materials
Article
Preparation, Characterization and Application of
a Molecularly Imprinted Polymer for Selective
Recognition of Sulpiride
Wei Zhang 1 , Xuhui She 2,3 , Liping Wang 2,4 , Huajun Fan 2, *, Qing Zhou 2 , Xiaowen Huang 2
and James Z. Tang 5
1
2
3
4
5
*
School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou 510006, China;
gzzhangw@163.com
School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China;
lab-shexuhui@kingmed.com.cn (X.S.); wangjiang0916@126.com (L.W.);
kytxor@163.com (Q.Z.); xiaowenh25@126.com (X.H.)
Guangzhou KingMed Center for Clinical Laboratory Co., Ltd., Guangzhou 510005, China
China National Analytical Center Guangzhou, Guangzhou 510070, China
Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton WV1 1LY, UK;
J.Z.Tang@wlv.ac.uk
Correspondence: junhuafan@126.com; Tel.: +86-020-3935-2135; Fax: +86-020-3935-2129
Academic Editor: Charley Chuan-yu Wu
Received: 18 February 2017; Accepted: 24 April 2017; Published: 28 April 2017
Abstract: A novel molecular imprinting polymer (MIP) was prepared by bulk polymerization
using sulpiride as the template molecule, itaconic acid (ITA) as the functional monomer and
ethylene glycol dimethacrylate (EGDMA) as the crosslinker. The formation of the MIP was
determined as the molar ratio of sulpiride-ITA-EGDMA of 1:4:15 by single-factor experiments.
The MIP showed good adsorption property with imprinting factor α of 5.36 and maximum
adsorption capacity of 61.13 µmol/g, and was characterized by scanning electron microscopy (SEM),
Fourier-transform infrared spectroscopy (FT-IR) and surface area analysis. With the structural analogs
(amisulpride, tiapride, lidocaine and cisapride) and small molecules containing a mono-functional
group (p-toluenesulfonamide, formamide and 1-methylpyrrolidine) as substrates, static adsorption,
kinetic adsorption, and rebinding experiments were also performed to investigate the selective
adsorption ability, kinetic characteristic, and recognition mechanism of the MIP. A serial study
suggested that the highly selective recognition ability of the MIP mainly depended on binding
sites provided by N-functional groups of amide and amine. Moreover, the MIP as solid-phase
extractant was successfully applied to extraction of sulpiride from the mixed solution (consisted of
p-toluenesulfonamide, sulfamethoxazole, sulfanilamide, p-nitroaniline, acetanilide and trimethoprim)
and serum sample, and extraction recoveries ranged from 81.57% to 86.63%. The tentative tests of
drug release in stimulated intestinal fluid (pH 6.8) demonstrated that the tablet with the MIP–sulpiride
could obviously inhibit sulpiride release rate. Thus, ITA-based MIP is an efficient and promising
alternative to solid-phase adsorbent for extraction of sulpiride and removal of interferences in
biosample analysis, and could be used as a potential carrier for controlled drug release.
Keywords: molecularly imprinted polymer; sulpiride; itaconic acid; serum analysis; drug release
1. Introduction
Sulpiride is a type of benzamide antipsychotic medication for schizophrenia. Chemically, it is
also a substituted benzamide derivative related to metoclopramide and trimethobenzamide. As an
antipsychotic drug of the benzamide class, sulpiride is mainly used in the treatment of psychosis
Materials 2017, 10, 475; doi:10.3390/ma10050475
www.mdpi.com/journal/materials
Materials 2017, 10, 475
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associated with schizophrenia and major depressive disorder, and sometimes used in low dosage to
treat anxiety and mild depression [1–3]. Recently, schizophrenia has a significant rise with China’s
economic booming, thus sulpiride is widely used in clinical applications and administrated in large
dose for typical acute treatment [1,4–7]. In addition, sulpiride as a relative old antipsychotic drug is
more cost-effective than newer drugs in developing countries, and also has had other uses including
treatment of peptic ulcer, vomiting and vertigo. To avoid overdose and side effects of sulpiride in
clinical applications, monitoring sulpiride, especially in China, has become increasingly demanded for
mental diseases.
Molecularly imprinted polymers (MIPs) have been widely developed for separations, sensors,
catalysis, biological mimics and other fields due to the specific molecular recognition of small and/or
large molecules and stable physichemical properties [8–15]. Considering their specific adsorption,
MIPs used as carrier materials have great potential in clinical and pharmaceutical applications such as
biosample analysis and drug delivery [16–19]. For the preparation of MIPs, the selection of functional
monomers is critical to the molecular recognition ability. An appropriate functional monomer can
not only improve the affinity of the template molecule but also reduce the nonspecific adsorption
of the MIP to enhance its specific recognition to the template molecule [16,20,21]. In previous
studies, the MIP using methacrylic acid (MAA) as functional monomer exhibited good selective
adsorption to sulpiride, but also maintained higher capacity for nonspecific adsorption [22,23]. In
consideration of the chemical structure, itaconic acid (ITA) as four-carbon dicarboxylic acid can provide
two carboxyl groups to a molecule of sulpiride when coming together and interacting with each other.
Compared with freer MMA, ITA is more likely to match sulpiride in space to reduce non-specific
adsorption. In our pre-experiment, we also found that using ITA as the functional monomer can
decrease significantly the adsorption amount of the non-imprinted polymers (NIP) by at least half
compared to that of the MMA-based NIP. Thus, our new approach is to prepare a MIP using ITA
as the functional monomer with ethylene glycol dimethacrylate (EGDMA) as crosslinking agent,
and its formulation conditions were optimized by single-factor experiment for enhancement of the
specific adsorption. Characterization of the made MIP was performed using Fourier Transform
Infrared (FT-IR), scanning electron microscope (SEM) and Brunauer–Emmett–Teller (BET) surface
area analysis for the connection with monomer/template interaction, structural morphologies and
surface parameters, respectively. To evaluate the adsorption capacity and selectivity of the MIP,
adsorption properties were systematically investigated by static equilibrium adsorption and isothermal
adsorption experiments in progression from sulpiride, its analogs and a mixture of sulpiride and
its analogs. Moreover, the recognition mechanism was tentatively studied by adsorption tests
of p-toluenesulfonamide, formamide and 1-methylpyrrolidine with individual functional groups
consisting of sulpiride. In further consideration of medicine uses, we attempted to apply the MIP
obtained to analysis of sulpiride in serum complex matrix, and the release features of the MIP loading
sulpiride and its tablet were also investigated in controlled drug release.
2. Materials and Methods
2.1. Materials and Reagents
Sulpiride was purchased from Advanced Technology & Industrial Co., Ltd. (Hong Kong,
China). Itaconic acid (ITA) was obtained from Shanghai Jing Chun Pty Ltd (Shanghai, China).
Ethylene glycol dimethacrylate (EGDMA) was purchased from Eternal Chemical Co., Ltd. (Taiwan).
Azoisobutyronitrile (AIBN) was bought from Tianjin Bai Shi Chemical Co., Ltd (Tianjin, China).
Acetonitrile (chromatography grade) was purchased from Merck (Darmstadt, Germany). All the other
reagents were analytical grade.
Sulpiride stock and standard solutions: Sulpiride (34.1 mg, 0.10 mmol) was weighed, dissolved
and diluted up to the volume of 100 mL with methanol in a volumetric flask. Then, 1.00 mmol/L of
Materials 2017, 10, 475
3 of 16
the stock solution was sealed properly and stored in a fridge. The working standard solution was
gradually diluted from the stock solution when used.
2.2. Preparation of the MIP
The template molecule sulpiride (102.4 mg, 0.3 mmol) and the functional monomer ITA (156.1 mg,
1.2 mmol) were added to 6 mL of methanol, and sonicated for 30 min. The crosslinker (EGDMA)
(892.0 mg, 4.5 mmol) and the initiator (AIBN) (60.0 mg, 0.37 mmol) were was added to the mixture
above, and sonicated for 5 min until well mixed. Under nitrogen protection, the polymerization was
carried out at 60 ◦ C for 24 h in a water bath (HH-6, Jintan, China). White bulk polymer was collected,
ground and sieved through a 200 mesh sieve (particle size of 74 µm or below).
MIP powder was refluxed in a Soxhlet apparatus with methanol-acetic acid (9:1 v/v) for removal
of the sulpiride. The reflux eluents were detected in intervals at 234 nm by UV-Vis spectrophotometer
until no sulpiride was found. The MIP was further washed with methanol to remove residual acetic
acid, and dried at 60 ◦ C under vacuum for 12 h. Reference non-imprinted polymers (NIPs) were
prepared under identical conditions without the presence of sulpiride; the obtained polymers were
ground in a mortar, and then passed through a 200 mesh sieve. MIP and NIP powders prepared
according to the above procedure were used for the following experiments.
2.3. Material Characterization [21]
FT-IR spectra of the MIP and the NIP were obtained by FT-IR analysis. KBr disks of the MIP and
the NIP were respectively prepared, and their spectra were recorded at 4000 cm−1 –400 cm−1 on a
WQF-410FT FT-IR spectrometer (Beijing, China). Electron micrographs were taken for evaluation of the
morphology with a Zeiss EVO 18 scanning electron microscope (SEM) (Carl-Zeiss-Strasse, Oberkochen,
Germany). Sample powder was attached to the sample holder, dried and sputtered with gold in a
SBC-12 Ion Sputtering Coater (Beijing, China). Morphologies of the MIP and the NIP were observed
under SEM scanning at the voltage of 20 kV. The specific surface area, pore volume and pore size
distribution of polymers were measured by a surface area analyzer (NOVA4200e, Quantachrome,
Boynton Beach, FL, USA). Then, 0.1 g of sample was outgassed under vacuum for 6 h at 100 ◦ C.
The surface area and pore size were determined at 77 K by N2 adsorption and desorption isotherms
using multipoint Brumauer-Emmett-Teller (BET) method.
2.4. Static Adsorption of the MIP
Static adsorption of the MIP and the NIP was carried out according to the following procedure.
Briefly, the MIP or NIP (20.0 mg) was added into a conical flask with 2.0 mL of 1.0 mmol/L sulpiride
(or other substrate) methanol solution. The flask sealed was shaken at 30 °C for 3 h in an oscillator.
The concentration of the final sulpiride solution was determined in triplicate at a 234 nm on UV-Vis
spectrophotometer [23,24]. The binding capacity of the MIP or NIP was calculated by Equation (1):
Q = (C0 − Ct ) V/m
(1)
where Q is the binding capacity (µmol/g), C0 is the initial concentration of sulpiride (µmol/L), Ct is
the concentration of sulpiride at time t (µmol/L), V is the volume of the initial sulpirde solution (L)
and m is the mass of the MIP or the NIP (g).
The imprinting factor was calculated by Equation (2):
α = QMIP /QNIP
(2)
where α is imprinting factor, QMIP is the adsorption capacity of the MIP (µmol/g), and QNIP is the
adsorption capacity of the NIP (µmol/g).
Materials 2017, 10, 475
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The specificity adsorption ratio was calculated by Equation (3):
Specific adsorption ratio (%) = [(QMIP − QNIP )/QMIP ] × 100%
(3)
The selectivity of the MIP was evaluated by the specific factor β, which was defined as the ratio of
the difference of the adsorption capacity between the MIP and NIP by a substrate against sulpiride.
The specific factor β was calculated using Equation (4):
β = Qsubstrate /Qsulpiride
(4)
where Qs ubstrate = (QMIP − QNIP )substrate and Qs ulpiride = (QMIP – QNIP )sulpiride . Both were characterized
by exploiting the following procedure.
2.5. Solid-Phase Extraction of the MIP
Briefly, the MIP or NIP (20.0 mg) was added into a conical flask with 2.0 mL of a mixed substrate
methanol solution (containing 0.20 mmol/L of sulfamethoxazole, sulfanilamide, p-toluenesulfonamide,
p-nitroaniline, acetanilide, trimethoprim and sulpiride,). The flask sealed was shaken at 30 ◦ C for 3 h.
The resulting solution was filtered and diluted with methanol, then the concentration was determined
at 250 nm at room temperature by an Agilent 1200 HPLC with UV detector (Agilent, Santa Clara, CA,
USA) using a Gemini C18 column (4.6 mm × 250 mm, 5 µm, Phenonmenex). The mobile phase was
comprised of methanol (A) and 0.1% ammonia solution (pH = 10.3) (B) according to the following
gradient mode: 0–4 min, 18% A (v/v); 4–10 min, 18%–40% A (v/v); 10–25 min, 40%–48% A (v/v);
25–26 min, 48%–18% A (v/v). The flow rate was 1.0 mL/min. The injection volume was 20 µL.
2.6. The Preparation and Analysis of Serum Samples
Rat serum (1.0 mL) containing sulpiride was added with 1.0 mL of acetonitrile and mixed well.
The mixture was centrifuged for 15 min. The filtrate was collected and evaporated. The obtained
residue was dissolved in 1.0 mL of methanol, where 10 mg of the MIP powder was added to
extract sulpiride. The mixture was shaken at 30 ◦ C for 3 h in an oscillator. The loaded MIP was
collected by filtration and then eluted with methanol-acetic acid (9:1). The collected wash-out was
evaporated to dryness. After the residue was redissolved with methanol, sulpiride extracted from
the MIP was determined at 234 nm under room temperature by HPLC using a Gemini C18 column
(4.6 mm × 250 mm, 5 µm, Phenonmenex) as the stationary phase. The mobile phase was made of
methanol and 0.1% ammonia solution (pH = 10.3) (45:55, v/v). The flow rate was 1.0 mL/min, and
injection volume was 20 µL.
2.7. Drug Loading and Preparation of MIP-Sulpiride Tablets
Drug loading: MIP–sulpiride was prepared by loading with sulpiride in the MIP. Briefly, 0.25 g
MIP powder was added in a conical flask with 15 mL of 2.5 mmol/L sulpiride methanol solution, then
placed and shook in an oscillator at 30 ◦ C for 12 h. The mixture was filtrated by 0.45 µm membrane,
and the MIP was dried in vacuo overnight. The filtrate was analyzed by UV spectrophotometry to
determine sulpiride in the MIP, and its loading capacity was determined as 30.69 µg/mg.
Preparation of tablets: MIP tablets were made by dry granulation tabletting using MIP–sulpiride
and pharmaceutical excipients such as microcrystalline cellulose (MCC), hydroxy propyl methyl
cellulose (HPMC), ethyl cellulose (EC) and povidone K30 (PVP-K30) according to the following
procedure. Twenty milligrams of MIP–sulpiride powder (containing 613.8 µg of sulpiride) was well
mixed with 200 mg of MCC, 40 mg of HPMC, 25 mg of EC and 15 mg of PVP-K30, and then made into
tablets on a DP single-punch tablet press (Shanghai, China). For comparison, sulpiride control tablets
were prepared according to the same procedure but without the MIP.
Materials 2017, 10, 475
5 of 16
2.8. Drug Release of the MIP
Triplicates of MIP–sulpiride or a tablet prepared above were respectively added in stoppered
conical flasks (250 mL) with 100 mL of 0.1 mol/L HCl buffer (pH 1.0, simulating the gastric fluid),
KH2 PO4 -Na2 HPO4 buffer (pH 6.8, simulating the intestinal fluid) and KH2 PO4 -Na2 HPO4 buffer
(pH 7.4, simulating the blood plasma. Controlled release of sulpiride was carried out at 37 ± 0.5 ◦ C
and 100 rpm in a ZRS-8G dissolution tester (Tianjin, China). Certain volumes of solutions were
Materials 2017,at10,appropriate
475
5 of 4
withdrawn
time intervals, and thus successively determined amounts of drug released
by HPLC. The cumulative release rate (%) can be calculated by the following equation:
(5)
Cumulative release rate (%) = (Mt/M∞) × 100
Cumulative release rate (%) = (Mt /M∞ ) × 100
(5)
where Mt is the accumulative amount of sulpiride at a certain moment, and M∞ is the accumulative
where
Mtofissulpiride
the accumulative
sulpiride at a certain moment, and M∞ is the accumulative
amount
at over anamount
infiniteof
time.
amount of sulpiride at over an infinite time.
3. Results and Discussion
3. Results and Discussion
3.1. Polymerization
PolymerizationConditions
ConditionsofofMIPs
MIPs
3.1.
The MIP
formulated
withwith
template-sulpiride,
monomer-ITA,
crosslinker-EGDMA,
initiatorThe
MIPwas
was
formulated
template-sulpiride,
monomer-ITA,
crosslinker-EGDMA,
AIBN, and solvent-methanol.
Although the
molar ratio
template/monomer/crosslinker
was empirically
initiator-AIBN,
and solvent-methanol.
Although
the of
molar
ratio of template/monomer/crosslinker
set
at
1:4:15
[13,21,22],
optimization
of
MIP
formulations
was
carried
out
and
assessed
against
the
was empirically set at 1:4:15 [13,21,22], optimization of MIP formulations was carried out and
assessed
adsorption
capacity
of
the
MIP
formed
using
single-factor
experiment.
The
results,
as
shown
in
against the adsorption capacity of the MIP formed using single-factor experiment. The results, as
Figure in1,Figure
demonstrated
the effects
of amounts
of ITA,
EGDMA,
AIBN
the
shown
1, demonstrated
the effects
of amounts
of ITA,
EGDMA,
AIBNand
andmethanol
methanol on
on the
adsorption
capacity
of
the
MIP
and
the
NIP.
The
adsorption
amounts
of
sulpiride
in
the
MIP
and
the
adsorption capacity of the MIP and the NIP. The adsorption amounts of sulpiride in the MIP and the
NIP
increased
with
ITA,
but
the
excess
of
ITA
did
not
translate
into
the
specific
adsorption,
Q
sulpiride
NIP increased with ITA, but the excess of ITA did not translate into the specific adsorption, Qsulpiride
[Qsulpiride = =(Q(Q
MIP – QNIP)sulpiride]. Similarly, the adsorption amounts of sulpiride decreased with increase
[Q
MIP – QNIP )sulpiride ]. Similarly, the adsorption amounts of sulpiride decreased with
sulpiride
of
EGDMA,
whereas
hardness
the MIPof
increased.
AIBN,More
otherwise,
produces
finerproduces
particles,
increase of EGDMA, the
whereas
the of
hardness
the MIPMore
increased.
AIBN,
otherwise,
resulting
in lossresulting
of Qsulpiride
(6 mL). as
solvent is
best
of the
specific
adsorption.
finer
particles,
in. Methanol
loss of Qsulpiride
Methanol
(6the
mL)
as choice
solventinisterms
the best
choice
in terms
of the
Thus,
optimization
polymerization
conditions
suggested
that
0.3
mmol
of
sulpiride,
1.2
mmol
ITA, 4.5
specific adsorption. Thus, optimization polymerization conditions suggested that 0.3 mmol of of
sulpiride,
mmol
of EGDMA,
mg ofofAIBN
and 660mL
for6 amL
MIP
to the
1.2
mmol
of ITA, 4.560mmol
EGDMA,
mgofofmethanol
AIBN and
of formulation,
methanol forcorresponding
a MIP formulation,
molar ratio of 1:4:15
template-sulpiride/monomer-ITA/crosslinker-EGDMA,
achieving a best value
corresponding
to thefor
molar
ratio of 1:4:15 for template-sulpiride/monomer-ITA/crosslinker-EGDMA,
of
specific
adsorption.
Recent
publications
frequently
used
the
molar
ratio
of
1:4
monomer
achieving a best value of specific adsorption. Recent publications frequently usedalthough
the molar
ratio of
could
be
ranging
from
1
to
10
times
the
template
in
mole
[25–35].
1:4 although monomer could be ranging from 1 to 10 times the template in mole [25–35].
90
80
MIP
NIP
Q=QMIPQNIP
a
80
70
b
70
MIP
NIP
Q=QMIPQNIP
60
60
Q (mol/g)
Q (mol/g)
50
50
40
30
40
30
20
20
10
10
0
0
0.4
0.8
1.2
1.6
2.0
3.0
2.4
4.0
60
c
MIP
NIP
Q=QMIPQNIP
70
60
50
30
Q (mol/g)
Q (mol/g)
50
40
6.0
7.0
80
Figure 1. Cont.
80
70
5.0
nEGDMA(mmol)
nITA(mmol)
40
30
20
20
10
10
d
MIP
NIP
Q=QMIPQNIP
8.0
Q(
Q(
30
30
20
20
10
10
0
0
Materials 0.4
2017, 10,0.8
475
1.2
1.6
2.0
3.0
2.4
4.0
c
70
MIP
NIP
Q=QMIPQNIP
60
Materials
2017, 10, 475
8.0 16
6 of
60
6 of 4
50
Q (mol/g)
Q (mol/g)
7.0
MIP
NIP
Q=QMIPQNIP
d
70
50
30
6.0
80
80
40
5.0
nEGDMA(mmol)
nITA(mmol)
Figure 1. Optimization of the molecularly imprinted polymer
(MIP) formulations against the
40
adsorption capacity of the MIP and the non-imprinted polymer (NIP): (a) itaconic acid (ITA); (b)
30
ethylene glycol dimethacrylate (EGDMA); (c) azoisobutyronitrile (AIBN); and (d) methanol.
20
20
3.210Characterization of the MIP
10
Sulpiride
had 60characteristic
absorption
bands at0 33804 cm−1 for6 N-H of8 the sulfonamide
group,
10
12
40
80
100
120
−1
−1
−1
Solvent
volume(mL)
W
(mg)
3080 cm for C–H of the aromatic ring, 1645 cm for C=O of amide I, and 1550 cm for N–H of amide
II [21,36]. The NIP absent of sulpiride has no N-H related amide I and II and aromatic ring. Figure 2
FigureFT-IR
1. Optimization
of MIPs
the molecularly
polymer
(MIP)
shows
spectra of the
before andimprinted
after elution
against
theformulations
NIP. FT-IR against
spectra the
illustrated
adsorption
capacity
of
the
MIP
and
the
non-imprinted
polymer
(NIP):
(a)
itaconic
acid
(ITA);
that the MIP after elution was almost identical to the NIP, which indicated the template was removed
(b) ethylene
glycol
dimethacrylate
(EGDMA);
(c) azoisobutyronitrile
(AIBN); and
(d) methanol.
from
the polymer
matrix.
The MIP before
elution
had comparable sulpiride
absorption
bands at 3338 cm−1,
1753 cm−1, 1647 cm−1 and 1530 cm−1, but the above characteristics obviously weakened or disappeared
3.2.after
Characterization
of the MIPstretching of C–O–C, asymmetric deformation peak of C–H and symmetric
elution. Asymmetric
−1−1for
stretching
C=O
were, respectively,
at 1155
, 1455
and
1733
cm−1sulfonamide
, exhibiting structural
Sulpirideofhad
characteristic
absorption
bandscm
at−13380
cmcm
N-H
of the
group,
−
1
−
1
characteristics
of EGDMA.
The presence
of thecm
above
characteristic
peaks
demonstrated
3080
cm for C–H
of the aromatic
ring, 1645
for
C=O of amide
I, and
1550 cm−1that
forMIP
N–Hwas
successfully
synthesized.
of amide
II [21,36].
The NIP absent of sulpiride has no N-H related amide I and II and aromatic
To evaluate
characteristics,
the before
morphology
andelution
surfaceagainst
parameters
of the
MIP
and NIP
ring. Figure
2 showssurface
FT-IR spectra
of the MIPs
and after
the NIP.
FT-IR
spectra
were further
investigated
scanning
andwhich
Brumauer-Emmett-Teller
(BET)
illustrated
that the
MIP afterby
elution
waselectron
almost microscope
identical to(SEM)
the NIP,
indicated the template
method.
From
the
SEM
micrographs
shown
in
Figure
3,
both
polymers
exhibited
a
rough
was removed from the polymer matrix. The MIP before elution had comparable sulpiride absorptionand
−1 , 1753 cm
−1 , 1647 specific
−1 ,pore
microporous
Moreover,
surface
area,
volume
and
pore size of obviously
the MIP and
bands
at 3338 cmstructure.
cm−1 and
1530 cm
but the
above
characteristics
NIP were
measured
through
N2 Asymmetric
adsorption–desorption
analysis;
results were
17.035 m2/g,
weakened
or also
disappeared
after
elution.
stretching of
C–O–C,the
asymmetric
deformation
−1the
−1 and
0.035
cm3/g,and
andsymmetric
6.808 nm for
the MIP, and
12.543
m2/g,respectively,
0.025 cm3/g, at
5.805
nmcm
for
NIP,cm
respectively.
peak
of C–H
stretching
of C=O
were,
1155
, 1455
−
1
Thus,
MIP showed
obviously
larger specific
surface
and of
more
multiporous
structure
1733
cm the
, exhibiting
structural
characteristics
of EGDMA.
Thearea
presence
the above
characteristic
compared
with the
NIP,
implying
that it facilitated
adsorption of sulpiride.
peaks
demonstrated
that
MIP
was successfully
synthesized.
0
20
AIBN
450
a
400
350
3271.23
2947.51
b
250
%T
576.10
1619.89 1339.79
300
3338.58
2916.33 2849.89
200
1753.53
1530.18
1647.81
c
150
3556.00
2988.29 2956.22
1455.69
100
1733.00
50
3563.72
2988.00 2956.63
1455.87
0
4000
1155.35
d
1733.11
3500
3000
2500
2000
cm
1500
1155.27
1000
500
-1
Figure
2. Fourier
Transform
Infrared
(FT-IR)
spectra
of the
NIP:
(a) sulpiride;
Figure
2. Fourier
Transform
Infrared
(FT-IR)
spectra
of the
MIPMIP
andand
the the
NIP:
(a) sulpiride;
(b) (b)
MIPMIP
with
sulpiride;
(c) NIP;
(d) MIP.
with
sulpiride;
(c) NIP;
andand
(d) MIP.
To evaluate surface characteristics, the morphology and surface parameters of the MIP and
NIP were further investigated by scanning electron microscope (SEM) and Brumauer-Emmett-Teller
Materials 2017, 10, 475
7 of 16
(BET) method. From the SEM micrographs shown in Figure 3, both polymers exhibited a rough and
microporous structure. Moreover, specific surface area, pore volume and pore size of the MIP and
NIP were also measured through N2 adsorption–desorption analysis; the results were 17.035 m2 /g,
0.035
cm3 /g, and
6.808 nm for the
MIP,
and 12.543 m2 /g, 0.025 cm3 /g, 5.805 nm for the NIP, respectively.
3.3. Adsorption
Characteristics
of the
MIP
Thus, the MIP showed obviously larger specific surface area and more multiporous structure compared
with
NIP, implying
that it facilitated
adsorption of sulpiride.
3.3.1.the
Adsorption
Performance
of the MIP
Materials 2017, 10, 475
7 of 4
The adsorption isotherm of the MIP and/or NIP can be obtained by adding incremental amounts
of template to a given amount of the MIP and/or NIP. In addition, Scatchard analysis model was used
for the evaluation of the adsorption of the MIP [37]. In Figure 4a, the adsorption amounts of polymers
increased with the increase of sulpiride concentration. Relatively, the adsorption capacity of the MIP
is much higher than that of the NIP, indicating that the MIP offered a stronger affinity to the template
than the NIP. The equilibrium data were well represented by the Langmuir adsorption model I [38,39],
and the MIP showed higher fitting degree with correlation coefficients (R2) of 0.9948.
The Scatchard analysis in Figure 4b follows the equation:
(6)
Q/C = (Qmax-Q)/Kd
where Q is the equilibrium adsorption capacity of sulpiride (μmol/g), Kd is the equilibrium
dissociation constant (mol/L) at the binding sites, Qmax is the maximum apparent adsorption at the
(a)
(b)
binding sites (μmol/g) and C is the concentration of sulpiride in the solution (mmol/L). Figure 4b
Figure
3. Scanning
electron
of: the MIP to
(a);low
andconcentration
the NIP (b).
indicates that there
are two
segments
in themicrographs
curve corresponding
Figure
3. Scanning
electron
micrographs
of: the MIP (a);
and the NIP (b). range and high
concentration range of sulpiride. The equations of the two segments are:
3.3. Adsorption Characteristics of the MIP
3.3. Adsorption Characteristics of
the=MIP
Q/C
0.0031Q + 0.1675 (= 0.9983)
(7)
3.3.1.
3.3.1. Adsorption
Adsorption Performance
Performance of
of the
the MIP
MIP
Q/C = −0.0119Q + 0.7274 (= 0.9832)
(8)
The
Theadsorption
adsorption isotherm
isotherm of
of the
the MIP
MIP and/or
and/orNIP
NIPcan
canbe
beobtained
obtainedby
byadding
addingincremental
incremental amounts
amounts
of
aa given
amount
of
MIP
NIP.
addition,
Scatchard
analysis
model
was
Their Kto
d were
calculated
be
μmol/L
andIn
μmol/L,
and Qmax
was 54.03
μmol/g
and
of template
template
to
given
amount to
of the
the322.58
MIP and/or
and/or
NIP.
In84.03
addition,
Scatchard
analysis
model
was used
used
for
the
evaluation
of
the
adsorption
of
the
MIP
[37].
In
Figure
4a,
the
adsorption
amounts
of
polymers
61.13
μmol/g,
respectively.
Two
linear
regression
equations
suggested
that
two
different
binding
sites
for the evaluation of the adsorption of the MIP [37]. In Figure 4a, the adsorption amounts of polymers
increased
with
the increase
increase
ofin
sulpiride
concentration.
Relatively,
thenon-specific
adsorptioncapacity
capacity
the
MIP
for sulpiride
formedof
the MIP,
known as Relatively,
specific
and
bindingofof
sites
from
increased
withwere
the
sulpiride
concentration.
the
adsorption
the
MIP
is
is
much
higher
than
that
of
the
NIP,
indicating
that
the
MIP
offered
a
stronger
affinity
to
the
template
imprinting
cavities
and
residual
monomer.
In
contrast,
Q
max
of
the
NIP
was
less
than
19.40
μmol/g,
much higher than that of the NIP, indicating that the MIP offered a stronger affinity to the template
than
the
NIP.
data
were
bydecreased
the
adsorption
model II [38,39],
and its
adsorption
capacity
wasrepresented
also greatlyby
compared
to MMA-based
NIP
than
thenon-specific
NIP. The
The equilibrium
equilibrium
data
were well
well
represented
the Langmuir
Langmuir
adsorption
model
[38,39],
2
and
the
MIP
coefficients (R
(R2)) of
(47.85
[23]. higher
and
theμmol/g)
MIP showed
showed
higher fitting
fitting degree
degree with
with correlation
correlation coefficients
of 0.9948.
0.9948.
The Scatchard analysis in Figure 4b follows the equation:
80
MIP
NIP
Langmuir fitting
a
0.35
(6)
Q/C = (Qmax-Q)/Kd
b
0.30
where
Q
is
the
equilibrium
adsorption
capacity
of
sulpiride
(μmol/g), Kd is the equilibrium
60
0.25
dissociation constant (mol/L) at the binding sites, Qmax is the maximum apparent adsorption at the
50
binding sites (μmol/g) and C is the concentration of sulpiride
in the solution (mmol/L). Figure 4b
0.20
40
indicates that there are two segments in the curve corresponding to low concentration range and high
0.15
30
concentration
range of sulpiride. The equations of the two segments are:
Q (mol)
Q/C (L/g)
70
0.10
20
(7)
Q/C = 0.0031Q + 0.1675 (= 0.9983)
0.05
10
0
0.0
0.4
0.8
1.2
Q/C2.0= −0.0119Q
+ 0.7274 0.00
(= 0.9832)
10
2.4
2.8
1.6
C(mmol/L)
20
30
40
Q (mol/g)
50
60
(8)
70
Their Kd were calculated to be 322.58 µ mol/L and 84.03 µ mol/L, and Qmax was 54.03 μmol/g and
61.13 Figure
μmol/g,
linearof
regression
equations
suggested
that two
different
The adsorption
adsorptionTwo
profile
of the binding
MIP (b). sites
4. respectively.
The
isotherms
the MIP and
the NIP (a);
and Scatchard
for sulpiride were formed in the MIP, known as specific and non-specific binding sites from
imprinting
cavities
and residual
monomer.
InMIP
contrast,
Qmax of the NIP was less than 19.40 μmol/g,
3.3.2.The
TheScatchard
Kinetic
Adsorption
the
analysis
inBehavior
Figure
4boffollows
the equation:
and its non-specific adsorption capacity was also greatly decreased compared to MMA-based NIP
The kinetic adsorption curves of the MIP and NIP were established by monitoring the
(47.85 μmol/g) [23].
Q/Cof=time
(Qmax
-Q)/Kthe
(6)
d MIP and NIP were placed in sulpiride
concentration of sulpiride during a period
while
methanol solution. The results in Figure 5 show that the adsorption capacity of the MIP increased
very quickly in the first 5 min, and the adsorption equilibrium was achieved at about 60 min. From
60 min to 180 min, its adsorption capacity was almost unchanged, indicating that the adsorption of
sulpiride on the MIP was saturated and stabilized. In contrast, the adsorption capacity of the NIP was
low and steady during the whole time. The specific adsorption Q increased with time, indicating
Materials 2017, 10, 475
8 of 16
Materials 2017, 10, 475
8 of 4
where
Q is the equilibrium adsorption capacity of sulpiride (µmol/g), Kd is the equilibrium dissociation
constant (µmol/L) at the binding sites, Qmax is the maximum apparent adsorption at the binding sites
80
0.35solution (mmol/L). Figure 4b indicates that
MIP
(µmol/g) and C is the concentration
of sulpiride in the
(a)
NIP
b
70
there are two segments in the
curve
corresponding to low
concentration
range and high concentration
Langmuir
fitting
0.30
range60 of sulpiride. The equations of the two segments are:
0.25
Q/C = 0.0031Q + 0.1675
0.20 (= 0.9983)
Q/C (L/g)
Q (mol)
50
40
(7)
0.15
Q/C = −0.0119Q + 0.7274 (= 0.9832)
30
(8)
0.10
20
Their Kd were calculated to be 322.58 µmol/L and 84.03 µmol/L, and Qmax was 54.03 µmol/g
0.05
10
and 61.13
µmol/g, respectively. Two linear regression equations
suggested that two different binding
sites for
sulpiride were formed in the MIP, known as0.00specific and non-specific binding sites from
0
10
20
30
40
50
60
70
0.0
0.4
0.8
1.2
1.6
2.0
2.4
2.8
imprinting cavities andC(mmol/L)
residual monomer. In contrast, Qmax of the NIP was
less than 19.40 µmol/g,
Q (mol/g)
and its non-specific adsorption capacity was also greatly decreased compared to MMA-based NIP
4. The
adsorption isotherms of the MIP and the NIP (a); and Scatchard profile of the MIP (b).
(47.85Figure
µmol/g)
[23].
3.3.2. The Kinetic Adsorption Behavior of the MIP
The kinetic
kinetic adsorption
adsorption curves
curves of
of the MIP and NIP were established by monitoring the
The
concentration of sulpiride during a period of time while the MIP and NIP were placed in sulpiride
methanol
5 show
that
thethe
adsorption
capacity
of the
increased
very
methanol solution.
solution.The
Theresults
resultsininFigure
Figure
5 show
that
adsorption
capacity
of MIP
the MIP
increased
quickly
in thein
first
min,5and
adsorption
equilibrium
was achieved
at about
min.60
From
min
very quickly
the5first
min,the
and
the adsorption
equilibrium
was achieved
at60
about
min.60From
to
its min,
adsorption
capacitycapacity
was almost
indicatingindicating
that the adsorption
of sulpiride
60 180
minmin,
to 180
its adsorption
wasunchanged,
almost unchanged,
that the adsorption
of
on
the MIP
saturated
and stabilized.
In contrast,
the adsorption
capacity
of theofNIP
low
sulpiride
on was
the MIP
was saturated
and stabilized.
In contrast,
the adsorption
capacity
the was
NIP was
and
during
the whole
time.time.
The The
specific
adsorption
∆Q increased
withwith
time,time,
indicating
the
low steady
and steady
during
the whole
specific
adsorption
Q increased
indicating
effectiveness
of imprinting
sulpiride.
TheThe
results
revealed
thatthat
the the
MIPMIP
cancan
be used
as aascarrier
for
the effectiveness
of imprinting
sulpiride.
results
revealed
be used
a carrier
adsorption
andand
extraction
of sulpiride.
for adsorption
extraction
of sulpiride.
80
MIP
NIP
Q=QMIPQNIP
70
60
Q (mol/g)
50
40
30
20
10
0
20
40
60
80
100
120
140
160
180
200
Time(min)
Figure
5. Kinetic
and NIP
NIP to
to sulpiride.
sulpiride.
Figure 5.
Kinetic adsorption
adsorption curves
curves of
of the
the MIP
MIP and
3.3.3. The
Selectivity of
of the
the MIP
MIP
3.3.3.
The Adsorption
Adsorption Selectivity
In
In order
order to
to evaluate
evaluate the
the adsorption
adsorption selectivity
selectivity of
of the
the MIP
MIP to
to sulpiride,
sulpiride, its
its structural
structural analogs,
analogs,
amisulpride,
tiapride,
lidocaine
and
cisapride,
were
chosen
as
substrates
for
the
comparative
amisulpride, tiapride, lidocaine and cisapride, were chosen as substrates for the comparativestudy.
study.
According
to
the
procedure
of
the
static
adsorption
experiment,
every
substrate
at
1.0
mmol/L
with
According to the procedure of the static adsorption experiment, every substrate at 1.0 mmol/L with
2.0 mL was mixed with the MIP for its adsorption selectivity experiment. The adsorption amounts of
2.0 mL was mixed with the MIP for its adsorption selectivity experiment. The adsorption amounts of
the MIP and NIP to sulpiride and the analogs were determined by UV spectrophotometry. Then, the
the MIP and NIP to sulpiride and the analogs were determined by UV spectrophotometry. Then, the
specific absorption ratio, imprinting factor α and specific factor β were calculated (Table 1).
specific absorption ratio, imprinting factor α and specific factor β were calculated (Table 1).
Materials 2017, 10, 475
Specific
Specific
Specific
Specific
Specific
Chemical
Structure
Adsorption
Imprinting
Specific
Chemical
Structure
AdsorptionImprinting
Chemical
Structure
Adsorption
Chemical
Structure
Adsorption
Factor,
α
Factor,
ββ β
Chemical Structure
QMIP (μmol/g)
QNIP (μmol/g)
(μmol/g) Adsorption
Factor,
Factor,
(μmol/g)
Factor,
α α
Factor,
(μmol/g)
α
βSpecific
Ratio
(%)
(μmol/g)Specific Ratio
Factor,
α Factor,Factor,
Factor,
β
Chemical Structure
QMIP (µmol/g)
QNIP (µmol/g)
∆Q (µmol/g)
Adsorption
Ratio
Imprinting
α
Factor, β
Ratio
(%)(%)Factor,
Ratio
(%)
(%)
Ratio (%)
Specific Imprinting
Specific
Table 1. Selective adsorption of the MIP to sulpiride
analogs.
QQQand itsSpecific
Specific
Imprinting
Imprinting
Q
Q
MIP
(μmol/g)
Q
NIP
(μmol/g)
Q
Q(μmol/g)
MIP
(μmol/g) Q
Q(μmol/g)
NIP
(μmol/g) (μmol/g)
QMIP
MIP
(μmol/g)
QNIP
NIP
(μmol/g)
Q
Substrate
Substrate
Substrate
Substrate
Substrate
Substrate
O
O
O
O
O
H2N
S
O
HS2N
H2N
OS
H2N
S
O
H2N
S
O
O
Sulpiride
Sulpiride
Sulpiride
Sulpiride
Sulpiride
Sulpiride
60.05
H
NH
H N
NH
N
O
O
O O
O
O
O
O O
OO
O
O
O
S
O
S
OS
S
O
S
O
Amisulpride
Amisulpride
Amisulpride
Amisulpride
Amisulpride
Amisulpride
H2N
H2N
H2N
H2N
H
N
O
S
S
O
S
O
O
O
O
O O
O
O
OS
O
H
N
O
HN
N N
N
N
Cl
Cl
Cl
Cl
O
O
N
48.85
48.85
48.85
48.85
48.85
81.35
81.35
81.35
81.35
81.35
81.35
5.36
5.365.36
5.36
5.36
5.36
1.00
1.00
1.00
1.00
1.00
1.00
55.00
55.00
55.00
55.00
55.00
55.00
15.10
15.10
15.10
15.10
15.10
15.10
39.90
39.90
39.90
39.90
39.90
39.90
72.55
72.55
72.55
72.55
72.55
72.55
3.64
3.643.64
3.64
3.64
3.64
0.82
0.82
0.82
0.82
0.82
0.82
50.35
50.35
50.35
50.35
50.35
50.35
15.55
15.55
15.55
15.55
15.55
15.55
34.80
34.80
34.80
34.80
34.80
34.80
69.12
69.12
69.12
69.12
69.12
69.12
3.24
3.24
3.24
3.24
3.24 3.24
0.71
0.71
0.71
0.71
0.71
0.71
25.75
25.75
25.75
25.75
25.75
25.75
6.60
6.60
6.60
6.60
6.60
6.60
19.15
19.15
19.15
19.15
19.15
19.15
74.37
74.37
74.37
74.37
74.37
74.37
3.90
3.903.90
3.90
3.90
3.90
0.39
0.39
0.39
0.39
0.39
0.39
18.50
18.50
18.50
18.50
18.50
18.50
6.55
6.55
6.55
6.55
6.55
6.55
11.95
11.95
11.95
11.95
11.95
11.95
64.59
64.59
64.59
64.59
64.59
64.59
2.82
2.822.82
2.82
2.82
2.82
0.24
0.24
0.24
0.24
0.24
0.24
N
N
N
N
N
N
O
N
O
O
O
O
H
O
N
H
N H
H N
NH
N
Cl
O
O
O
48.85
H
N
O
O
O
O
O
O
11.20
11.20
11.20
11.20
11.20
O
H
NH
H N
NH
N
Lidocaine
Lidocaine
Lidocaine
Lidocaine
Lidocaine
Lidocaine
11.20
O
O
O O
O
O
O
N
N
N
H
NH
H N
NH
N
O
O
60.05
60.05
60.05
60.05
60.05
O
O
O
OO
Tiapride
Tiapride
Tiapride
Tiapride
Tiapride
Tiapride
H2N
N
N
O
H
NH
H N
NH
N
O
H2N
H2N
H2N
H2N
N
N
N
H2N
O
O
S
Cisapride
Cisapride
Cisapride
Cisapride
Cisapride
Cisapride
9 of 16
Table
1.1.Selective
adsorption
of
to
and
its
Table
1. Selective
adsorption
of MIP
the
MIP
to sulpiride
its analogs.
Table
Selective
adsorption
ofthe
the
MIP
tosulpiride
sulpiride
andand
itsanalogs.
analogs.
Table
Table 1.
1. Selective
Selective adsorption
adsorption of
of the
the MIP
MIP to
to sulpiride
sulpiride and
and its
its analogs.
analogs.
O
O
O
N
N
N
N
O
NO
(CH2O)3
(CH2)3
(CH2)3O
(CH2)3
O
(CH2)3
F
F
F
F
F
Materials
2017,
10,
doi:
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2017,
10,
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2017,
10,475;
475;475;
doi:doi:
10.3390/ma10050475
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2017, 10,
10, 475;
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doi: 10.3390/ma10050475
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Materials 2017, 10, 475
10 of 16
InTable
Table1,1,the
the MIPhad
had relativelyhigh
highadsorption
adsorptionability
abilityto
tosulpiride
sulpirideand
andits
itsanalogs
analogscompared
compared
In
In
1, the
theMIP
MIP had
hadrelatively
relativelyhigh
highadsorption
adsorptionability
abilityto
tosulpiride
sulpirideand
andits
its
analogs
compared
In Table
Table
1,
MIP
relatively
analogs
compared
to
to
that
of
the
NIP.
Moreover,
sulpiride
had
the
highest
selectivity
among
structural
analogs,
to
that
of
the
NIP.
sulpiride
had
highest
selectivity
among
structural
analogs,
to
that
of NIP.
the Moreover,
NIP. Moreover,
Moreover,
sulpiride
had the
the
highest among
selectivity
among
structural
analogs,
that
of
the
sulpiride
had
the
highest
selectivity
structural
analogs,
demonstrating
demonstratingmore
morespecifically
specificallyimprinted
imprintedon
onthe
the MIP.The
Thehigher
higherwas
was thesimilarity
similarityin
in chemical
demonstrating
demonstrating
more
specifically
imprinted
on higher
the MIP.
MIP.
The
higher
was the
thechemical
similaritystructure,
in chemical
chemical
more
specifically
imprinted
on
the
MIP.
The
was
the
similarity
in
the
structure,the
thestronger
strongerwas
wasthe
theselective
selectiveadsorption.
adsorption.For
Foramisulpride
amisulprideand
andtiapride,
tiapride,their
theirselectivity
selectivity
structure,
structure,
the
stronger
was
the
selective
adsorption.
For
amisulpride
and
tiapride,
their
selectivity
stronger
was
the
selective
adsorption.
For
amisulpride
and
tiapride,
their
selectivity
and
capacity
was
and capacity
capacity was
was attributed
attributed to
to the high
high level
level similarity of
of N-contained functional
functional groups
groups and
and
and
and
capacity
washigh
attributed
to the
the high
level similarity
similarity
of N-contained
N-contained
functional
groups
and
attributed
to the
level
similarity
of N-contained
functional
groups
and
molecular
size
as well
molecular
size
as
well
as
shape,
providing
evidence
of
amide
and/or
amine
interaction
with
monomer
molecular
size
as
providing
evidence
of
and/or
amine
interaction
with
molecular
sizeas
aswell
wellevidence
asshape,
shape,of
providing
evidence
ofamide
amide
and/orwith
amine
interaction
withmonomer
monomer
as shape,hydrogen
providing
amide
and/or
amine
interaction
monomer
through
hydrogen
through
bonding
[39].
In
addition,
the
steric
structure
of
the
N-contained
functional
group
through
hydrogen
bonding
[39].
In
addition,
the
steric
structure
of
the
N-contained
functional
group
through
hydrogen
bonding
[39].
In
addition,
the
steric
structure
of
the
N-contained
functional
bonding
[39].
In
addition,
the
steric
structure
of
the
N-contained
functional
group
also
played
a group
role
in
also
played
a
role
in
selective
binding.
Compared
to
sulpiride,
amisulpride
and
tiapride
have
one
also
played
aa role
in
selective
binding.
Compared
to
sulpiride,
amisulpride
and
tiapride
have
one
also
played
role
in
selective
binding.
Compared
to
sulpiride,
amisulpride
and
tiapride
have
one
selective
binding.
Compared
to sulpiride,
amisulpride
and tiapride
have
oneFollowing
and two steric
and
two steric
changes,
respectively,
affecting
stericselection
selection
in binding
sites.
stericchanges,
change
and
two
changes,
respectively,
affecting
steric
in
sites.
steric
change
and
twosteric
stericaffecting
changes,steric
respectively,
affecting
steric
selection
inbinding
binding
sites.Following
Following
steric
change
respectively,
selection
in
binding
sites.
Following
steric
change
affecting
the
interaction
affecting
the
interaction
of
monomer
functional
group
with
target
compound,
specific
factor

might
affecting
the
of
functional
group
with
compound,
specific factor
might
affecting
theinteraction
interaction
ofmonomer
monomer
functional
groupspecific
withtarget
target
compound,
might
of monomer
functionalfor
group
with target
compound,
factor
β
might bespecific
thestudy
bestfactor
parameter
for
be
the
best
parameter
evaluation
of
selectivity
of
the
MIP.
This
comparative
exhibited
the
be
the
best
parameter
for
evaluation
of
selectivity
of
the
MIP.
This
comparative
study
exhibited
the
be
the
best
parameter
for
evaluation
of
selectivity
of
the
MIP.
This
comparative
study
exhibited
the
evaluation
of selectivity
of thewas
MIP.restricted
This comparative
study
the ability
of specific
ability
of specific
recognition
andaffected
affected
by exhibited
the structural
matching
degree.recognition
Asresult,
result,
ability
of
recognition
was
restricted
and
matching
degree.
As
ability
ofspecific
specific
recognition
was
restricted
and
affectedby
bythe
thestructural
structural
matching
degree.
As
result,
was
restricted
and
affected
by
the
structural
matching
degree.
As
result,
imprinting
factorhad
α of
5.36
imprinting
factor
α
of
5.36
and
specific
adsorption
ratio
of
81.3%
proved
that
the
MIP
good
imprinting
factor
αα of
and
specific
adsorption
ratio
of
81.3%
proved
that
the
good
imprinting
factor
of 5.36
5.36
and
specific
adsorption
ratio
of
81.3%
proved
that
the MIP
MIPtohad
had
good
and
specific
adsorption
ratio
of
81.3%
proved
that
the
MIP
had
good
specific
recognition
sulpiride.
specificrecognition
recognitionto
to sulpiride.Thus,
Thus, it couldbe
be usedfor
for theextraction
extraction andenrichment.
enrichment.
specific
specific
tosulpiride.
sulpiride.
Thus,ititcould
could
beused
used forthe
the extractionand
and enrichment.
Thus, it recognition
could be used
for the extraction
and
enrichment.
3.4.Investigation
Investigationofofthe
theRecognition
RecognitionMechanism
Mechanismofofthe
theMIP
MIP
3.4.
3.4.
ofthe
theRecognition
RecognitionMechanism
Mechanism
MIP
3.4. Investigation
Investigation of
of of
thethe
MIP
Substratestudied
studiedabove
abovedid
didnot
not provideenough
enoughevidence
evidencesupporting
supportingamide
amide and/oramine
amine binding
Substrate
Substrate
above
diddid
notprovide
provide
enough
evidence
supporting
amideand/or
and/or and/or
aminebinding
binding
Substratestudied
studied
above
not
provide
enough
evidence
supporting
amide
amine
and
also
did
not
exclude
possible
binding
of
other
functional
groups
which
might
also
contributetoto
and
also
did
not
exclude
possible
binding
of
other
functional
groups
which
might
also
contribute
and
also and
did not
of binding
other functional
which
might which
also contribute
to
binding
alsoexclude
did notpossible
excludebinding
possible
of othergroups
functional
groups
might also
selectivebinding.
binding.Based
Based onchemical
chemical structure,sulpiride
sulpiridemay
maybe
be conceivedas
as a combinationof
of threeparts:
parts:
selective
selective
binding.
Basedon
on
chemicalstructure,
structure,
beconceived
conceived
asaacombination
combination
ofthree
three parts:
contribute
to selective
binding.
Based
onsulpiride
chemicalmay
structure,
sulpiride
may be conceived
as a
p-toluenesulfonamide, formamide
formamide and
and 1-methylpyrrolidine. Accordingly,
Accordingly, p-toluenesulfonamide,
p-toluenesulfonamide,
p-toluenesulfonamide,
p-toluenesulfonamide,
formamide
and 1-methylpyrrolidine.
1-methylpyrrolidine.
Accordingly,
p-toluenesulfonamide,
combination of three parts:
p-toluenesulfonamide,
formamide and
1-methylpyrrolidine.
Accordingly,
formamide
and
1-methylpyrrolidine
were
used
as
model
substrates
to
mimick
individual functional
functional
formamide
and
as
to
formamide
and 1-methylpyrrolidine
1-methylpyrrolidine
were
used
as model
model substrates
substrates
to mimick
mimick
individual
functional
p-toluenesulfonamide,
formamidewere
and used
1-methylpyrrolidine
were
used
asindividual
model substrates
to
groupsfor
forfurther
further investigationof
of bindingsites
sitesthrough
throughstatic
static adsorptionexperiments.
experiments.Formamide
Formamide
groups
groups
furtherinvestigation
investigation
ofbinding
binding
through
staticadsorption
adsorption
experiments.
Formamide
mimickfor
individual
functional groups
forsites
further
investigation
of binding
sites through
static
and1-methyl
1-methylpyrrolidine
pyrrolidine weredetermined
determinedby
byGC
GC andp-toluenesulphonamide
p-toluenesulphonamidewas
was determinedby
by
and
and
1-methylexperiments.
pyrrolidinewere
were
determined
GCand
and p-toluenesulphonamide
wasdetermined
determined
by
adsorption
Formamide
andby1-methyl
pyrrolidine were determined
by GC and
HPLC.
Table
2
lists
selective
adsorption
results
of
the
MIP
to
p-toluenesulfonamide,
formamide
and
HPLC.
Table
adsorption
results
to
formamide
and
HPLC.
Table22lists
listsselective
selective
adsorption
results
ofthe
theMIP
MIP
top-toluenesulfonamide,
p-toluenesulfonamide,
formamide
and
p-toluenesulphonamide
was
determined
by of
HPLC.
Table
2 lists selective adsorption
results
of
1-methylpyrrolidine,
providing
correlation
of
functional
groups
in
terms
of
selective
binding.
The
1-methylpyrrolidine,
providing
correlation
of
functional
groups
in
terms
of
selective
binding.
The
1-methylpyrrolidine,
providing
correlation
of
functional
groups
in
terms
of
selective
binding.
The
the MIP to p-toluenesulfonamide, formamide and 1-methylpyrrolidine, providing correlation of
results demonstrated
demonstrated that
that the adsorption
adsorption capacity
capacity decreased
decreased in
in the following
following order:
order:
results
results
demonstrated
that ofthe
the
adsorption
decreased
in the
the that
following
order:
functional
groups in terms
selective
binding.capacity
The results
demonstrated
the adsorption
1-methylpyrrolidine >> formamide
formamide >> p-toluenesulfonamide.
p-toluenesulfonamide. 1-methyl
1-methyl pyrrolidine
pyrrolidine exhibited
exhibited strong
1-methylpyrrolidine
1-methylpyrrolidine
formamide
p-toluenesulfonamide.
1-methyl
pyrrolidine
exhibited strong
strong
capacity decreased in>the
following >order:
1-methylpyrrolidine
> formamide
> p-toluenesulfonamide.
binding
capacity,
and
even
seemed
to
be
not
selective
in
terms
of
imprinting
factor
. .Hereby,
Hereby,ititisis
binding
capacity,
and
even
seemed
to
be
not
selective
in
terms
of
imprinting
factor

binding
capacity,
and
even
seemed
to
be
not
selective
in
terms
of
imprinting
factor

.
Hereby,
it is
1-methyl pyrrolidine exhibited strong binding capacity, and even seemed to be not selective in terms
proven that
that binding
binding sites
sites basically
basically originated
originated from
from N-contained
N-contained functional
functional group
group of
of template,
template,
proven
proven
that binding
basically
originated
from N-contained
functional
group
template,
of imprinting
factor α.sites
Hereby,
it is proven
that binding
sites basically
originated
from of
N-contained
resultingin
inthe
the strongadsorption
adsorptionbetween
betweentemplate
templateand
andpolymers.
polymers. Inaddition,
addition,the
the bindingcapacity
capacityof
of
resulting
resulting
thestrong
strong
adsorption
betweenin
template
andadsorption
polymers.In
In
addition,template
thebinding
binding
of
functionalingroup
of template,
resulting
the strong
between
andcapacity
polymers.
p-toluenesulfonamide
in
both
MIP
and
NIP
is
relatively
weak,
and
it
could
be
only
steric
effect.
p-toluenesulfonamide
in
both
NIP
and
ititcould
be
steric
p-toluenesulfonamide
incapacity
bothMIP
MIP
and
NIPisisrelatively
relativelyweak,
weak,
and
could
beonly
only
stericeffect.
effect.
In addition, the binding
ofand
p-toluenesulfonamide
in both
MIP
and NIP
is relatively
weak, and
it could
be only steric
effect.selective adsorption of the MIP to p-toluenesulfonamide, formamide and
Table 2. Theresults
results ofselective
Table
Table 2.2. The
The results of
of selective adsorption
adsorption of
of the
the MIP
MIP to
to p-toluenesulfonamide,
p-toluenesulfonamide, formamide
formamide and
and
1-methylpyrrolidine
1-methylpyrrolidine
1-methylpyrrolidine
Table 2. The results of selective adsorption of the MIP to p-toluenesulfonamide, formamide
and 1-methylpyrrolidine
Specific
Substrate
Substrate
Substrate
Substrate
Chemical Structure
Chemical
ChemicalStructure
Structure
Chemical Structure
QMIP
MIP
QQ
MIP
(μmol/g)
(μmol/g)
QMIP
(µmol/g)
(μmol/g)
QNIP
NIP
QQ
NIP
Q
(μmol/g)
NIP
(μmol/g)
(μmol/g)
(µmol/g)
Q
QQ
∆Q
(μmol/g)
(μmol/g)
(μmol/g)
(µmol/g)
Specific
Specific
Imprinting
Imprinting
Adsorption
Ratio Imprinting
Adsorption
Ratio
Adsorption
Ratio Imprinting
Specific
Adsorption
Factor,
Factor,
Factor,
(%)
Ratio
(%)
Factor,
α 
(%)
(%)
O
O
O
S
S
S
p-Toluenesulfonamide
p-Toluenesulfonamide
p-Toluenesulfonamide
p-Toluenesulfonamide
H3C
H3C
H3C
Formamide
Formamide
Formamide
Formamide
1-Methylpyrrolidine
1-Methylpyrrolidine
1-Methylpyrrolidine
1-Methylpyrrolidine
NH2
NH2
NH2
O
O
O
0.51
0.51
0.51
0.51
0.01
0.01
0.01
0.01
0.50
0.50
0.50
0.50
98.04
98.04
98.04
98.04
– –
–
7.53
7.53
7.53
7.53
2.51
2.51
2.51
2.51
5.02
5.02
5.02
5.02
66.67
66.67
66.67
66.67
3.01
3.01
3.01
85.01
85.01
85.01
85.01
62.46
62.46
62.46
62.46
22.55
22.55
22.55
22.55
26.52
26.52
26.52
26.52
1.36
1.36
1.36
1.36
–
O
O
O
H
H
H
NH
NH2 2
NH2
N
N
N
3.01
CH3
CH3
CH3
Basedon
onthe
theresults
resultsof
ofsulpiride
sulpirideanalogs
analogsand
andmodel
modelgroups,
groups,Figure
Figure66shows
showsthe
theformation
formationof
of
Based
Based
results
of
analogs
and
model
Figure
66 shows
the
of
Based on
on the
theof
results
of sulpiride
sulpiride
analogs
and
model groups,
groups,
Figure
shows
the formation
formation
of
imprinting
cavity
the
MIP
with
sulpiride.
It
is
illustrated
that
four
monomer
molecules
could
form
imprinting
cavity
of
the
MIP
with
sulpiride.
ItItisisillustrated
that
four
monomer
molecules
could
form
imprinting
cavity
of
the
MIP
with
sulpiride.
illustrated
that
four
monomer
molecules
could
form
imprintingwith
cavity
of the MIP
with sulpiride.
It is
illustrated
that four
monomer
molecules
could
interaction
amolecule
molecule
of sulpiride.
Only two
functional
groups,
amide
and tertiary
amine, could
interaction
with
of
Only
functional
groups,
amide
amine,
interaction
withaawith
molecule
ofsulpiride.
sulpiride.
Onlytwo
two
functional
groups,groups,
amideand
andtertiary
tertiary
amine,could
could
form interaction
a molecule
of sulpiride.
Only
two functional
amide
and tertiary
amine,
Materials 2017,10,
10, 475;doi:
doi: 10.3390/ma10050475
Materials
Materials2017,
2017, 10,475;
475; doi:10.3390/ma10050475
10.3390/ma10050475
www.mdpi.com/journal/materials
www.mdpi.com/journal/materials
www.mdpi.com/journal/materials
Materials 2017, 10, 475
Materials 2017, 10, 475
11 of 16
2 of 4
could
possibly
strong
binding
through
hydrogen
bondformation,
formation,which
whichcontribute
contribute more to
possibly
formform
strong
binding
through
hydrogen
bond
to the
the
selective
adsorption.
The
other
two
functional
groups,
sulfonamide
and
aromatic
ether,
could
only
selective adsorption. The other two functional groups, sulfonamide and aromatic ether, could only
provide
providesteric
stericweak
weakinteraction
interactiondue
duetotopresences
presencesofofNNand
andO.
O.This
Thisisispartially
partiallydue
duetotothe
therigid
rigidstructure,
structure,
which
whichisislack
lackofofflexibility
flexibilityininthe
thesoft
softimprinting
imprintingcavity
cavityof
ofthe
theMIP.
MIP.There
Thereisisininagreement
agreementwith
withthat
that
1-methyl
pyrrolidine
exhibits
strong
binding
capacity
but
p-toluenesulfonamide
did
not
[40,41].
1-methyl pyrrolidine exhibits strong binding capacity but p-toluenesulfonamide did not [40,41].
OH
H2C
O
O
H2N
S
O
o
O
OH
H 2C
O
O
O
O
H
OH
H
N
O
HO
+
N
CH2
N
H
Self-assembiy
S
O
O
H
O
O
N
O
N
H
HO
O
O
O
O
H
O
O
O
OH
H 3C
CH2
O
O
H 3C
H 2C
O
O
O
O
H 2C
O
OH
O
HO
O
O
O
O
N
H
S
O
O
EGDMA
N
O
Adsorption
N
O
H
O
OH
HO
O
HO
CH3
Elution
H
AIBN
H 2C
HO
H
O
O
H2C
O
OH
O
OH
H2C
O
CH2
H3C
CH2
HO
H2C
H 2C
O
O
H2C
HO
O
O
OH
H
C
H2
O
O
O
O
C
H2
OH
O
CH2
HO
O
O
CH2
HO
Figure6.6.The
Theformation
formationprocess
processofofimprinting
imprintingcavity
cavityofofthe
theMIP
MIPwith
withsulpiride.
sulpiride.
Figure
3.5.Applications
Applicationsofofthe
theMIP
MIP
3.5.
3.5.1.Selective
SelectiveSolid-Phase
Solid-PhaseExtraction
Extraction
3.5.1.
Tovalidate
validatethe
theselectivity
selectivityofof
the
MIP,
solid-phase
extraction
(SPE)
of sulpiride
performed
To
the
MIP,
solid-phase
extraction
(SPE)
of sulpiride
waswas
performed
by
by monitoring
adsorption
amounts
of every
compound
a mixed
substrate
solution.The
Themixed
mixedsubstrate
substrate
monitoring
adsorption
amounts
of every
compound
in ainmixed
substrate
solution.
solution consisted
consisted ofofdifferent
differentdrugs,
drugs,such
suchasassulpiride,
sulpiride,sulfonamide
sulfonamideseries
series(p-toluenesulfonamide,
(p-toluenesulfonamide,
solution
sulfamethoxazole and
andsulfanilamide),
sulfanilamide), aniline
anilineseries
series(p-nitroaniline
(p-nitroanilineand
andacetanilide),
acetanilide),and
andheterocyclic
heterocyclic
sulfamethoxazole
series(trimethoprim)
(trimethoprim)(as
(asshown
shownin
inTable
Table3)3)atataaconcentration
concentrationof
of0.20
0.20mmol/L
mmol/L each.
each. Figure
Figure77illustrates
illustrates
series
HPLCchromatograms
chromatograms of
of the
the mixed substrate solution
HPLC
solution before
beforeand
andafter
afterSPE.
SPE.The
Thespecial
specialselectivity
selectivityof
was
characterized
inin
terms
ofof
specific
factor
. β.
Table
3 presents
thethe
specific
adsorption
of the
ofthe
theMIP
MIP
was
characterized
terms
specific
factor
Table
3 presents
specific
adsorption
of
MIP
to to
different
compounds
sulpiride was
wasselectively
selectively
the
MIP
different
compoundsthrough
throughSPE.
SPE.The
Theresults
results demonstrated
demonstrated that sulpiride
imprintedininthe
theMIP
MIPwith
withextraction
extractionrecovery
recoveryofof86.9%,
86.9%,followed
followedby
bytrimethoprim,
trimethoprim,suggesting
suggestingthat
that
imprinted
hydrogenbonding
bonding indeed
indeed introduced
introduced strong
strong interaction
interaction caused
caused by
by monomer
monomer functional
functional groups.
groups.
hydrogen
Accordingly,this
thisimplied
impliedthat
thatthe
thecombination
combinationofofamide
amideand
andamine
amineinteraction
interactionplus
plusadditional
additionalsteric
steric
Accordingly,
effectmight
mightaffect
affectadsorption
adsorptionselectivity.
selectivity.This
Thisstudy
studyalso
alsoexhibited
exhibitedthat
thatthe
theMIP
MIPhad
hadgood
goodspecific
specific
effect
recognitiontotosulpiride,
sulpiride,and
andititcould
couldbe
beused
usedfor
forextraction
extractionand
andenrichment.
enrichment.
recognition
Materials
2017,
10,
475
Materials
2017,
10,
475
Materials
Materials2017,
2017,10,
10,475
475
Materials
Materials2017,
2017,10,
10,475
475
ofof
33333of
of4444
3ofof44
Table
The
results
of
solid-phase
extraction
of
different
compounds
with
the
MIP.
Table
3.3.3.The
The
results
of
solid-phase
extraction
of
different
compounds
with
the
MIP.
Table
Table3.
Theresults
resultsof
ofsolid-phase
solid-phaseextraction
extractionof
ofdifferent
differentcompounds
compoundswith
withthe
theMIP.
MIP.
Table
Theresults
resultsofofsolid-phase
solid-phaseextraction
extractionofofdifferent
differentcompounds
compoundswith
withthe
theMIP.
MIP.
Materials 2017,Table
10, 4753.3.The
12 of 16
Specific
Factor,
Specific
Factor,
Specific
SpecificFactor,
Factor,
Specific
Substrate
Chemical
Structure
MIP(μmol/g)
(μmol/g)
NIP(μmol/g)
(μmol/g)
Recovery
(%)
Substrate
Chemical
Structure
QQ
MIP
QQ
NIP
Recovery
(%)
SpecificFactor,
Factor,
Table
3.
The
results
of
solid-phase
extraction
of
different
compounds
with
the
MIP.
Substrate
Chemical
Structure
Q
MIP
(μmol/g)
Q
NIP
(μmol/g)
Recovery
(%)
Substrate
Chemical
Structure
Q
MIP
(μmol/g)
Q
NIP
(μmol/g)
Recovery
(%)
MIP
NIP
Substrate
Chemical
QQMIP
(μmol/g)
(μmol/g)
β
Substrate
ChemicalStructure
Structure
MIP
(μmol/g) QQNIP
NIP
(μmol/g) Recovery
Recovery(%)
(%)
β
β
βββ
Substrate
Sulfamethoxazole
Sulfamethoxazole
Sulfamethoxazole
Sulfamethoxazole
Sulfamethoxazole
Sulfamethoxazole
Sulfamethoxazole
Chemical Structure
OO
O
NN OO
N
O
O HH
O
N
O
N NO O
OO H
OO
SS H
NNH N N O
S
N
H
H HN
S
SN
S
SS N
NN
OO
O
O
O
O
OO
OO
HH
N2N
H
22N
H
N
H N
H
N
H222H
N 2N
2
Sulfanilamide
Sulfanilamide
Sulfanilamide
Sulfanilamide
Sulfanilamide
Sulfanilamide
Sulfanilamide
2N
2N
HH
2
H
N
H 2N
H
H222HN
NN
p-Toluenesulfonamide
p-Toluenesulfonamide
p-Toluenesulfonamide
p-Toluenesulfonamide
p-Toluenesulfonamide
p-Toluenesulfonamide
p-Toluenesulfonamide
3C
3C
HH
3
H
C
H 3C
H
H333HC
CC
3
p-Nitroaniline
p-Nitroaniline
p-Nitroaniline
p-Nitroaniline
p-Nitroaniline
p-Nitroaniline
p-Nitroaniline
O
O
O
O
OO
NH
22
SS NH
NH
2
S
S
NH
22 2
S
S S NH
NH
2 2
NH
O
O
O
O
O
OO
OO
O
O
O
OO
NH
22
SS NH
NH
2
S
S
NH
22 2
S
S S NH
NH
2 2
NH
OO
O
O
O
OO
2
OO
N
2N
22O
O
N
O
N2N
O2O
2
2N2N
Acetanilide
Acetanilide
Acetanilide
Acetanilide
Acetanilide
Acetanilide
Acetanilide
Trimethoprim
Trimethoprim
Trimethoprim
Trimethoprim
Trimethoprim
Trimethoprim
Trimethoprim
Q MIP (µmol/g)
NH
NH
22 2
NH
NH
22 2
NH
NH
2 2
NH
NH
NH
NH
NH
NH
NH
NH
OO
O
O
O
OO
CH
CC CH
CH
33 3
C
C CH
33 3
C
C C CH
CH
3 3
CH
OO
O
O
O
O
OO
HH
N2N
NN
H
N
N
22N
H
N
H N
N
H
N
H222HN
N 2N
NN
2
NN
N
N
N
N
NN
NH
NH
NH
22 2
NH
2 2
NHNH
2
2
NH
OONH
2
O
O
O
O
OO
HH
N2N S
SS O
OO
H
22N
H
H 2NS
SO
O
2N
H
N
S
O
H 22HN N S S O O
OO
O
O
O
O
OO
OO
O
O
O
O
OO
QNIP (µmol/g)
Recovery (%)
Specific Factor, β
00000
00
000000
0
000000
0
000000
0
0.21
0.21
0.21
0.21
0.21
0.21
0.21
0.03
0.03
0.03
0.03
0.03
0.03
0.03
2.10
2.10
2.10
2.10
2.10
2.10
2.10
0.03
0.03
0.03
0.03
0.03
0.03
0.03
00
00
0
00
0
000000
0
000000
0
000000
0
0.24
0.24
0.24
0.24
0.24
0.24
0.24
0.13
0.13
0.13
0.13
0.13
0.13
0.13
2.39
2.39
2.39
2.39
2.39
2.39
2.39
0.02
0.02
0.02
0.02
0.02
0.02
0.02
00
00
000
00000
0
000000
0
000000
0
6.43
6.43
6.43
6.43
6.43
6.43
6.43
3.26
3.26
3.26
3.26
3.26
3.26
3.26
64.3
64.3
64.3
64.3
64.3
64.3
64.3
0.52
0.52
0.52
0.52
0.52
0.52
0.52
8.39
8.39
8.39
8.39
8.39
8.39
8.39
2.28
2.28
2.28
2.28
2.28
2.28
2.28
86.9
86.9
86.9
86.9
86.9
86.9
86.9
1.00
1.00
1.00
1.00
1.00
1.00
1.00
2
Sulpiride
Sulpiride
Sulpiride
Sulpiride
Sulpiride
Sulpiride
Sulpiride
HH
H
H
NNH
N
H
H
N
HN
N
NN
OO
O
O
O
O
OO
OO
O
O
O
O
OO
500
500
500
500
500
500
1
11
1
1
11
300
300
300
300
300
300
3
33
3 33
22
22 2
2
400
400
400
400
400
400
mV
mV
mV
mV
mV
mV
mV
mV
NN
N
N
N
N
NN
6
66
6 66
7
77
7 77
55
455 5
44
4 445
aaa
a
aa
1
11
1
1
11
33
33 3
3
2
22
2 22
200
200
200
200
200
200
55
455 5
44
4 445
6
66
6 66
1
11
1
1
11
100
100
100
100
100
100
3
33
3 33
2
22
2 22
55
455 5
44
4 445
6
66
6 66
7
77
7 77
bbb
bb
b
77
77 7
7
ccccc
c
0
00
0 00
0
00
0 00
5
55
5 55
10
10
10
10
1010
15
15
15
15
1515
t/min
t/min
t/min
t/min
t/min
t/min
20
20
20
20
2020
25
25
25
25
2525
30
30
30
30
3030
Figure
HPLC
chromatograms
of
the
mixed
solution
mol/L):
before
(a);
and
after
(b)
solid-phase
Figure
7.7.7.HPLC
HPLC
chromatograms
of
the
mixed
solution
(1(1
mol/L):
before
(a);
and
after
(b)
solid-phase
Figure
7.
chromatograms
of
mixed
solution
(1
before
(a);
Figure
HPLC
chromatograms
ofthe
thethe
mixed
solution
(1mol/L):
mol/L):
before
(a);and
and
after(b)
(b)solid-phase
solid-phase
Figure
HPLC
chromatograms
of
mixed
solution
(1 µmol/L):
before
(a);after
and
the
eluent
after
Figure
7.7.7.
HPLC
chromatograms
ofof
the
mixed
solution
(1(1
mol/L):
before
(a);
and
after
(b)
solid-phase
Figure
HPLC
chromatograms
the
mixed
solution
mol/L):
before
(a);
and
after
(b)
solid-phase
extraction
with
the
MIP;
and
after
solid-phase
extraction
with
the
NIP
(c).
1:
sulfamethoxazole;
extraction
with
the
MIP;
and
after
solid-phase
extraction
with
the
NIP
(c).
1:
sulfamethoxazole;
extraction
with
the
MIP;
and
after
solid-phase
extraction
with
the
NIP
(c).
1:
sulfamethoxazole;
extraction
with
the
MIP;
and
after
solid-phase
extraction
with
the
NIP
(c).
1:
sulfamethoxazole;
solid-phase
extraction
(SPE)
MIP (b); and
after SPE
with
the
NIP(c).
(c).1:1:
1:sulfamethoxazole;
sulfamethoxazole;
extraction
with
the
and
after
solid-phase
extraction
with
the
NIP
extraction
with
the MIP;
MIP;
andwith
afterthe
solid-phase
extraction
with
the
NIP
(c).
sulfamethoxazole;
sulfanilamide;
p-toluenesulfonamide;
p-nitroaniline;
acetanilide;
trimethoprim;
sulpiride.
2:2:2:
sulfanilamide;
3:3:3:p-toluenesulfonamide;
p-toluenesulfonamide;
4:4:4:p-nitroaniline;
p-nitroaniline;
5:5:5:acetanilide;
acetanilide;
6:6:6:trimethoprim;
trimethoprim;
7:7:7:sulpiride.
sulpiride.
2:
sulfanilamide;
3:
4:
5:
6:
7:
sulfanilamide;
p-toluenesulfonamide;
p-nitroaniline;
acetanilide;
trimethoprim;
sulpiride.
sulfanilamide;
3:p-toluenesulfonamide;
p-toluenesulfonamide;
4:
p-nitroaniline;
5: acetanilide;
6: trimethoprim;
7: sulpiride.
2:2:2:
sulfanilamide;
3:3:p-toluenesulfonamide;
4:4:p-nitroaniline;
5:5:acetanilide;
6:6:trimethoprim;
7:7:sulpiride.
sulfanilamide;
p-nitroaniline;
acetanilide;
trimethoprim;
sulpiride.
3.5.2.
Solid-Phase
Extraction
of
Serum
Sample
3.5.2.
Solid-Phase
Extraction
of
Serum
Sample
3.5.2.
Solid-Phase
Extraction
of
Serum
Sample
3.5.2.
Solid-Phase
Extraction
of
Serum
Sample
3.5.2.
Solid-Phase
Extraction
ofof
Serum
Sample
3.5.2.
Solid-Phase
Extraction
of
Serum
Sample
3.5.2.
Solid-Phase
Extraction
Serum
Sample
Considering
real
application
of
the
MIP
as
solid-phase
extractant
[42,43],
serum
sample
was
Considering
real
application
of
the
MIP
as
solid-phase
extractant
[42,43],
serum
sample
was
Considering
real
application
of
the
MIP
as
aaaaaaasolid-phase
extractant
[42,43],
Considering
real
application
of
the
MIP
as
solid-phase
extractant
[42,43],
serum
sample
was
Considering
real
application
ofof
the
MIP
as
solid-phase
extractant
[42,43],
serum
sample
was
Considering
real
application
of
the
MIP
as
solid-phase
extractant
[42,43],serum
serumsample
samplewas
was
Considering
real
application
the
MIP
as
solid-phase
extractant
[42,43],
serum
sample
was
used
to
investigate
the
effect
of
complex
matrix
on
the
MIP
adsorption
of
sulpiride.
Solid-phase
used
to
investigate
the
effect
of
complex
matrix
on
the
MIP
adsorption
of
sulpiride.
Solid-phase
used
to
investigate
the
effect
of
complex
matrix
on
the
MIP
adsorption
of
sulpiride.
Solid-phase
used
to
investigate
the
effect
of
complex
matrix
on
the
MIP
adsorption
of
sulpiride.
Solid-phase
used
usedtoto
toinvestigate
investigatethe
theeffect
effectofof
ofcomplex
complexmatrix
matrixon
onthe
theMIP
adsorptionofofsulpiride.
Solid-phase
used
investigate
the
effect
complex
matrix
on
the
MIPadsorption
adsorption
sulpiride.Solid-phase
Solid-phase
extraction
of
sulpiride
in
rat
serum
was
performed
by
the
MIP
adsorption
(Shown
in
Figure
8),
and
extraction
of
sulpiride
in
rat
serum
was
performed
by
the
MIP
adsorption
(Shown
in
Figure
8),
and
extraction
of
sulpiride
in
rat
serum
was
performed
by
the
MIP
adsorption
(Shown
in
Figure
8),
and
extraction
of
sulpiride
in
rat
serum
was
performed
by
the
MIP
adsorption
(Shown
in
Figure
8),
and
extraction
ofof
sulpiride
inin
rat
serum
was
performed
by
the
MIP
adsorption
(Shown
inin
Figure
8),
and
extraction
of
sulpiride
in
rat
serum
was
performed
by
the
MIP
adsorption
(Shown
in
Figure
8),
and
extraction
sulpiride
rat
serum
was
performed
by
the
MIP
adsorption
(Shown
Figure
8),
and
recovery
tests
were
also
completed
by
spiking
sulpiride
at
different
levels.
After
elution
of
sulpiride
recovery
tests
were
also
completed
by
spiking
sulpiride
at
different
levels.
After
elution
of
sulpiride
recovery
tests
were
also
completed
by
spiking
sulpiride
at
different
levels.
After
elution
of
sulpiride
recovery
tests
were
also
completed
by
spiking
sulpiride
at
different
levels.
After
elution
of
sulpiride
recovery
tests
were
also
completed
by
spiking
sulpiride
at
different
levels.
After
elution
of
sulpiride
recoverytests
testswere
werealso
alsocompleted
completedby
byspiking
spikingsulpiride
sulpirideat
atdifferent
differentlevels.
levels.After
Afterelution
elutionof
ofsulpiride
sulpiride
recovery
adsorbed
by
the
MIP,
its
concentration
was
determined
by
HPLC.
As
shown
in
Table
recoveries
of
adsorbed
by
the
MIP,
its
concentration
was
determined
by
HPLC.
As
shown
in
Table
4,4,
recoveries
of
adsorbed
by
the
MIP,
determined
by
HPLC.
As
shown
in
Table
4,
recoveries
of
adsorbed
by
the
MIP,
its
concentration
was
determined
by
HPLC.
As
shown
in
Table
4,
recoveries
of
adsorbed
by
the
MIP,
its
concentration
was
determined
by
HPLC.
As
shown
inin
Table
4,4,
recoveries
ofof
adsorbed
by
the
MIP,its
itsconcentration
concentrationwas
was
determined
by
HPLC.
As
shown
in
Table
4,
recoveries
of
adsorbed
by
the
MIP,
its
concentration
was
determined
by
HPLC.
As
shown
Table
recoveries
sulpiride
adsorbed
by
the
MIP
ranged
from
81.57%
to
86.63%.
The
results
exhibited
that
there
is
no
sulpiride
adsorbed
by
the
MIP
ranged
from
81.57%
to
86.63%.
The
results
exhibited
that
there
is
no
sulpiride
adsorbed
by
the
MIP
ranged
from
81.57%
to
86.63%.
The
results
exhibited
that
there
is
no
sulpiride
adsorbed
by
the
MIP
ranged
from
81.57%
to
86.63%.
The
results
exhibited
that
there
is
no
sulpiride
adsorbed
by
the
MIP
ranged
from
81.57%
to
86.63%.
The
results
exhibited
that
there
is
no
sulpirideadsorbed
adsorbedby
bythe
theMIP
MIPranged
rangedfrom
from81.57%
81.57%to
to86.63%.
86.63%.The
Theresults
resultsexhibited
exhibitedthat
thatthere
thereisisno
no
sulpiride
significant
interference
of
serum
matrix
to
the
MIP
adsorption.
ItItis
also
noted
that
the
spike
level
significant
interference
of
serum
matrix
to
the
MIP
adsorption.
It
isisisalso
also
noted
that
the
spike
level
significant
interference
of
serum
to
noted
that
significant
interference
of
serum
matrix
to
the
MIP
adsorption.
also
noted
that
the
spike
level
significant
interference
ofof
serum
matrix
toto
the
MIP
adsorption.
ItIt
noted
that
the
spike
level
significant
interference
of
serummatrix
matrix
tothe
theMIP
MIPadsorption.
adsorption.It
Itisis
isalso
also
noted
thatthe
thespike
spikelevel
level
significant
interference
serum
matrix
the
MIP
adsorption.
also
noted
that
the
spike
level
should
ideally
be
controlled
at
lower
than
1.00
μmol
for
10
mg
of
the
MIP,
because
too
high
spike
should
ideally
be
controlled
at
lower
than
1.00
μmol
for
10
mg
of
the
MIP,
because
too
high
spike
should
ideally
be
controlled
at
lower
than
1.00
μmol
for
10
mg
of
the
MIP,
aaaaaaaspike
should
ideally
be
controlled
at
lower
than
1.00
μmol
for
10
mg
of
the
MIP,
because
too
high
spike
should
ideally
be
controlled
atat
lower
than
1.00
μmol
for
10
mg
ofof
the
MIP,
because
too
high
spike
should
ideally
be
controlled
at
lower
than
1.00
µmol
for
10
mg
of
the
MIP,because
becausetoo
toohigh
high
spike
should
ideally
be
controlled
lower
than
1.00
μmol
for
10
mg
the
MIP,
because
too
high
spike
level could not ensure sulpiride recovery at more than 86%. As a result, the MIP could effectively
Materials
2017,
10, 10,
475475
Materials
2017,
13 of 416of 4
level could not ensure sulpiride recovery at more than 86%. As a result, the MIP could effectively
extract sulpiride from the serum sample, suggesting that it can be used as a potential solid-phase
extract sulpiride from the serum sample, suggesting that it can be used as a potential solid-phase
extractant for preconcentration and cleanup in complex biological samples.
extractant for preconcentration and cleanup in complex biological samples.
Table 4. The results of solid-phase extraction of sulpiride from rat serum samples by the MIP (n = 3).
Table 4. The results of solid-phase extraction of sulpiride from rat serum samples by the MIP (n = 3).
Sample
Sample
Spike
SpikeLevels
Levels(µmol/L)
(μmol/L)
Determined
(µmol/L)
Determined
(μmol/L)
Recovery
(%) (%)
Recovery
1 1
2 2
3 3
0.050
0.050
0.100
0.100
0.150
0.150
0.432
 0.005
0.432
± 0.005
0.862
± 0.038
0.862
 0.038
1.223
± 0.041
1.223
 0.041
86.63 86.63
± 0.75 0.75
86.23 86.23
± 3.75 3.75
81.57 81.57
± 2.73 2.73
20
18
16
14
12
c
mV
10
8
6
b
4
2
0
a
0
2
4
6
8
10
12
14
16
t/min
Figure
8. 8.
The
HPLC
chromatograms
with the
Figure
The
HPLC
chromatogramsof:of:rat
ratserum
serumblank
blank(a);
(a);rat
ratserum
serumsample
sampleafter
after SPE
extraction
with
MIP
(b);
and
standard
solution
of
sulpiride
at
0.100
µmol/L
(c).
the MIP (b); and standard solution of sulpiride at 0.100 µ mol/L (c).
3.5.3.
Drug
Release
MIP
[44]
3.5.3.
Drug
Release
of of
thethe
MIP
[44]
controlled
release
MIP–sulpiride
was
carried
simulated
gastric
fluid
(pH
1.0),
TheThe
controlled
release
of of
MIP–sulpiride
was
carried
outout
in in
simulated
gastric
fluid
(pH
1.0),
◦ C.
intestinal
fluid
(pH
and
blood
plasma
(pH
under
continuous
stirring
at ±
370.5
± 0.5
C.
The
results
intestinal
fluid
(pH
6.8)6.8)
and
blood
plasma
(pH
7.4)7.4)
under
continuous
stirring
at 37
The
results
indicated
thatthe
thedrug
drugcumulative
cumulative release
release rate depends
medium.
TheThe
release
raterate
at pH
indicated
that
dependson
onthe
thepH
pHofof
medium.
release
7.4 was
slowerslower
than that
atthat
pH 1.0.
The1.0.
reason
that sulpiride
as a weak
at 6.8
pHand/or
6.8 and/or
7.4remarkably
was remarkably
than
at pH
The is
reason
is that sulpiride
asbase
a
was
easily
dissolved
in
the
gastric
fluid,
and
resulted
in
the
MIP
collapsed.
Clearly,
the
MIP
(as
shown
weak base was easily dissolved in the gastric fluid, and resulted in the MIP collapsed. Clearly, the
in (as
Figure
9a) in
at Figure
pH 6.89a)
andat7.4
better
ability
of controlling
release.drug
Thisrelease.
effect is
MIP
shown
pHshowed
6.8 and a7.4
showed
a better
ability of drug
controlling
ascribable
specific binding
sites
in the sites
polymeric
which
slowly
release
the drug.
Thus,
This
effect is to
ascribable
to specific
binding
in thenetwork
polymeric
network
which
slowly
release
the a
MIP–sulpiride
tablet was tablet
taken was
to conduct
release
in simulated
intestinal
fluid (pH
6.8)
drug.
Thus, a MIP–sulpiride
taken todrug
conduct
drugtest
release
test in simulated
intestinal
fluid
according
to the procedure
described
in Section
2.8. In 2.8.
contrast,
a drug atablet
of identical
(pH
6.8) according
to the procedure
described
in Section
In contrast,
drugconsisting
tablet consisting
of
pharmaceutical
excipients
was also
As shown
in Figure
9b, the
rate rate
of contrast
tablet
identical
pharmaceutical
excipients
wastested.
also tested.
As shown
in Figure
9b,release
the release
of contrast
waswas
up to
while
only
48.7%
of the
drug
was
released
from
thethe
MIP
tablet.
Furthermore,
the
tablet
up80.3%
to 80.3%
while
only
48.7%
of the
drug
was
released
from
MIP
tablet.
Furthermore,
without
thethe
MIP
was
almost
completely
released
within
60 min,
whereas
MIP tablet
took 240
min
thetablet
tablet
without
MIP
was
almost
completely
released
within
60 min,
whereas
MIP tablet
took
formin
thefor
release
to be completed.
It revealed
that drugthat
release
the from
contrast
wastablet
remarkably
240
the release
to be completed.
It revealed
drugfrom
release
thetablet
contrast
was
faster thanfaster
that of
thethat
MIPoftablet.
Thetablet.
resultsThe
confirmed
the MIP
used
a carrier
could
control
remarkably
than
the MIP
results that
confirmed
that
theasMIP
used as
a carrier
the release
a certainto
extent.
Therefore,
the MIP may
utilized
asutilized
potential
could
control of
thesulpiride
release oftosulpiride
a certain
extent. Therefore,
thebe
MIP
may be
as recognition
potential
material for
controlled
release, enabling
sulpiride
to be delivered
to thetotargeted
site in
recognition
material
for controlled
release, enabling
sulpiride
to be delivered
the targeted
siteclinic
in
applications.
clinic
applications.
Materials 2017, 10, 475
a
100
b
100
90
Cumulative release rate(%)
Cumulative release rate(%)
14 of 16
pH 1.0
pH 6.8
pH 7.4
80
70
60
50
80
Tablet without MIP
Tablet with MIP
60
40
20
0
40
0
20
40
60
80
100
120
140
160
0
Time(min)
50
100
150
200
250
300
Time(min)
Figure 9. Release curves of: MIP–sulpiride in the different pH media (a); and sulpiride tablets with
Figure 9. Release curves of: MIP–sulpiride in the different pH media (a); and sulpiride tablets with
and without MIP (b).
and without MIP (b).
4. Conclusions
4. Conclusions
In this work, a MIP was prepared by bulk polymerization using sulpiride as the template
molecule,
ITAa as
thewas
functional
monomer
and EGDMA as using
the crosslinker.
The
optimized
In
this work,
MIP
prepared
by bulk polymerization
sulpiride as
theMIP
template
molecule,
according
to template-monomer-crosslinker
of 1:4:15
showed good
adsorption
property
with
ITA as
the functional
monomer and EGDMAratio
as the
crosslinker.
The MIP
optimized
according
to
imprinting
factor
α
of
5.36
and
maximum
adsorption
capacity
of
61.13
μmol/g.
The
ITA-based
MIP
template-monomer-crosslinker ratio of 1:4:15 showed good adsorption property with imprinting factor
greatly
theadsorption
nonspecific capacity
adsorption
to the The
MMA-based
MIP
[22,23].
Thedecreased
MIP
α of 5.36
anddecreased
maximum
of compared
61.13 µmol/g.
ITA-based
MIP
greatly
demonstrated high selectivity and binding capacity towards sulpiride against the structural analogs
the nonspecific adsorption compared to the MMA-based MIP [22,23]. The MIP demonstrated high
including amisulpride, tiapride, lidocaine and cisapride. Rebinding experiments of small molecules
selectivity
and binding capacity towards sulpiride against the structural analogs including amisulpride,
and analogs with similar functional groups revealed the adsorption recognition mechanism of the
tiapride,
lidocaine
Rebinding
experiments
of small
with similar
MIP, suggestingand
thatcisapride.
its high selective
ability
mainly depended
on molecules
the bindingand
sitesanalogs
from functional
functional
revealed
thewhich
adsorption
mechanism
of the
MIP, suggesting
that its high
groupsgroups
of amide
and amine,
formedrecognition
hydrogen bindings
between
sulpiride
and ITA in addition
selective
ability
mainlyBased
depended
the binding
sitesand
from
of the
amide
amine,
to space
matching.
on the on
kinetic
characteristic
thefunctional
adsorptiongroups
capacity,
MIPand
could
provide
potential carrier
material
for solid-phase
extraction
drug to
release
to the larger
which
formeda hydrogen
bindings
between
sulpiride and
ITA inand
addition
spacedue
matching.
Based on
surfacecharacteristic
area and porosity.
the MIP
could be
used
to selectively
extractasulpiride
a mixed
the kinetic
andAccordingly,
the adsorption
capacity,
the
MIP
could provide
potentialfrom
carrier
material
solution
containing
different
constituents
(p-toluenesulfonamide,
sulfamethoxazole
sulfanilamide,
pfor solid-phase extraction and drug release due to the larger surface area and porosity. Accordingly,
nitroaniline, acetanilide and trimethoprim) prior to HPLC analysis. Moreover, the MIP, as a solid-phase
the MIP could be used to selectively extract sulpiride from a mixed solution containing different
extractant, was also successfully applied in serum analysis, achieving high recoveries from 81.57% to
constituents (p-toluenesulfonamide, sulfamethoxazole sulfanilamide, p-nitroaniline, acetanilide and
86.63%, which meant the MIP effectively extract sulpiride from complicated serum matrix for
trimethoprim)
prior to HPLC analysis. Moreover, the MIP, as a solid-phase extractant, was also
removal of interferences. Finally, the drug release tests of a tablet loading the MIP–sulpiride exhibited
successfully
in serum
analysis,
high recoveries
from 81.57%
86.63%,
which
that the applied
adsorption
ability of
the MIPachieving
could obviously
inhibit sulpiride
releaseto
rate
compared
to ameant
the MIP
effectively
extract
sulpiride
complicated
serumalternative
matrix for
ofextraction
interferences.
contrast.
Thus, the
MIP prepared
wasfrom
proven
to be a promising
to removal
solid-phase
Finally,
drug release
andthe
controlled
release. tests of a tablet loading the MIP–sulpiride exhibited that the adsorption
ability of the MIP could obviously inhibit sulpiride release rate compared to a contrast. Thus, the MIP
Acknowledgements: The authors would like to thank the Science and Technology Planning Project of Guangdong
prepared
was proven to be a promising alternative to solid-phase extraction and controlled release.
Province (2016A040403119), The Science and Technology Program of Guangzhou City (No. 2008Z1-E301) and the
Fund Project of Guangdong Pharmaceutical University (No. 52104109) for finically supporting this work.
Acknowledgments: The authors would like to thank the Science and Technology Planning Project of Guangdong
Province
(2016A040403119),
The Science
and
Technology
Program
of Guangzhou
City (No.Wei
2008Z1-E301)
and the
Author
Contributions: Huajun
Fan and
Xuhui
She conceived
and designed
the experiments.
Zhang, Xuhui
FundShe
Project
of Guangdong
Pharmaceutical
University
(No.and
52104109)
finically
supporting
thisofwork.
and Liping
Wang performed
experiments.
Drug release
material for
study
were done
by guidance
James
Z. Tang.
Qing Zhou, Huajun
Xiaowen Fan
Huang
participated
in drug
analysis.
Alldesigned
authors took
in topic discussion,
Author
Contributions:
and
Xuhui She
conceived
and
thepart
experiments.
Wei Zhang,
andWang
reviewperformed
of the results.
Huajun Fan Drug
and James
Z. Tang
wrote the study
paper. were done by guidance of
Xuhuiinterpretation,
She and Liping
experiments.
release
and material
JamesConflicts
Z. Tang. of
Qing
Zhou, Xiaowen Huang participated in drug analysis. All authors took part in topic discussion,
Interest: The authors declare no conflict of interest.
interpretation, and review of the results. Huajun Fan and James Z. Tang wrote the paper.
Conflicts
of Interest: The authors declare no conflict of interest.
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