Enantioseparation of racemic amlodipine using immobilized ionic liquid by solid-phase extraction

Article abstract of DOI:10.1002/chir.23231

In this paper, a novel l-glutamate based immobilized chiral ionic liquid (SBA-IL (Glu)) was prepared by chemical bonding method and applied as a solid sorbent for chiral separation of amlodipine. The performance of SBA-IL (Glu) was investigated for the absorption of (S)-amlodipine and separation of amlodipine enantiomer. The static experiment showed that equilibrium adsorption was achieved within 80 minutes, and the saturation adsorptions capacity was 12 mg/g. The complex was then packed in a glass chromatographic column for the separation of amlodipine and the enantiomeric excess (%ee) of (S)-amlodipine reached 24.67%. The immobilized ionic liquids exhibit good reusability, and the separation efficiency remains 18.24% after reused five times, which allows potential scale-up for the chiral separation of amlodipine.

Full text of DOI:10.1002/chir.23231

Received: 12 February 2020
DOI: 10.1002/chir.23231
Revised: 20 March 2020
Accepted: 1 April 2020
R E G U L A R A R T I C L E
Enantioseparation of racemic amlodipine using
immobilized ionic liquid by solid-phase extraction
1
,2
1,2
1,2
1,2
3
Min Liu
| Zhong-Qian Liu
| Hai Zhu
| Chao-Hong He
| Ke-Jun Wu
1
Zhejiang Provincial Key Laboratory of
Advanced Chemical Engineering
Abstract
Manufacture Technology, College of
Chemical and Biological Engineering,
Zhejiang University, Hangzhou, China
In this paper, a novel L-glutamate based immobilized chiral ionic liquid (SBA-
IL (Glu)) was prepared by chemical bonding method and applied as a solid sor-
bent for chiral separation of amlodipine. The performance of SBA-IL (Glu)
was investigated for the absorption of (S)-amlodipine and separation of
amlodipine enantiomer. The static experiment showed that equilibrium
adsorption was achieved within 80 minutes, and the saturation adsorptions
capacity was 12 mg/g. The complex was then packed in a glass chromato-
graphic column for the separation of amlodipine and the enantiomeric excess
2
Institute of Zhejiang University-Quzhou,
Quzhou, China
3
School of Chemical and Process
Engineering, University of Leeds, Leeds,
UK
Correspondence
Chao-Hong He, Zhejiang Provincial Key
Laboratory of Advanced Chemical
Engineering Manufacture Technology,
College of Chemical and Biological
Engineering, Zhejiang University,
Hangzhou 310027, China.
(
%ee) of (S)-amlodipine reached 24.67%. The immobilized ionic liquids exhibit
good reusability, and the separation efficiency remains 18.24% after reused five
times, which allows potential scale-up for the chiral separation of amlodipine.
K E Y W O R D S
Email: chhezju@zju.edu.cn
amlodipine, enantioseparation, immobilized amino ionic liquid, solid-phase extraction
Ke-Jun Wu, School of Chemical and
Process Engineering, University of Leeds,
Leeds LS2 9JT, UK.
Email: k.j.wu@leeds.ac.uk
Funding information
National Natural Science Foundation of
China, Grant/Award Number:
No.21576231
1
| INTRODUCTION
However, the direct synthesis of (S)-amlodipine on an
4
,5
industrial scale has been rarely reported.
(S)-
Hypertension is the most common chronic disease and
the main risk factor of cardiovascular and cerebrovascu-
lar disease. Cardiovascular drug remains the main phar-
amlodipine is usually obtained by the racemic synthesis
of amlodipine racemate, followed by enantioselective sep-
6
,7
aration of amlodipine racemate using chromatography,
1
8
9,10
maceutical in fatalities. Amlodipine possessing (S)- and
preferential crystallization, capillary electrophoresis,
11,12
(
R)- isomers (Figure 1) have been widely used in clinical
and liquid–liquid extraction, etc.
Amlodipine race-
treatment of hypertension and angina pectoris. As is well
known, the hypotensive activity of (S)-amlodipine is
about 2000 times higher than that of (R)-amlodipine, and
mate can be separated by high-performance liquid chro-
matography (HPLC) with chiral stationary phases or
chiral mobile phase additives. Using Chiralcel OJ chiral
column, the resolution of amlodipine racemate was as
high as 3.23, and the resolution could achieve 2.08 with
C18 column by adding SBE-β-CD to mobile phase.
(
R)-amlodipine might cause side effects such as periph-
2,3
eral edema.
Thus, optically pure (S)-amlodipine is
intensely demanded.
Chirality. 2020;1–10.
wileyonlinelibrary.com/journal/chir
© 2020 Wiley Periodicals LLC
1

2
LIU ET AL.
16
amino acid CILs in our previous study. Although CILs
serving as extractant exhibited high performance in
enantioselective separation, the high pressure drop and
poor mass transfer properties trigged by the high viscos-
ity of CILs and the high cost and environmental issues
caused by the low recyclability of CILs hampered the
large scale application of liquid-liquid extraction based
on CILs.
FIGURE 1 The structures of (A) (R)-amlodipine and (B) (S)-
amlodipine
To overcome the drawbacks of CILs in liquid-liquid
extraction induced by liquidus nature and take advantage
of the availability of CILs in enantioselective separation,
one of the most effective approaches was to immobilize
CILs over solid supports. To date, a wide range of solid
supports (silica, SBA-15, MCM-41) was employed. The
immobilization of CILs over the surface of solid supports
can be achieved through immersion, covalent anchoring,
However, single enantiomer was mandatory for chroma-
tography, which led to a high separation cost. Preferen-
4
tial crystallization of (S)-amlodipine or (R)-amlodipine
from the mixture of tartaric acid and racemic amlodipine
in organic solvents (e.g., DMSO, DMF, or DCM) is indus-
trially feasible. However, the large amount of organic sol-
vents used always brings about safety and environmental
problems. Besides, too many operations such as mixing,
crystallization, solid separation make the process
17
and physical encapsulation methods. The immersion
method is carried out by directly impregnating the solid
supports in CILs, and a thin film of CILs is coated on the
solid supports by a physical adsorption. In this case, the
leaching of CILs cannot be avoided. When CILs are con-
nected with the surface of solid support via covalent
bonds, the stability of immobilized CILs was improved,
but the chemical bonding may limit the degree of
freedom of cations or anions. The physical encapsulation
method is established by using porous solid
supports such as silica gel, NaY zeolite and aluminum
oxide. The CILs are confined in matrices and form a
high-concentration environment. The as-fabricated
immobilized ionic liquids combine the advantages of
ionic liquids and solid supports (e.g., large specific sur-
face area, easy separation, good reusability). Therefore,
the immobilized ionic liquids exhibit superior
performance in comparison with their counterparts.
Immobilized ionic liquids are widely used in solid
7
complicated and time-consuming. Enantioselective sepa-
ration by capillary electrophoresis is performed by adding
chiral additives (e.g., cyclodextrin derivatives, proteins, or
maltodextrin) to the running buffer. For example, the
resolution of amlodipine racemate was improved from
0
.93 to 2.59 after adding amino-functionalized silica
8
nanoparticles to background electrolyte. Nevertheless,
the application of capillary electrophoresis is only appli-
cable in laboratory scale due to its small sample through-
put, long processing time and high cost. Liquid-liquid
extraction is widely considered as an alternative
approach to address the disadvantages of aforementioned
methods. The commonly used chiral extractants include
tartaric acid derivatives and cyclodextrin derivatives,
most of which exhibit poor extraction efficiency and need
to be handled at low temperature. In order to improve
the extraction efficiency and reduce energy consumption,
many efforts have been made to develop new extractants.
Because of the outstanding thermal stability, designable
structure, negligible vapor pressure, and good chiral rec-
ognition ability, chiral ionic liquids (CILs) have attracted
more and more attention in enantioselective liquid-liquid
18,19
phase extraction (SPE).
As the adsorbent of SPE,
immobilized CILs not only exhibit good separation ability
and selectivity but also reduce the use of toxic organic
solvents and realize the recycling of CILs.
In this work, immobilized L-glutamate-based ionic
liquid is synthesized and applied in SPE for
enantioselective separation of amlodipine racemate. The
morphology and structure of as-prepared immobilized
CIL was characterized. The static adsorption perfor-
mance of the immobilized CIL was studied to test the
adsorption property. In the dynamic adsorption process,
the enantiomeric recognition and separation potency
were tested. In addition, the regeneration and recycle
performance of the immobilized ionic liquids were also
investigated. SBA-IL (Glu) is a rather stable and efficient
absorbent, which could resolve the problem of toxic pol-
lution (ILs residues in target products) and stability in
previous works.
5,11–13
extraction as extractants.
CILs were used as solvent and acceptor, and
ethylacetate as donor phase when applied in extracting
more L-phenylalanine through ligand-exchange mecha-
nism. After single-step extraction, the value of %ee
14
achieved 50.6%. CILs in organic phase were used as
chiral selector in extraction of flurbiprofen in aqueous
phase and the maximum enantioselectivity was up to
15
1
.20. As for enantioselective separation of amlodipine
racemate, enantioselectivity up to 1.35 at 298.15 K was
obtained by a novel extraction system consisting of n-
decanol, NaAc/HAc buffer solution, and [Bmim][Glu]

LIU ET AL.
3
2
2
| MATERIALS AND METHODS
.1 | Chemicals
acetonitrile, followed by the ultrasonic dispersion of 4 g
of SBA-15 for 30 minutes. This suspension was kept at
ꢀ
80 C for 24 hours under magnetic stirring to obtain
2
1–23
immobilized halogenated ionic liquid (SBA-IL (Cl)).
SBA-15 was purchased from Xianfeng nanomaterial
technology Co. Ltd (Jiangsu, China). 1-methyl-imidazole
The as-prepared SBA-IL (Cl) was filtered, washed with
acetonitrile, acetone, and dichloromethane three times
each and then dried for 24 hours in a vacuum oven. Sub-
sequently, SBA-IL (Cl) was dispersed into 1000 mL of
NaOH aqueous solution (0.01 mol/L) by ultrasonic treat-
ment and stirred for 2 hours to perform ionic exchange at
room temperature. Then, alkalized immobilized ionic liq-
uid (SBA-IL (OH)) was collected, filtered, washed with
deionized water three times, and dried for 24 hours in a
(AR, 98%), (3-chloropropyl)trimethoxysilane (AR, 98%),
ethanol (HPLC grade, 99.8%), n-decanol (AR, 98%),
methanol (HPLC grade, 99.5%), n-hexane (AR, 98%), and
acetonitrile (HPLC grade, 98%) were purchased from
Aladdin Reagent Co. Ltd (Shanghai, China). Amlodipine
(racemate, HPLC grade, 99%) was purchased from Dalian
Meilun Biotech Co. Ltd (Liaoning, China). Sodium ace-
tate (AR, 99%) and acetate (AR, 99.5%) were purchased
from Sinopharm Chemical Reagent Co., Ltd (Shanghai,
China). L-Glutamic acid (AR, 99%) was purchased from
Shanghai Darui fine chemicals Co., LTD (China). All
chemicals were used as received without any further
treatment. By mixing sodium acetate and acetate solution
24
vacuum oven. The as-prepared SBA-IL (OH) was
suspended in 0.1 mol/L L-glutamate aqueous solution to
conduct anion exchange with stirring for 24 hours at
25
room temperature. Finally, the immobilized CIL SBA-
IL (Glu) was obtained after being washed with ethanol
and deionized water in sequence.
(both 0.3 mol/L) in different proportions, NaAc/HAc
buffer solutions with different pH values were prepared.
2.3 | Characterization of SBA-IL (Glu)
2
.2 | The preparation of SBA-IL (Glu)
Fourier-transform infrared (FT-IR) spectra were
recorded on Nicolet 5700 spectrometer (Thermo Electron
Corporation, America) using KBr pellets. Si NMR spec-
troscopy was performed on a Bruker AVANCE III HD
spectrometer (400 MHz, Bruker, Germany). Elemental
analysis was carried out by using Vario Micro analyzer
29
First, an equimolar mixture of (3-chloropropyl)
trimethoxysilane and 1-methylimidazole was stirred with
a magnetic stirrer under nitrogen atmosphere at 110 C
for 16 hours (Scheme 1). The ionic liquid precursor gen-
erated was filtered, washed three times with ethyl ace-
tate, dried in a rotary evaporator (40 C), and denoted as
ꢀ
20
(Analysensysteme GmbH, Germany). The N adsorption-
2
ꢀ
desorption isotherms were measured using the
AUTOSORB-IQ2-MP apparatus at 77 K (Quantachrome,
America). The specific surface and pore structure were
determined by Brunauer-Emmett-Teller (BET) and
Barrett-Joyner-Halenda (BJH) methods, respectively. X-
ray powder diffraction (XRD) spectra were recorded
on X-pert Powder diffractometer (PANalytical B. V.,
IL (Cl); 0.015 mol IL (Cl) was dissolved in 300 mL
ꢀ
ꢀ
Netherlands) from 0.5 to 10 using Cu target (voltage:
0 kV, current: 40 mA). The thermo gravimetric (TG)
4
curves were collected on a TA-Q500 instrument. Trans-
mission electron microscopy (TEM) was performed using
an HT-7700 microscope (Hitachi Limited, Japan).
3
| STATIC ADSORPTION OF (S)-
AMLODIPINE
3.1 | Kinetic experiment
A certain amount of (S)-amlodipine was dissolved into
0 mL NaAc/HAc buffer solution (pH = 6) to prepare
S)-amlodipine solution; 0.1 g of SBA-IL (Glu) was
added into 10 mL (S)-amlodipine solution with the
1
(
SCHEME 1 Synthesis of SBA-IL (Glu)

4
LIU ET AL.
concentration of 250 mg/L. Several milliliters of the sus-
pension were withdrawn at different time intervals and
centrifuged to separate the solid adsorbent. An aliquot of
the supernatant was taken to determine the concentra-
tion of amlodipine by HPLC (Agilent 1260 Infinity LC
on adsorption amount was studied with the temperature
ꢀ
ꢀ
varies from 5 C to 45 C; 0.1 g SBA-IL (Glu) were used to
adsorb (S)-amlodipine (250 mg/L, 10 mL) at different
temperature for 2 hours. The adsorption amount was
calculated.
system). The Enantiopak SCDP column (5 μm,
2
4
.6 × 250 mm ) was employed with the mobile phase
consisting of n-hexane (containing 0.1% trifluoroacetic
acid) and ethanol (90/10, v/v) at 25 C. The flow rate of
3.4 | Cycle ability
ꢀ
the mobile phase was set at 1 mL/min, and the UV wave-
length was set at 237 nm. The standard measurement
errors are u(T) = 0.1 C, u (pH) = 0.01, and u for
The cycle ability of SBA-IL (Glu) was evaluated.
After each absorption cycle, after static adsorption
of 250 mg/L (S)-amlodipine, the used SBA-IL (Glu)
(0.1 g) was immerged into 10 mL desorption solution
(methanol/water, 50/50, v/v) for 60 minutes. After centri-
fugation, the concentration of amlodipine in the desorp-
tion solution was analyzed by HPLC. The SBA-IL (Glu)
will be reused after desorption and drying for the next
cycle.
ꢀ
amlodipine concentration measurement is 0.6%.
The adsorption amount of (S)-amlodipine (q ) was cal-
t
culated from the following equation:
V
q = ðc −c Þ
,
ð1Þ
t
0
t
W
where c is the initial concentration of (S)-amlodipine
0
and c is the concentration of (S)-amlodipine at time t.
4 | SEPARATION OF AMLODIPINE
RACEMATE ON SBA-IL (GLU)
COLUMN
t
V and W represent the volume of (S)-amlodipine solution
and weight of SBA-IL (Glu) used for static adsorption,
respectively.
A total of 0.5 g SBA-IL (Glu) was mixed with 5 mL of
NaAc/HAc buffer solution (pH = 6) and then used as the
absorbent to pack a glass chromatography column
3.2 | Equilibrium experiment
(
length = 20 cm, i.d. = 1 cm) via wet-packing method.
A certain amount of (S)-amlodipine was dissolved into
This glass chromatography column was employed to sep-
arate 1 mL of racemic amlodipine with the concentration
of 500 mg/L. A mixture of NaAc/HAc buffer solution
(pH = 3) and methanol (50/50, v/v) was selected as the
mobile phase. The elution rate was set at 0.05 mL/min,
and the solution are collected every 10 minutes, then
analyzed with HPLC. The recycle ability of SBA-IL (Glu)
was evaluated. After desorption and drying, the used col-
umn is used to the next cycle.
−
1
0
.3 molꢁL NaAc/HAc buffer solution (pH = 6) to pre-
pare (S)-amlodipine solutions with different concentra-
tions; 0.1 g of SBA-IL (Glu) was added into 10 mL (S)-
amlodipine solutions with different concentrations. All
equilibrium experiments were carried out under the same
condition with the kinetic experiment. After the adsorp-
tion equilibrium was established, the suspension was
withdrawn and centrifuged. An aliquot of the superna-
tant was taken to determine the equilibrium concentra-
tion of amlodipine by HPLC. The equilibrium adsorption
amount of (S)-amlodipine (q ) was calculated from the
equation as follows:
5 | RESULTS AND DISCUSSION
e
5
.1 | Characterization of SBA-IL (Glu)
V
q = ðc −c Þ
,
ð2Þ
e
0
e
W
Figure 2A shows the FT-IR spectra of IL (Cl), SBA-15,
and SBA-15 supported ionic liquid obtained at different
steps. The typical Si-O-Si stretching vibration bands
around 1081, 794, and 457 cm− can be easily observed in
where ce is the equilibrium concentration of (S)-
1
amlodipine.
26
all the tested samples except IL (Cl).
3
.3 | Influence of temperature on the
Comparing to the FT-IR spectra of SBA-15, the char-
acteristic absorption peaks of stretching vibration of C=N
adsorption of (S)-amlodipine
−1
and C=C bond can be found around 1630 and 1560 cm
27
Temperature is an important factor that affects the
adsorption of (S)-amlodipine. The effect of temperature
for products of each step, which is the evidence of the
immobilization of CILs. For the end product SBA-IL

LIU ET AL.
5
FIGURE 2 (A) Fourier-transform
infrared (FT-IR) spectra of IL-Cl, SBA-
1
5, SBA-IL (Cl), SBA-IL (OH), and SBA-
2
9
IL (Glu); (B) Si-NMR of SBA-15 and
SBA-IL (Glu)
1
(
Glu), the characteristic adsorption band at 1718 cm−
shown in Figure 3A, SBA-15 shows no obvious weight
ꢀ
ꢀ
represents the stretching vibration C=O in carboxyl of
loss with the temperature ranging from 120 C to 700 C,
indicating the high thermal stability of SBA-15. The TGA
curve of SBA-IL (Cl) exhibits two distinct weight loss
stages in the same temperature range. The first weight
28
chiral amino acid. The bands located at 2952 and
1
2
917 cm− are corresponding to the vibration of unsatu-
29
rated C-H and saturated C-H. These characteristic
absorption peaks show that CIL has been successfully
grafted onto the surface of carrier. The typical broad peak
was assigned to the presence of OH
group.
Solid-state Si NMR was used to study the interaction
between ionic liquid and SBA-15. The Si NMR spectra
of SBA-15 and SBA-IL (Glu) were displayed in Figure 2B.
The spectrum of SBA-15 has three characteristic peaks
in the −110.6 ppm, Q [Si (OSi) ]; −102.2 ppm,
Q [Si (OSi) (OH)] and −93.2 ppm, Q [Si (OSi) (OH) ]. The
spectra present five peaks in Figure 2B. Compared
with SBA-15, SBA-IL (Glu) shows a decrease in
the −102.2 ppm, Q [Si (OSi) (OH)]; and −93.2 ppm,
Q [Si (OSi) (OH) ]; and an increase in the −110.6 ppm,
Q [Si (OSi) ]. New peaks are located at −69.8 ppm, T [SiC
OSi) ]; and −64.9 ppm, T [SiC (OSi) (OH)]. The pres-
ꢀ
ꢀ
loss stage between 200 C and 400 C (10.32%) can be
attributed to the decomposition of organic moieties like
−1
22
at 3500 cm
amino acid and imidazole ring, whereas the second
weight loss (10.13%) occurred over 400 C is mainly due
to the break of the residual methoxy side group.
21
ꢀ
29
32
29
For SBA-IL (Cl), the loading ratio is close to 20%, but
because of the corrosion in the alkalization process, the
total loading mass fraction of SBA-IL (OH) deceased to
8.22%. Compared with SBA-IL (OH), the mass loss rate of
4
4
3
2
ꢀ
ꢀ
SBA-IL (Glu) from 400 C to 700 C is almost unchanged,
whereas the mass loss in the first stage increased from
3.58% to 5.10%, due to the larger group weight of L-
glutamate than hydroxyl. These behaviors indicate the
process of ions exchange and the successful immobiliza-
tion of the CIL, and it was deduced that the loading of
ionic liquid is 86.4 mg/g.
3
2
2
3
3
2
2
2
4
3
4
2
(
3
2
2
3
ence of T and T signal confirmed that SBA-15 was
functionalized with ionic liquid by covalent bound.
Triethoxysilane of IL (Cl) reacts with the alcohol
hydroxyl group on the surface of SBA-15 by condensation
reaction, then SBA-15 (pure silicon skeleton) turns to
organosilicon material. There are some residual non-
Elemental analysis was carried out to support the
above results of the chemical immobilization of ionic liq-
uid. We found IL (Glu) [C H N O Si] in SBA-IL (Glu)
14
28 4 5
was C, 1.48%; N, 5.54%; H, 1.89%. The element analysis
result of C/N ratio (3.74) for SBA-IL (Glu) matches well
with the calculated one (3.71), which indicates that the
synthetic sample has high purity. The calculated load of
amino ILs in SBA-IL (Glu) is 71.1 mg/g.
30,31
condensed silanol groups on the surface of SBA-15.
The thermal stabilities of SBA-15 and SBA-15
supported ionic liquid obtained at different steps were
evaluated by thermo gravimetric analysis (TGA). As
Figure 3B presents the N adsorption-desorption iso-
2
therms and pore size distribution of SBA-15 and SBA-IL
FIGURE 3 (A) Thermo
gravimetric analysis (TGA) analysis of
SBA-15 and modified SBA-15 samples;
(
B) Nitrogen adsorption desorption
isotherms of SBA-15 and SBA-IL (Glu)

6
LIU ET AL.
(
Glu). Both isotherms exhibit type IV isotherms with
indicating the immobilization of ionic liquid inside the
mesoporous channel of SBA-15.
34,35
H1 type hysteresis loop for the capillary con-
densation/evaporation of nitrogen in cylindrical open-
The TEM images of SBA-15 and SBA-IL (Glu) are
shown in Figure 4B to G. SBA-15 and SBA-IL (Glu) pos-
sessed uniform and well-ordered mesopores with the
diameter of 8 to 10 nm arranged in hexagonal structure.
In TEM picture, the structure of SBA-15 can still be
observed, indicating that the modification of CILs onto
the surface of SBA-15 did not destroy the Si-O-Si network
33
ended mesopores of SBA-15. This indicated that SBA-IL
Glu) preserved the mesoporous structure of SBA-15.
(
Table 1 summarizes the specific surface area (SBET) and
pore properties of SBA-15 and SBA-IL (Glu). SBA-15 has
a large specific surface area of 599 m /g, pore volume of
2
0
.76 cc/g, and pore diameter of 7.80 nm. After the immo-
21
bilization of amino ionic liquid over SBA-15, the specific
surface area and pore volume both decreased, whereas
the pore diameter increased slightly. The decrease in spe-
cific surface area and pore volume may be attributed to
the modification of CILs on the surface and in the chan-
nels of SBA-15. The slight increase of pore diameter may
be resultant of the selective closing of small pores in the
modification process.
of the supporting materials.
5.2 | Static adsorption of (S)-amlodipine
over SBA-IL (Glu)
The equilibration time is a key factor of the adsorption
process. The influence of contact time in the adsorption
process is investigated, and the results are shown in
Figure 5A. It is found that the initial adsorption rate is
fast, and most (S)-amlodipine was adsorbed within half
an hour. More than 65% saturation adsorption could be
obtained within 20 minutes because in the initial stage,
large amount of binding sites are empty. With the
increase of adsorption time, the concentration of
amlodipine in the solution deceased, which caused the
decline of the adsorption rate. The adsorption amount
increases gradually and the adsorption reaches equilibra-
tion at 80 minutes approximately.
Figure 4A shows the small-angel powder XRD pat-
terns of SBA-15 and SBA-IL (Glu). The diffraction peaks
ꢀ
ꢀ
ꢀ
at 2θ = 0.91 , 1.59 , 1.83 in the XRD pattern of SBA-15
can be assigned to (100), (110), and (200) reflections,
respectively. SBA-IL (Glu) exhibits a similar XRD pattern
to that of SBA-15, indicating the preservation of two-
dimensional hexagonal mesostructure of SBA-15. This is
in good accordance with the results of N physisorption.
Moreover, the intensities of diffraction peaks of SBA-IL
2
(Glu) were much smaller than those of SBA-15,
Figure 5B depicts the influence of initial concentra-
tion of (S)-amlodipine on the equilibrium adsorption
amount. The equilibrium adsorption amount increased
dramatically from 0 to 12 mg/g as the initial con-
centration of (S)-amlodipine increased from 5 to
TABLE 1
Glu)
The structure properties for SBA-15 and SBA-IL
(
S
BET
2
,
Pore Volume,
cc/g
Pore Diameter,
nm
Sample
m /g
−1
250 mg L . Then, the equilibrium adsorption amount
SBA-15
SBA-IL
599
0.76
0.73
7.80
7.83
achieved a plateau with the increase in initial concen-
tration of (S)-amlodipine. Because the coordination
sites of carrier are limited, the adsorption capacity
435
(
Glu)
FIGURE 4 (A) The small angle
powder X-ray diffraction patterns of
SBA-15 and SBA-IL (Glu); (B, C, D)
transmission electron microscopy
(
TEM) images of SBA-15 and (E, F,
G) SBA-IL (Glu)

LIU ET AL.
7
FIGURE 5 The adsorption experiment
of SBA-IL (Glu) for (S)-amlodipine. (A) The
kinetic experiments, (S)-amlodipine
concentration: 250 mg/L, absorbent dose:
1
00 mg/10 mL; (B) the equilibrium
experiments, absorbent dose: 100 mg/10 mL,
equilibrium time: 2 h
tends to saturate while more amlodipine molecular are
existing than the adsorption capacity of SBA-IL (Glu);
thus, the adsorption amount increases slowly, and then
the adsorption reaches a maximum. The adsorption
capacity of SBA-IL (Glu) are affected by the amounts
of groups like car-boxyl and hydroxyl on SBA-IL (Glu)
that can form multiplex hydrogen bond with
5.4 | The correlation of static adsorption
data
Adsorption rate data are correlated by the pseudo-first-
order kinetic model and pseudo-second-order equation,
respectively.
−
1
amlodipine molecules. So, 250 mg L is selected as
the optimized concentration.
lnðq −q Þ = lnq −k1t,
ð3Þ
ð4Þ
e
t
e
t
1
t
=
+
,
qt k2q 2e qe
5
.3 | Influence of temperature on the
adsorption of (S)-amlodipine
k is the pseudo-first-order rate constant for the adsorp-
1
−
1
tion process (min ), and k is the pseudo-second-order
2
rate constant for the adsorption (g mg− min ). The cal-
culated parameters are listed in Table 2, and linear fitting
curves are presented in Figure 7A,B. The correlation
1
−1
The influence of temperature on adsorption
amount is shown in Figure 6. The absorbed
amount of (S)-amlodipine decreased with the increase
of temperature. Because interactions between SBA-IL
2
value R of pseudo-second-order kinetic model is larger
(
Glu) and (S)-amlodipine get weakened under higher
than that of the pseudo-first-order kinetic model, indicat-
ing that pseudo-second-order kinetic model is more suit-
able for the adsorption process of amlodipine.
Langmuir adsorption isotherm model and Freundlich
adsorption isotherm model are the two most widely
used models in adsorption process. The corresponding
equations can be expressed as follows:
temperature. Lower temperature is beneficial to
improve the adsorption amount. Taking the energy
saving and cost reducing into account, the room tem-
perature (around 25 C) is the suitable adsorption
temperature.
ꢀ
1
1
1
=
+
,
ð5Þ
ð6Þ
qe qm k q c
m
e
L
ce
logq = logkF + log
,
e
n
TABLE 2
Parameters according to pseudo-first-order kinetic
model and pseudo-second-order kinetic model for (S)-amlodipine
adsorption by SBA-IL (Glu)
Pseudo-First-Order
Kinetic Model
Pseudo-Second-Order Kinetic
Model
k
1
q
e
k
2
q
e
(mg/g)
2
2
(
mg/L)
(mg/g)
R
(mg/g)
R
FIGURE 6 The influence of temperature on adsorption of (S)-
amlodipine
0.0487
7.7006
0.9884 0.0108
12.1654
0.9997

8
LIU ET AL.
FIGURE 7 Line fitting of SBA-IL (Glu)
towards (S)-amlodipine. (A) Pseudo-first-
order kinetic models, (B) pseudo-second-
order kinetic models, (C) Langmuir models,
(
D) Freundlich models
where q is the maximum adsorption amount, k and k
F
(Figure 8). This indicates SBA-IL (Glu) achieves good sta-
bility and reusability performance.
m
L
represent the Langmuir adsorption constant and the
Freundlich adsorption constant, respectively. n is an
empirical adsorption constant.
Isothermal parameters are listed in Table 3, and iso-
therm constants are calculated through linear regression
method (Figure 7C,D). The correlation value R of Lang-
5.6 | Separation of amlodipine
enantiomer on SBA-IL (Glu) column
2
muir adsorption isotherm model is .9942, which shows a
better fit with the experimental data. It can be deduced
that the adsorption of amlodipine on immobilization CIL
is accordance with a single molecule adsorption process.
The separation results in column are shown in
Figure 9A. Two enantiomers of amlodipine were
adsorbed selectively, and when the column was eluted
with 2.5 mL elution, the enantiomeric excess (%ee)
reached 24.67%. The SBA-IL-(Glu) interacts more
strongly with (R)-amlodipine than (S)-amlodipine; the
(R)-amlodipine adsorbed by SBA-IL (Glu) have longer
5.5 | Amlodipine static desorption studied
of SBA-IL (Glu) and cyclic performance
In order to investigate the reusability and stability of the
prepared SBA-IL (Glu), five cycles of amlodipine
adsorption-desorption were studied. As a result, SBA-IL
(Glu) can achieve three adsorption-desorption cycles with
more than 90% of saturation adsorption capacity
remained and decreased when reused for more times
TABLE 3
Parameters according to Langmuir and Freundlich
equilibrium models for (S)-amlodipine adsorption by SBA-IL (Glu)
Langmuir Isotherm
Constants
Freundlich Isotherm
Constants
k
L
q
m
k
F
(mg/g)
2
2
(
mg/L)
(mg/g)
R
n
R
FIGURE 8 Adsorption performance of SBA-IL (Glu) for (S)-
amlodipine for five cycles
0
.0076
17.8571
0.9951 0.4767
1.1574 0.9779

LIU ET AL.
9
FIGURE 9 (A) Enantiomeric
excess of (S)-amlodipine by
chromatography column of SBA-IL
(
Glu); (B) separation performance of
SBA-IL (Glu) for five cycles
retention time than (S)-amlodipine when the adsorbed
amlodipine racemates were gradually eluted with eluent
solution. Thus, the eluting solutions obtained an appre-
ciable enantiomeric excess of (S)-amlodipine. At first, %
ee is low because the adsorbed amlodipine is limited
compared with amlodipine in the solution. When more
and more (S)-amlodipine is eluted, the proportion of
adsorbed (R)-amlodipine increased, then %ee gets higher.
At last, most racemates are eluted, the adsorbed (R)-
amlodipine decreased, as well as %ee.
column chromatography for the chiral separation of
amlodipine racemates, and good enantioselectivity is
achieved. This work provides a probable reference for
chiral separation of amlodipine in industrial production.
ACKNOWLEDGMENTS
The authors are grateful for the financial support from
National Natural Science Foundation of China (Grant
no. 21576231) to this work.
SBA-IL (Glu) shows appreciable enantiomeric
enantioseparation of amlodipine, good repeatability, and
little waste discharged. The absorbent is used five times,
and the separation efficiency remains 18.24% (Figure 9B),
without significant deterioration. The specific recognition
ability of SBA-IL (Glu) is due to the ionic hydrophobic
and the hydrogen-bonding interactions.
Enantiomeric excess (%ee) is of great importance for
chiral pharmaceuticals separation. %ee can be expressed
as the following equation:
ORCID
Chao-Hong He https://orcid.org/0000-0003-1322-5914
Ke-Jun Wu https://orcid.org/0000-0001-8658-5449
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