Enantioselective partitioning of racemic ibuprofen in a biphasic recognition chiral extraction system

Article abstract of DOI:10.1002/cjoc.201090026

Enantioselective partitioning of ibuprofen enantiomers in a biphasic recognition chiral extraction system was studied. A combination of hydrophobic L-isobutyl tartrate in organic phase and hydrophilic β-cyclodextrin derivative in aqueous phase is necessary to establish a biphasic recognition chiral extraction system. The studies performed involve an enantioselective extraction in a biphasic system, where ibuprofen enantiomers form four complexes with the β-cyclodextrin derivative in aqueous phase and the D(L)-isobutyl tartrate in organic phase, respectively. In these biphasic resolutions, the types and the concentrations of the extractants, pH and temperature all exert a considerable influence on the biphasic recognition process. Good enantioselectivities for ibuprofen enantiomers were obtained at pH≤2.5 and a ratio of 2:1 of [L-isobutyl tartrate] to [HP-β-CD]. Biphasic recognition chiral extraction is of strong chiral separation ability, and may be very helpful to optimize the extraction systems and realize the large-scale production of enantiomers.

Full text of DOI:10.1002/cjoc.201090026

FULL PAPER
Enantioselective Partitioning of Racemic Ibuprofen in a
Biphasic Recognition Chiral Extraction System
Tang, Kewen*,a(唐课文)
Song, Litaob(松丽涛)
Pan, Yanga(潘洋)
Jiang, Xinyub(蒋新宇)
Miao, Jiabingb(苗家兵)
a Department of Chemistry and Chemical Engineering, Hunan Institute of Science and Technology, Yueyang, Hunan
414006, China
b College of Chemistry and Chemical Engineering, Central South University, Changsha, Hunan 410083, China
Enantioselective partitioning of ibuprofen enantiomers in a biphasic recognition chiral extraction system was
studied. A combination of hydrophobic L-isobutyl tartrate in organic phase and hydrophilic β-cyclodextrin deriva-
tive in aqueous phase is necessary to establish a biphasic recognition chiral extraction system. The studies per-
formed involve an enantioselective extraction in a biphasic system, where ibuprofen enantiomers form four com-
plexes with the β-cyclodextrin derivative in aqueous phase and the D(L)-isobutyl tartrate in organic phase, respec-
tively. In these biphasic resolutions, the types and the concentrations of the extractants, pH and temperature all exert
a considerable influence on the biphasic recognition process. Good enantioselectivities for ibuprofen enantiomers
were obtained at pH≤2.5 and a ratio of 2∶1 of [L-isobutyl tartrate] to [HP-β-CD]. Biphasic recognition chiral ex-
traction is of strong chiral separation ability, and may be very helpful to optimize the extraction systems and realize
the large-scale production of enantiomers.
Keywords L-isobutyl tartrate, hydroxypropyl-β-cyclodextrin, ibuprofen enantiomer, biphasic recognition chiral
extraction
Introduction
tives,17-19 crown ethers,20 cholestery L-glutamate21 and
so on.7 However, the enantioselectivities of the chiral
extractants are somewhat low, and a large number of
transfer units are required in chiral solvent extraction
process. Until now, few new types of extractants have
been tested to separate enantiomers. To look for new
extraction techniques with high enantioselectivity will
speed up the application of chiral solvent extraction, and
realize large-scale production with low energy cost.
More recently, the chiral ligand-exchange concept has
been applied to liquid-liquid extraction technology and
obtained high enantioselectivities holding advantages
over chiral ligand-exchange chromatography for
large-scale applications.5 Tartaric acid derivatives and
cyclodextrins are normal selectors for separation of en-
antiomers. Cyclodextrins have been used for chiral rec-
ognition in liquid system,22 and for extraction of toluene,
o-xylene from heptane and benzyl alcohol from tolu-
ene.23 Enantioselectivities for some enantiomers have
been improved by biphasic recognition chiral extraction
(BRCE) in our recent work.24,25
Development of new chiral technologies continues
to be a very active field of research in the chemical in-
dustry.1 Preparative separation of racemic compounds is
an important method of producing single enantiomer
drugs.2,3 Many researchers have attempted the separa-
tion of optically active compounds.4-13 Such chiral
separation technologies as crystallization, chromatog-
raphy, kinetic resolution, etc. accelerate researches
about chiral compounds, but there still exist some de-
fects for most racemic compounds. Membrane-based
approaches will most certainly become very important
for continuous operation, but at the moment still suffer
from being generally less enantioselective.14-16
As a potential large-scale production technique,
chiral solvent extraction has attracted the attention of
many of researchers to make great efforts in recent
years.4-10 Enantioselectivity (α) is the most important
parameter for chiral extraction. For example, for a 99%
pure product (R/S＝100) about 190 NTU (number of
transfer units) are required for an enantioselectivity α of
1.05, but the number decreases to approximately 30
when α increases to a value of 1.20.17 There are several
normal chiral extractants, such as tartaric acid deriva-
This work presents more extensive results of separa-
tion of ibuprofen (HA) enantiomers by biphasic recog-
nition chiral extraction, which is commonly used as
non-steroidal anti-inflammatory drugs (shown in Figure
*
E-mail: tangkewen@sina.com; Tel.: 0086-0730-8846925; Fax: 0086-0730-8640921
Received May 10, 2009; revised July 30, 2009; accepted September 23, 2009.
Project supported by the National Natural Science Foundation of China (No. 20776038), Program for New Century Excellent Talents in University,
and Scientific Research Fund of Hunan Provincial Education Department (No. 06A022).
Chin. J. Chem. 2010, 28, 119— 124
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Tang et al.
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1). Recent studies show that S-ibuprofen is the active
form both in vitro and in vivo and is 28 times more
physiologically potent than R-enantiomer, while
R-ibuprofen can cause gastrointestinal toxicity, water
sodium retention, kidney perfusion and increase the al-
lergic reactions and other side effects. Factors affecting
the extraction efficiency were investigated, namely the
influence of the types of β-CD derivatives, isobu-
tyl tartrate configurations, the concentrations of the ex-
tractants, pH and temperature.
Figure 2 Chromatogram of ibuprofen enantiomers in the aque-
ous phase.
sample obtained from aqueous phase was analyzed by
HPLC. Each experiment was duplicated under identical
conditions. Owing to that the change of volume is very
small and can be neglected, the concentration of HA in
organic phase was calculated by a subtractive method.
The distribution ratio of R-HA and S-HA can be calcu-
lated by the following formulas, kR＝CO,R/CW,R and kS＝
CO,S/CW,S, where CO,R and CW,R represent concentrations
of R-HA in organic phase and aqueous phase, respec-
tively; CO,S and CW,S represent the concentrations of
S-HA in organic phase and aqueous phase, respectively.
Enantioselectivity α＝kR/kS.
Figure 1 Molecular structure of ibuprofen.
Experimental
Materials
The aqueous phase was prepared by dissolving ibu-
profen enantiomers (HA) (Zhejiang Juhua Co., Ltd.,
Zhejiang, China) in 0.1 mol/L NaH2PO4/H3PO4 buffer
solution containing β-cyclodextrin derivative. Hydro-
xypropyl-β-cyclodextrin (HP-β-CD), hydroxyethyl-
β-cyclodextrin (HE-β-CD), and methyl-β-cyclodextrin
(Me-β-CD) were bought from Xinda Fine Chemical Co.
Inc. (Shandong, China). The organic phase was a solu-
tion of D(L)-tartaric acid esters in 1,2-dichloroethane.
D(L)-isobutyl tartrate esters were synthesized as de-
scribed in the literature,26 from D- and L-tartaric acid
with a purity＞99.85% (Shanghai Xinpu Chemical Fac-
tory, Shanghai, China). All other chemicals are of ana-
lytical-reagent grade.
In a BRCE system, hydrophobic L-isobutyl tartrate
and hydrophilic β-cyclodextrin derivative were used as
chiral selectors in organic and aqueous phases, respec-
tively, which preferentially recognize R-enantiomer and
S-enantiomer, respectively (in Figure 3). In the biphasic
recognition process, the two ibuprofen enantiomers
firstly form two diastereomeric complexes with
β-cyclodextrin derivative in aqueous phase due to such
molecular interactions as polarization, induction, elec-
trostatics and hydrogen-bonding interaction. As the two
ibuprofen enantiomers are partly soluble in organic
phase, the complexation reactions take place in organic
phase simultaneously. In the meantime, two dissociation
equilibria of the enantiomers exist in aqueous phase.
Analytical method
The quantification of HA enantiomers in the aqueous
phase was performed by HPLC using a UV detector
(Merck, Hitachi, Japan) at a wavelength of 254 nm. The
column was chiralcel OJ-RH, with 5 µm particle size of
the packing material, 150 mm×4.6 mm i.d. (Hanbon
Science & Technology Co., Ltd.). The mobile phase
was 0.5 mol/L sodium perchlorate buffer solution (pH＝
2.0)/acetonitrile (V∶V＝65∶35) at a flow rate of 0.5
mL/min. The pH of the aqueous phases was measured
with a pH meter (Orion, model 720A, USA). The reten-
tion time of R-enantiomer is less than that of
S-enantiomer (Figure 2).
Extraction method
The extraction experiments were performed in 25
mL glass-stoppered tubes. Equal volumes (each 2 mL)
of the aqueous and the organic phase were placed to-
gether and shaken sufficiently (5 h) before being kept in
a water bath (24 h) at a fixed temperature until the dis-
tribution behavior achieved equilibrium. The mixing
time was sufficient to reach the equilibrium state. The
Figure 3 Schematic diagram of the optical resolution of enan-
tiomers by BRCE.
According to the possible mechanism in BRCE for
ibuprofen enantiomers, the types of β-CD derivatives,
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Chin. J. Chem. 2010, 28, 119— 124

Enantioselective Partitioning of Racemic Ibuprofen
isobutyl tartrate configurations, the concentrations of
the extractants, pH and temperature could affect the ex-
traction efficiency.
an opposite tendency. It can be explained by that the
larger amount of complex is formed in the organic
phase leading to an increase of the distribution ratios,
and the enantioselectivities are the results of the coop-
eration of HP-β-CD and L-isobutyl tartrate. It is found
that the maximum enantioselectivity is achieved at the
ratio of 2∶1 of [L-isobutyl tartrate] to [HP-β-CD].
Results and discussion
Screening of extractants
Distribution ratio and enantioselectivity for ibupro-
fen enantiomers were investigated in several different
chiral extraction systems (Table 1). A number of sig-
nificant observations may be obtained from Table 1.
It is seen from Table 1 that kR is always larger than
kS in the extraction systems containing β-CD derivative
(HP-β-CD, HE-β-CD or Me-β-CD) in aqueous phase
and without tartrate (L-isobutyl tartrate or D-isobutyl
tartrate) in organic phase, which indicates that the three
β-CD derivatives preferentially recognize S-enantiomer.
And HP-β-CD is of the strongest recognition ability
among them.
It is also observed that, in BRCE system, α for ibu-
profen enantiomers is improved by adding L-isobutyl
tartrate in organic phase, but it decreases by adding
D-isobutyl tartrate, indicating that L-isobutyl tartrate has
stronger recognition ability for R-HA than for S-HA,
and D-isobutyl tartrate has reversed recognition ability
for them. It is concluded that, in the BRCE system for
separation of ibuprofen enantiomers, HP-β-CD and
L-isobutyl tartrate should be chosen as chiral selectors
in the aqueous phase and the organic phase, respec-
tively.
Table 1 k and α of R- and S-HA in different extraction systemsa
L-isobutyl tartrate D-isobutyl tartrate Non extractant
Extractant
kR
kS
α
kR
kS
α
kR kS
α
HP-β-CD 5.85 4.39 1.33 6.91 5.81 1.19 4.51 3.76 1.20
Me-β-CD 5.36 4.91 1.09 4.80 5.04 0.95 5.65 5.53 1.02
HE-β-CD 5.33 4.31 1.24 6.45 6.26 1.03 6.60 6.23 1.06
Figure 4 Effect of concention of L-isobutyl tartrate on k and α.
Aqueous phase: [HP-β-CD]＝0.1 mol/L, [HA]＝10.0 mmol/L,
pH 2.5, temperature 5 ℃.
a
Organic phase: [L-isobutyl tartrate]＝0.2 mol/L, [D-isobutyl
Influence of HP-β-CD concentration
tartrate]＝0.2 mol/L; aqueous phase: [HP-β-CD]＝0.1 mol/L,
[HE-β-CD]＝0.1 mol/L, [Me-β-CD]＝0.1 mol/L, [HA]＝10.0
mmol/L, pH 2.5, temperature 5 ℃.
Figure 5 shows the influence of HP-β-CD concentra-
tion on distribution behavior of HA enantiomers in a
BRCE system. As expected, the following significant
conclusions can be seen in this study: (1) the distribu-
tion ratios remarkably decrease with the increase of
HP-β-CD concentration. (2) the enantioselectivities all
increase remarkably before the concentration of
HP-β-CD is up to 0.1 mol/L. (3) the distribution ratios
and enantioselectivities continuously decrease with a
further increase in the concentration of HP-β-CD. (4)
the enantioselectivity reaches the maximum at the ratio
of 2∶1 of [L-isobutyl tartrate] to [HP-β-CD]. It also can
be observed that HP-β-CD not only improves the solu-
bility of HA in a buffer solution, but also enhance enan-
tioselectivities of HA enantiomers in a BRCE system.
These phenomena can be explained by the differential
inclusion of the two enantiomers and the differential
behaviour of the two inclusion complexes formed be-
Influence of L-isobutyl tartrate concentration
The influence of L-isobutyl tartrate concentration on
extraction efficiency was studied under condition that
the pH value and the concentration of HP-β-CD in the
buffer solution were kept constant at 2.5 and 0.1 mol/L,
respectively (in Figure 4). When L-isobutyl tartrate is
not added to the organic phase, HP-β-CD shows the
enantioselectivities towards HA enantiomers, but with
small distribution ratios. With the increase of L-isobutyl
tartrate concentration, the distribution ratios are en-
hanced greatly. Meanwhile, the enantioselectivities all
increase before the concentration of L-isobutyl tartrate
is up to 0.2 mol/L. When the concentration of L-isobutyl
tartrate is increased further, the distribution ratios con-
tinuously increase, while the enantioselectivities follow
Chin. J. Chem. 2010, 28, 119— 124
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Tang et al.
FULL PAPER
tween the HP-β-CD and the two enantiomers. A good
separation was also obtained at the ratio of 2∶1 of
[L-isobutyl tartrate] to [HP-β-CD], which is in accor-
dance with the above results.
L-isobutyl tartrate in 1,2-dichloroethane solution and 0.1
mol/L HP-β-CD in 0.1 mol/L NaH2PO4/H3PO4 buffer
solution at different pH values (Figure 6). It is seen
from Figure 6 that the influence of pH on distribution
behavior is notable, and the distribution ratios and enan-
tioselectivities all greatly decrease with the increase of
pH.
The possible reasons for these may be that the
amount of ionic HA (A－ ) increases with the rise of the
pH, but molecular HA decreases with the rise of the pH
value. At pH≤2.5, HA mainly exists in molecular state,
but at high pH it mainly exists in ionic state. HP-β-CD
and L-isobutyl tartrate mainly have chiral recognition
ability and affinity for molecular HA, but not for ionic
HA. Ionic HA only exists in aqueous phase. The con-
centration of complexes formed by L-isobutyl tartrate
and enantiomers decreased with the increase of the pH.
As a result, kR, kS and α greatly decrease with the rise of
the pH. So it should be kept at low pH value to carry out
the extraction process.
Figure 5 Effect of HP-β-CD concentration on k and α. Organic
phase: [L-isobutyl tartrate]＝0.2 mol/L, [HA]＝10.0 mmol/L, pH
2.5, temperature 5 ℃.
Influence of pH
Each ibuprofen enantiomer has one carboxylic group
and one aromatic group. One dissociation equilibrium
exists in aqueous solutions:
Ka
HA←⎯→ A－ +H－
(1)
The dissociation constant for Eq. 1 can be described
by
[H＋ ][A－ ]
Figure 6 Effect of pH on k and α. Organic phase: [L-isobutyl
tartrate]＝0.2 mol/L, aqueous phase: [HP-β-CD]＝0.1 mol/L,
[HA]＝10.0 mmol/L, temperature 5 ℃.
Ka＝
(2)
[HA]
where HA and A− are neutral molecule and anion of
R(S)-ibuprofen, respectively. In aqueous solution, HA
exists in two states of neutral molecule and anion.
Therefore, there exists influence of pH on distribu-
tion behavior of HA enantiomers in a BRCE system. To
better understand the effect of pH on the distribution
behavior, distribution ratios and enantioselectivities
were studied in the BRCE systems with 0.2 mol/L
Influence of temperature
The influence of temperature on the distribution be-
havior of HA was investigated in the range of 5—30 ℃.
A peculiar effect is observed from Table 2 that higher
temperature leads to an increase in distribution ratios
but a decrease in enantioselectivities. The fact that an
increasing distribution ratio is obtained indicates that
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Chin. J. Chem. 2010, 28, 119— 124

Enantioselective Partitioning of Racemic Ibuprofen
a
the non-selective physical partitioning is increased with
temperature and CD complexation decreased with tem-
perature. A decrease in enantioselectivities can be ex-
plained by that the selector-enantiomer interaction
weakens with temperature and the discrimination ability
of the selectors for HA enantiomers weakens as well.
Figure 7 shows the variations of ln k and ln α ver-
sus 1/T. The results can be described as fitting very well
with the Van’t Hoff model, indicating that the com-
plexes do not change in conformation and that enanti-
oselective interactions remain unchanged in the tem-
perature range studied.27,28
Table 2 Influence of temperature on k and α
Temperature/℃
kR
kS
α
5
5.85
6.75
7.75
8.36
9.11
10.13
4.39
5.17
5.83
6.72
7.44
8.52
1.33
1.31
1.33
1.24
1.22
1.19
10
15
20
25
30
a Organic phase: [L-isobutyl tartrate]＝0.2 mol/L, aqueous phase:
[HP-β-CD]＝0.1 mol/L, [HA]＝10.0 mmol/L, pH 2.5.
Conclusion
Liquid-liquid extraction proved to be a promising
alternative for chiral separation. However, a high enan-
tioselectivity was required in order to optimize the ex-
traction process. Based on our previous work, enanti-
oselective partitioning of racemic ibuprofen was inves-
tigated in a BRCE system containing hydrophobic
L-isobutyl tartrate in organic phase and hydrophilic
HP-β-CD in aqueous phase, which could preferentially
recognize R-HA and S-HA, respectively. The influences
of such factors as the types of β-CD derivatives, isobu-
tyl tartrate configurations, the concentrations of the ex-
tractants, pH and temperature were examined.
It was found that the enantioselectivities in a BRCE
system were greatly improved due to the utilization of
the cooperations of the separation forces of L-isobutyl
tartrate and HP-β-CD. HP-β-CD has the strongest rec-
ognition ability among HP-β-CD, HE-β-CD, and
Me-β-CD. A high enantioseparation efficiency was ob-
tained at low pH and a ratio of 2∶1 of [L-isobutyl tar-
trate] to [HP-β-CD].
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