was presented by
the monolithic MIP-carbon composite iber developed by Prasad
and coworkers [37]. DPASV was employed for quantitative chiral
assessment of aqueous samples, linearity being observed in two
concentration ranges: 0.90–18.60 ng mL−1 and 24.23–840.22 ng mL−1.
Good precision and recoveries were achieved with a LOD of
0.24 ng mL–1. The described MIP-sensor did not reveal any cross-
reactivity with none of the eight studied common interferents
of Trp and was successfully applied for the analysis of biological
luids (human serum and cerebrospinal luid) without any
preliminary treatment.
The enantiomers of phenylalanine anilide were analyzed on
an imprinted poly(EDMA-co-MAA) polymer grafted onto an ITO
glass electrode based on the chiral discriminative gate effect of the
MIP in organic solvents [49]. The chiral differentiation implied the
evaluation of the effect of phenylalanine anilide enantiomers on
the faradic current of redox species (ferrocene), effect caused by a
morphological change in the polymer’s matrix. In the presence of

template enantiomer, an important decrease in ferrocene’s anodic
current was observed in comparison with the same effect in the
presence of the other enantiomer. Because of the very narrow
linear dynamic range (0.5–1 μM), the obtained sensor can only be
employed for qualitative analysis and exclusively in non-polar
solvents.
The chiral recognition of another amino acid, phenylalanine,
was achieved by electro-generating PPy nanowires using a pseudo-
template, D- or L-camphorsulfonic acid (CSA) [65]. The acidic
surfactant, CSA, in aqueous solutions formed micelles with the
monomer, acting as a protecting agent for the prevention of radial

overgrowth of PPy nanowires. By the electrostatic interactions
between its –SO–3 group and the positively charged PPy backbone
as well as by hydrogen bonding between its own carbonyl oxygen
and the N atom of PPy also ensured an eficient imprinting process.
The de-doped PPy nanowires coated Pt electrodes were able not
only to recognize the template enantiomers, but also enantiomers
of molecules with similar molecular size and conformation,
i.e., phenylalanine. The enantioselective capabilities of the MIP
nanowires were investigated by electrochemical impedance
spectroscopy and circular dichroism. A new hybrid MIP chiral
sensor was also developed using L-phenylalanine as template and
its chiral performance was investigated by open circuit potential-
time technique [66]. The proposed sensor showed a relatively
good ability to discriminate between the enantiomers with a
selectivity coeficient of KLD = 5.75 × 10−4 and a limited interference
of amino acids with similar coniguration. A linear range of
2.5 × 10–6 – 2.5 × 10–2 M and a detection limit of 1.37 μM were
achieved.
Electropolymerization of benzidine in the presence of L- or
D-MET was employed in order to generate enantiospeciic cavities
for MET enantiomers [61]. During the MIP ilm electrogeneration
as well as during the template enantiomer’s re-binding process
MET is converted to its oxidized form, methionine sulfone. The
obtained sensor presented a rapid and cost-effective preparation
and was characterized by DPCSV showing absolute discriminative
properties between MET enantiomers. It proved to have a
good intermediate precision (RSD < 4%) and a linearity in the
concentration range of 11.7–206.3 ng mL−1 (aqueous solutions),
11.7–197.4 ng mL−1 (pharmaceutical matrix), and 11.8–152.3 ng mL−1

(blood serum matrix). The lowest LOD (2.4 ng mL–1) compared to
other sensors developed for Met analysis, along with the striking
electrode reproducibility and stability, in the absence of any
nonspeciic binding of potential interferents, makes it the best
option for trace analysis of Met in different clinical applications.
A new poly(aniline-co-m-aminophenol) chiral conductive
stationary phase was developed for L-glutamic acid analysis [55].
The resulted column was tested by applying different potentials
on the copolymer for the release (negative potential for reduction
of polymer) and then for the re-attachment (positive potential)
of template. The enantioselective recognition was evaluated by

monitoring the luorescence of L- and D-glutamic acid re-bounded
to the packed electrode column. The results were also conirmed
by QCM analysis. The re-binding ratio of L- to D-glutamic acid was
found to be 2.38. Chiral analysis of one of glutamic acid’s derivative,
pyroglutamic acid, was achieved with the aid of Cu2+ incorporated
MIP modiied PGE [62]. The highly conductive imprinted ilm was
evaluated by DPASV showing a linear response in the concentration
interval of 2.8–170 ng mL–1, with a detection limit of 0.77 ng mL–1.
The obtained sensor was applied in the pyroglutamic acid’s chiral
determination from different real samples (urine, cerebrospinal
luid, plasma) without any cross-reactivity and false-positive
results.
Self-assembled monolayer and layer-by-layer approaches
were combined by thermal cross-linking on the surface of a silver
electrode in order to develop a MIP-based sensor for the chiral
analysis of thyroxine, a thyroid hormone with an amino-acid side
chain [53]. The DPASV response peak current was linear to the
concentration of thyroxine in the range from 0.010 to 17.2 ng mL–1
and the achieved detection limit was 0.0060 ng mL–1. The
molecularly imprinted ilm displayed absolute enantioselectivity
to the template enantiomer and was applied for the determination
of thyroxine in aqueous, blood and pharmaceutical samples with
no interference from related compounds.
17.4.2.2 Monosaccharides
A well-known shortcoming of MIPs based on non-covalent
interactions is the relatively low number of speciic imprinted
cavities. However, this drawback may be overcome by employing
covalent interactions between the template and the functional

monomer. A popular approach in saccharide analysis is based on
their complexation with boronic acid [69]. Based on these
interactions, Granot et al. [46] prepared imprinted polymeric ilms
with D-glucose or D-mannose, as shown in Fig. 17.4. The
electrochemical detection of monosaccharides is achieved by
competitive interactions with the polymer between the target
monosaccharide and a ferrocene-labeled monosaccharide. For
(a)
(b)
(c)
Figure 17.4 (a) Preparation of the boronic acid complex. (b) Preparation
of the monosaccharide imprinted polyphenol. (c) The
competitive assay for the detection of D-glucose using the
D-glucose-imprinted polymer. Reproduced with permission
from [46].
For example, in the analysis of D-glucose using the D-glucose

imprinted polymer, the amperometric response of ferrocene-
functionalized D-glucose was monitored. With the increasing
concentration of D-glucose, the current response of the redox-labeled
monosaccharide decreases due to the competitive interactions
toward the D-glucose imprinted cavities of the polymer (D-glucose
removes the ferrocene-derivative from the polymer). The obtained
sensor showed good selectivity toward other monosaccharides and
a slight discrimination between glucose enantiomers. Nonetheless,
this method may be applicable for the development of sensors
designed for different diol-containing molecules.
17.5 Conclusions and Future Perspectives

Molecularly imprinting technology seems to expand every year
being more and more frequently applied in various ields of
science. Only recently, MIPs started to be employed as chiral sensing
interfaces in electrochemistry.
As it has been shown, basically all chiral MIP-based
electrochemical sensors were developed up till now for amino
acids or monosaccharides. However, chiral pharmaceuticals present
more complex structures compared to the already mentioned
molecules; thus, their eficient molecular imprint is considered to be
more dificult. Moreover, in the case of amino acids, the asymmetric
carbon is at the molecule’s extremity carrying two functional
groups (–NH2 and –COOH) strongly interacting with the used
common functional monomers, thus easily leading to highly
enantiospeciic imprinted cavities.
In order to really prove the versatility and real analytical
potentials of MIP-based chiral electrochemical sensors, in the
near future their performance also toward more complex chiral
molecules ought to be demonstrated so they could overcome the
laboratory scale barrier.
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Chiral Electrochemical Sensors Based On Molecularly Imprinted Polymers With Pharmaceutical Applications

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Chapter 17

Chiral Electrochemical Sensors Based on

Bogdan-Cezar Iacob, Ede Bodoki, and Radu Oprean

Handbook of Sustainable Polymers: Processing and Applications

is represented by synthetic chemical compounds able to interact

In this chapter, we present the evolution in the development

17.2 Molecular Imprinting Approach

extractions. Other important areas in which MIPs have found their

of synthesis parameters. The nature of functional monomer

Figure 17.1 Scheme of molecular imprinting in chiral analysis using the

The versatility of molecular imprinting resides in the fact that

monomer–template complex formation and template rebinding,

large excess of functional monomer compared to the template

The semi-covalent approach combines the advantages of the

monomers, template(s), initiator, and cross-linking agent(s). The

constituents [14, 15].

of polymer lexibility is required. Thus, for the synthesis of MIPs

17.3 Chiral Electrochemical Sensors

One of the alternatives to chromatographic methods in chiral

discrimination between enantiomers is based on the diﬀerence

17.4 Chiral Electrochemical MIP-Based Sensors

1990s by Mosbach and coworkers [40, 41]. Since then, important

developed for pharmaceutically active compounds in which the

17.4.1 MIP Anchoring Onto the Transducer

prepared in advance, mostly by bulk polymerization, resulting

sensors present the advantage of a facile renewal of the active

Compared to the “grafting to” approach, the “grafting from” method

surface of which a silane self-assembled monolayer (SAM) was

phase illed into a porous ceramic column for enantioselective

rate, number of voltammetric cycles, concentration of monomer,

+2.0 V. During over-oxidation, dopant molecules (L- or D-aspartic

Figure 17.2 MIP deposition by electropolymerization using cyclic

also used as an electro-active monomer in the electrochemical

One of the most utilized conducting polymers in

process, reproducibility and a more controllable growth of the

linker agent” oﬀering a better grafting on the electrode surface.

17.4.2 Chiral MIP Applications

17.4.2.1 Amino acids

piezoelectric quartz crystal technique [58]. It was observed that

only a limited afinity toward these molecules. An inorganic MIP-

a complex with template (L-His) and acryl phosphate functional

Figure 17.3 Preparation of L-His imprinted sensor. Reproduced with

For the enantioselective analysis of D- or L-Asp Prasad et al.

conductivity and sensitivity. Interestingly, both Asp imprinted

to the strong MIP surface adsorption of the interfering enantiomer.

morphological change in the polymer’s matrix. In the presence of

monomer, acting as a protecting agent for the prevention of radial

11.7–197.4 ng mL−1 (pharmaceutical matrix), and 11.8–152.3 ng mL−1

of template. The enantioselective recognition was evaluated by

covalent interactions between the template and the functional

For example, in the analysis of D-glucose using the D-glucose

17.5 Conclusions and Future Perspectives

1. Andersson, L., and Mosbach, K. (1990). Enantiomeric resolution on

2. Schweitz, L., Andersson, L. I., and Nilsson, S. (1997). Capillary

6. Mosbach, K., and Ramstrom, O. (1996). The emerging technique

Electrophoresis, 34, 1375–1382.

28. Wulﬀ, G. (2002). Enzyme-like catalysis by molecularly imprinted

Univ. Comenianae., 50, 7–23.

42. Deore, B., Chen, Z. D., and Nagaoka, T. (2000). Potential-induced

45. Prasad, B., Srivastava, A., and Tiwari, M. P. (2013). Molecularly

Landes Bioscience, Georgetown.

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