Enantioseparation of racemic mixtures based on solvent sublation

Article abstract of DOI:10.1002/chir.22067

A method of solvent sublation was developed for the enantioseparation of racemic ofloxacin (rac Oflx) and racemic tryptophan (rac Trp). In this method, dibenzoyl-L-tartaric acid (L-DBTA) and di-(2-ethylhexyl) phosphoric acid (D2EHPA) and sodium lauryl sulfate (SDS) were used as chiral coextractants and foamer, respectively. Several important parameters influencing the separation performances, such as pH in aqueous phase, concentrations of rac mixtures, L-DBTA, D2EHPA, and SDS, were investigated. Under the optimal operation conditions, the enantiomeric excess and enantioselectivity were 60.08% and 5.58 for Oflx and 65.09% and 6.31 for Trp, respectively. The yields of D-enantiomer and L-enantiomer were 34.23% and 8.54% for Oflx and 18.59% and 3.93% for Trp, respectively. The results suggest that the enantioselectivities have been enhanced compared with the traditional chiral extraction. This technique is an efficient chiral separation method, with many advantages such as low expenditures of organic solvent, low consumption of chiral extractant, and easy realization of multistage operation. Chirality 24:661-667, 2012. 2012 Wiley Periodicals, Inc. Copyright

Full text of DOI:10.1002/chir.22067

CHIRALITY (2012)
Enantioseparation of Racemic Mixtures Based on Solvent Sublation
1
1
2
1
1
1
3
*
FEIPENG JIAO, WEIJIE YANG, FEN WANG, LINGXING TIAN, LIN LI, XIAOQING CHEN, AND KELANG MU
1School of Chemistry and Chemical Engineering, Central South University, Changsha, China
2The Third Xiangya Hospital, Central South University, Changsha, China
3School of Minerals Processing & Bioengineering, Central South University, Changsha, China
ABSTRACT
A method of solvent sublation was developed for the enantioseparation of racemic
ofloxacin (rac Oflx) and racemic tryptophan (rac Trp). In this method, dibenzoyl-L-tartaric acid
(L-DBTA) and di-(2-ethylhexyl) phosphoric acid (D2EHPA) and sodium lauryl sulfate (SDS) were
used as chiral coextractants and foamer, respectively. Several important parameters influencing
the separation performances, such as pH in aqueous phase, concentrations of rac mixtures, L-DBTA,
D2EHPA, and SDS, were investigated. Under the optimal operation conditions, the enantiomeric ex-
cess and enantioselectivity were 60.08% and 5.58 for Oflx and 65.09% and 6.31 for Trp, respectively.
The yields of D-enantiomer and L-enantiomer were 34.23% and 8.54% for Oflx and 18.59% and 3.93%
for Trp, respectively. The results suggest that the enantioselectivities have been enhanced compared
with the traditional chiral extraction. This technique is an efficient chiral separation method, with
many advantages such as low expenditures of organic solvent, low consumption of chiral extractant,
and easy realization of multistage operation. Chirality 00:000-000, 2012. © 2012 Wiley Periodicals, Inc.
KEY WORDS: solvent sublation; enantioseparation; chiral coextractants; rac Oflx; rac Trp
D2EHPA were bought from Sinopharm Chemical Reagent Co. Ltd.
(Shanghai, China); SDS (chemical-reagent grade) was purchased from
Xilong Chemical Plant (Guangdong, China); L-DBTA (biochemical
INTRODUCTION
Chirotechnology has promoted the development of global
pharmaceutical industry, and the production of single-
enantiomer drugs is one of the hot topics in the world. To
provide single enantiomer with high quality and low cost is
the key for the development of pharmaceutical industry.1–4
Solvent sublation technique is a kind of bubble separa-
tion process in which the hydrophobic compounds in
water are adsorbed on the bubble surfaces of an ascend-
ing gas stream and then collected in an immiscible liquid
layer (usually an organic solvent lighter than water)
placed on the top of the bulk aqueous phase of the col-
umn.5 This technique has many advantages, such as si-
multaneous separation and purification, high concentration
efficiency and low expenditure of organic solvent, and so
on.6 Solvent sublation has attracted much attention in the
fields of environmental analysis, wastewater treatment,
and extraction of active constituents.7–10
28
reagent, ½aꢀD ¼ ꢁ114ꢂ to ꢁ 117ꢂ) was purchased from Lingxing Chem-
ical Regents Co. Ltd. (Zhejiang, China); n-octanol (analytical pure) was
purchased from Hengxing Chemical Material Co. Ltd. (Tianjin, China).
All other chemicals were of analytical-regent grade, and water was
deionized and bidistilled.
The apparatus of solvent sublation in this study is shown in Figure 1
(assembled by Hunan University Instrument Plant, China). It consists
of four basic parts: (1) a sample cell (7 ꢃ 6 cm i.d.), which is used as
the storage for sample solution, (2) an air introduction section with a
rotameter to control the air flow rate, which is separated from sample
cell and used to generate air into the column, (3) a glass column
(40 ꢃ 2 cm i.d.) with ceramic raschig rings (1.5 ꢃ 1.5 cm i.d.) as packing
material, which is used for the adsorption and interaction, and (4) a
collection device, which is used to make bubbles flow into the
container, where the aqueous phase can be collected and the organic
phase be left.
In this work, solvent sublation technique was adopted for
the enantioseparation of rac mixtures.11 The paper was
carried out in a conventional bubble column by taking
racemic ofloxacin (rac Oflx) and racemic tryptophan (rac
Trp) as the research models, while using sodium lauryl sulfate
(SDS) as surfactant, n-octanol as diluent, and di-(2-ethylhexyl)
phosphoric acid (D2EHPA) and dibenzoyl-L-tartaric acid
(L-DBTA) as chiral coextractants, which were reported for
the enantioseparation of amino acids with high enantios-
electivity.12,13 Compared with the traditional method of chi-
ral extraction, our aim was to provide an efficient approach
to chiral separation.14–20 To our knowledge, no literature
about the enantioseparation by solvent sublation is
available.
Analytical Method
The quantification of Oflx enantiomers and Trp enantiomers in the
aqueous phase was performed by high-performance liquid chromatogra-
phy (HPLC) using an ultraviolet (UV) detector (Shimadzu, Japan) at the
UV wavelength of 288 nm and 279 nm, respectively. The column was Kro-
mail C18, 5 mm particle size of the Packing Material, 250 ꢃ 4.6 mm i.d.
(Hanbon Science and Technology Co. Ltd., China).
Contract grant sponsor: National Science Foundation of China; Contract grant
numbers: 21176263. 20805058.
Contract grant sponsor: Provincial Natural Science Foundation of Hunan;
Contract grant number: 09JJ3026.
*Correspondence to: C. Xiaoqing, School of Chemistry and Chemical
Engineering, Central South University, Changsha 410083, Hunan, China.
E-mail:xqchen@csu.edu.cn
Received for publication 31 August 2011; Revised 16 March 2012; Accepted
28 March 2012
MATERIALS AND METHODS
Materials and Apparatus
Rac Oflx (purity > 99.0%) was bought from Pulokangyu Institute of
Fine Chemicals (Zhejiang, China); Rac Trp (purity > 98.0%) and
DOI: 10.1002/chir.22067
Published online in Wiley Online Library
(wileyonlinelibrary.com).
© 2012 Wiley Periodicals, Inc.

JIAO ET AL.
The mobile phase for Oflx enantiomers was 3 mmol/l CuSO4 and
6 mmol/l L-phenylalanine aqueous solution: methanol (85:15, v/v) at a
flow of 0.8 ml/min. The corresponding column temperature was 25 ꢂC.
The retention time of L-Oflx was less than that of D-Oflx.21
The mobile phase for Trp enantiomers was 3 mmol/l CuSO4 and
6 mmol/l L-phenylalanine aqueous solution: methanol (86:14, v/v) at a
Fig. 1. Schematic showing the apparatus used in this work. (1) Air pump,
(2) control valve, (3) rotameter, (4) inlet for solution, (5) outlet for solution,
(6) gas distributor, (7) sample pool, (8) microporous plate, (9) glass column,
(10) ceramic ring, and (11) bubble receiver.
Fig. 3. Enantioseparation process based on solvent sublation. D2EHPA,
di-(2-ethylhexyl) phosphoric acid; L-DBTA, dibenzoyl-L-tartaric acid; Oflx,
ofloxacin; Trp, tryptophan.
Fig. 2. High-performance liquid chromatography chromatograms of rac Oflx and rac Trp: (a, b) before and (c, d) after solvent sublation.
Chirality DOI 10.1002/chir

ENANTIOSEPARATION OF RACEMIC MIXTURES BASED ON SOLVENT SUBLATION
flow of 1.0 ml/min with pH 3.5 adjusted by acetic acid. The corresponding
Experiment of Solvent Sublation
column temperature was 30 ꢂC. The retention time of D-Trp was less than
The aqueous phase was prepared by dissolving rac mixtures and
surfactant SDS in water. The pH value was adjusted with phosphate salt
buffer solution and measured using a pH meter before extraction for each
experiment. L-DBTA and D2EHPA were used as the chiral coextractants
whereas n-octanol as the diluent. We placed 140 ml of the organic and
aqueous phases (1:6, v/v) into the sample pool under room temperature.
Then, air was introduced into the aqueous phase to form bubbles.
Refluxed for several hours, the bubbles were collected under a certain
gas velocity. After static defoamed and phase separation, the concentra-
tions of enantiomer in aqueous phase were analyzed using HPLC. Each
experiment was duplicated under identical conditions, and the standard
deviation is in the range of ꢄ2%. Because the change in volume was very
small, it could be seen as negligible. All the experiments were performed
at a certain packing height and a steady air flow rate.
that of L-Trp.22
The chromatograms of these two racemic compounds are shown in
Figure 2. It can be calculated that the peak area of D-enantiomer is equal
to that of L-enantiomer, which indicates that the content of D-enantiomer
is the same as that of L-enantiomer.
TABLE 1. Effect of reflux time on enantioselectivity
Oflxa
Trpb
Reflux
time (h)
b e.e.% (aqueous phase)
b e.e.% (aqueous phase)
1
2
3
4
5
6
2.75
4.25
4.73
5.58
4.31
3.67
36.54
45.23
51.76
60.08
41.85
21.74
2.24
3.89
4.79
6.31
4.25
2.76
34.96
53.51
57.26
65.09
54.74
34.63
RESULTS AND DISCUSSION
As Tan’s study in the suggested mechanism of chiral
12,13
coextraction method,
the possible reaction mechanism in
this paper is shown in Figure 3. According to that, some factors
that affected the enantioseparation efficiency were investigated.
In the separation process of solvent sublation, the extrac-
tion of rac Oflx and rac Trp by n-octanol can be considered
as negligible. The distribution ratio (D), the value of enantio-
meric excess (e.e.%), and enantioselectivity (b) at equilibrium
as the evaluated parameters are defined by
aInitial concentration of racemic ofloxacin (Oflx), dibenzoyl-L-tartaric acid
(L-DBTA), di-(2-ethylhexyl) phosphoric acid (D2EHPA), and sodium lauryl
sulfate (SDS): 1.67 mg/ml, 0.11 g/l, 0.91 mol/l, and 0.42 mg/ml, respectively.
pH 7 in aqueous phase.
bInitial concentration of racemic tryptophan (Trp), L-DBTA, D2EHPA, and SDS:
1.40mg/ml, 0.20 g/l, 1.51 mol/l, and 0.60mg/ml, respectively. pH6 in aqueous
phase.
Fig. 4. Influence of the initial concentration of dibenzoyl-L-tartaric acid (L-DBTA) on the distribution behavior. (a) Initial concentration of racemic ofloxacin,
di-(2-ethylhexyl) phosphoric acid (D2EHPA), and sodium lauryl sulfate (SDS): 1.67 mg/ml, 0.91 mol/l, and 0.42 mg/ml, respectively. pH 7 in aqueous phase and
reflux time of 4 h. (b) Initial concentration of racemic tryptophan, D2EHPA, and SDS: 0.80 mg/ml, 1.51 mol/l, and 0.42 mg/ml, respectively. pH 5 in aqueous
phase and reflux time of 4 h.
Chirality DOI 10.1002/chir

JIAO ET AL.
diastereomeric complexes with D-enantiomer or L-enantiomer,
initial½Dꢀor initial½Lꢀ
½Dꢀor½Lꢀ
distribution ratio of D enantiomer
distribution ratio of L enantiomer
DDðLÞ ¼
ꢁ 1
(1)
respectively, which depends on the various molecular interac-
tions during the process of solvent sublation. Therefore, it
could be seen that b and e.e.% increase obviously with the
increase of L-DBTA concentration and then reach maximum
at a certain concentration. However, b and e.e.% would show a
decrease tendency when the L-DBTA concentration exceeds a
certain value because of the micelles formed by the excess
L-DBTA, which could make the unexpected enantiomer be
adsorbed. What’s more, the initial concentration of L-DBTA
also has an influence to D. Generally, except for the abnormal-
ity at the concentration of 0.22g/ml for Trp, DD(L) tends to
decrease with increasing L-DBTA concentration, which should
be also attributed to the forming of complex by L-DBTA and
D2EHPA. D2EHPA has relatively large extraction capacity
but without any chiral recognition ability, and the extraction
capacity might be impaired with the decrease of its concentra-
tion caused by increasing the L-DBTA concentration. The value
of DD is always larger than that of DL, which suggests that
D-Oflx and D-Trp are all preferentially extracted by the
chiral coextractants.
b ¼
ee% ¼
(2)
(3)
½Lꢀðor½DꢀÞ ꢁ ½Dꢀðor½LꢀÞ
ꢃ 100%
½Lꢀ þ ½Dꢀ
Among which, [] was the concentration (mg/ml) of enantiomer
in the aqueous phase.
Effect of Reflux Time
The influence of reflux time on enantioseparation is listed in
Table 1. The results suggest that e.e.% and b increase with
extending reflux time before up to 4 h and then decrease. It
is because the interphase force and the contact area of
interphase increase with extending reflux time; in that case,
e.e.% and b show an increasing tendency. But, with continuous
refluxing, the foam layer becomes thicker, which would
increase the transfer resistance of enantiomers and decrease
the extraction efficiency. Therefore, e.e.% and b decrease with
the further increase of reflux time.23 So, the relux time is fixed
at 4 h in this work.
Effect of Initial Concentration of Racemic Mixtures
Figure 5 shows the influence of concentration of rac mix-
tures on the distribution behavior. e.e.% and b are enhanced
with the increasing initial concentration of rac Oflx, whereas
e.e.% and b increase firstly and then decrease with the
increase of initial concentration of rac Trp. The values of DD
Effect of Initial Concentration of L-DBTA
Figure 4 shows the influence of L-DBTA concentration on
the distribution behavior. In this work, the chiral coextrac-
tants formed by L-DBTA and D2EHPA could form two
Fig. 5. Influence of the initial concentration of racemic ofloxacin (rac Oflx) and racemic tryptophan (rac Trp) on the distribution behavior. (a) Initial concentra-
tion of dibenzoyl-L-tartaric acid (L-DBTA), di-(2-ethylhexyl) phosphoric acid (D2EHPA), and sodium lauryl sulfate (SDS): 0.11 g/l, 0.91 mol/l, and 0.42 mg/ml, re-
spectively. pH 7 in aqueous phase and reflux time of 4 h. (b) Initial concentration of L-DBTA, D2EHPA, and SDS: 0.20 g/l, 1.51 mol/l, and 0.42 mg/ml, respectively.
pH 5 in aqueous phase and reflux time of 4h.
Chirality DOI 10.1002/chir

ENANTIOSEPARATION OF RACEMIC MIXTURES BASED ON SOLVENT SUBLATION
and DL tend to decrease at the higher concentration of rac
For Trp, b and e.e.% reach the maximum values at pH = 5.8,
which could be seen in Figure 6b. D (or L)-Trp has one
carboxylic group, one amino group, and a side chain (b-indolyl).
Because of its special structure, two dissociation equilibria exist
in aqueous solution: 12
mixtures. The rather abrupt leveling-off of DD and DL at a
certain concentration strongly suggests the formation of a
D2EHPA-(L-DBTA) complex as efficient chiral coextractants,
which we presume the complex to be mediated by hydrogen
bonding. A reasonable explanation is that the Oflx (or Trp)
complexes formed in organic phase are stronger extractants
for Oflx (or Trp) than the initial chiral coextractants. If this
is so, then it appears that the Oflx (or Trp) complexes in
organic phase are inferior chiral coextractants. What’s more,
the salvation ability of n-octanol makes the enantioselectivity
decrease at the higher concentration of rac mixtures.3
þ
RCH2ðNH3 ÞCHCOOH K RCH2ðNH3þÞCHCOOꢁ þ Hþ
(4)
(5)
a1
RCH2ðNH3þÞCHCOOꢁ RCH2ðNH2ÞCHCOO þ H
ꢁ
þ
Ka2
From the equilibria, we could find that a larger fraction of
Trp+ is available at lower pH. On the contrary, at higher
pH, there would be many Trp-. However, the chiral coextrac-
tants tend to complex with Trpꢄ, and therefore, only the
amphoteric ion can be solvated into organic phase effectively.
What’s more, Trp exists as Trpꢄ only at its pI (pI = (pKa1
+
Effect of pH in Aqueous Phase
pKa2)/2)), and the pI of Trp is 5.8. In that case, e.e.% and b
are both enhanced with increasing pH and then decreased
significantly. Therefore, pH = 5.8 is chosen as the optimum
condition for Trp.
To investigate the influence of pH on distribution behavior,
D and enantioselectivities are studied at different pH. The
results are shown in Figure 6, which could be seen that the
24
influence of pH on distribution behavior is notable.
For Oflx, b and e.e.% become larger at higher pH and reach
the highest separation efficiency at pH 7 then decrease.
Because at the acid medium of 2.0 < pH < 7.0, the structure
of Oflx would be mainly in the form of quinoline instead of
ketone because of the charge transfer reaction on the double
bonds. At pH > 7.0, the ionization extent of Oflx increases
gradually with the increase of pH, so the intermolecular
repulsive forces and solubility increase, which results in
the decrease of enantioselectvities. At pH = 7, Oflx exists in
the form of amphoteric ion and can be solvated into organic
phase effectively by n-octanol. Therefore, pH = 7 is the better
choice for Oflx.
Effect of Initial Concentration of D2EHPA
The effect of concentration of D2EHPA in the organic phase
on b, e.e.%, and D is shown in Figure 7. D2EHPA is suitable for
a nonpolar solvent system, so n-octanol is selected as the
extraction solvent. As could be seen from Figure 7, with the
increasing D2EHPA concentration, both e.e.% and b keep an
increase tendency firstly and then drop obviously. D begins
to decrease and then increase with the increasing D2EHPA
concentration. The reason for this phenomenon is also
due to the chiral coextractants formation between L-DBTA
and D2EHPA; therefore, the enantioselectivities increase,
Fig. 6. Influence of pH on the distribution behavior. (a) Initial concentration of racemic ofloxacin, dibenzoyl-L-tartaric acid (L-DBTA), di-(2-ethylhexyl) phospho-
ric acid (D2EHPA), and sodium lauryl sulfate (SDS): 1.67 mg/ml, 0.11 g/l, 0.91 mol/l, and 0.42 mg/ml, respectively. Reflux time of 4 h. (b) Initial concentration of
racemic tryptophan, L-DBTA, D2EHPA, and SDS: 1.40 mg/ml, 0.20 g/l, 1.51 mol/l, and 0.42 mg/ml, respectively. Reflux time of 4h.
Chirality DOI 10.1002/chir

JIAO ET AL.
Fig. 7. Influence of the initial concentration of di-(2-ethylhexyl) phosphoric acid (D2EHPA) on the distribution behavior. (a) Initial concentration of racemic
ofloxacin, dibenzoyl-L-tartaric acid (L-DBTA), and sodium lauryl sulfate (SDS) is 1.67 mg/ml, 0.11 g/l, and 0.42 mg/ml, respectively. pH 7.0 and reflux time of
4 h. (b) Initial concentration of racemic tryptophan, L-DBTA, and SDS is 1.40 mg/ml, 0.20 g/l, and 0.42 mg/ml, respectively. pH 5.8 and reflux time of 4 h.
whereas D decreases with the increase of D2EHPA concen-
tration. However, D2EHPA does not have any chiral separa-
tion ability but could enhance the extraction capability. As a
result, the enantioselectivities decrease, whereas D follows
an opposite tendency. In addition, the excess concentration
of D2EHPA in the organic phase could cause emulsification
of the organic phase and increase the difficulty in phase
separation, and it could increase the solubility of D2EHPA
in the aqueous phase. So, the concentration of D2EHPA
in the organic phase is fixed at 0.91 and 1.51 mol/l for Oflx
and Trp, respectively.
easily found. In this situation, the enantiomeric excess and
enantioselectivity were 60.08% and 5.58 for Oflx and 65.09%
and 6.31 for Trp, respectively. Then, the yields of D-enatiomer
and L-enantiomer in this study were defined as
initial½Dꢀ ꢁ ½Dꢀ
D% ¼
L% ¼
ꢃ 100%
(6)
(7)
initial½Dꢀ
initial½Lꢀ ꢁ ½Lꢀ
initial½Lꢀ
ꢃ 100%
According to the [D] and [L] under the optimal operational
conditions, D% and L% were calculated to be 34.23% and 8.54%,
respectively, for Oflx, whereas 18.59% and 3.93%, respectively,
for Trp. Although the yields were not high to some extent,
solvent sublation has still some advantages when used for
enantioseparation purposes such as easy operation, low
expenditure of organic solvent, little consumption of chiral
selectors, and so on. Especially to be noticed, the aqueous
phase after enantioseparation by solvent sublation can be
very easily reused in the next stage still by using this
method, so all the amount of the enantiomers can be
separated in theory.
Effect of Initial Concentration of SDS
The effect of SDS concentration in the aqueous phase is
shown in Figure 8. It suggests that b becomes larger with
the increase of SDS concentration and then reaches maxi-
mum at the SDS concentration of 0.42 and 0.60 mg/ml for
Oflx and Trp, respectively. But, with the further increasing
SDS concentration, b decreases obviously. What’s more,
when the SDS concentration increases continuously, some
white flocculent precipitates would be found in the sample
cell, which in turn affect the results. Therefore, 0.42 and
0.60 mg/ml might be the optimal SDS concentration for Oflx
and Trp, respectively.
Yields of Enantiomers under the Optimal Conditions
CONCLUSIONS
By investigating the factors that influence the enantiose-
paration process of solvent sublation, the optimal operational
conditions for the chiral separation of Oflx and Trp can be
Chirality DOI 10.1002/chir
We found an effective method using solvent sublation for the
separation of racemic mixtures. Both the distribution ratio and
enantioselectivity were greatly improved with this technology

ENANTIOSEPARATION OF RACEMIC MIXTURES BASED ON SOLVENT SUBLATION
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extraction. Under the optimal operational conditions, the
enantiomeric excess and enantioselectivity were 60.08% and
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Chirality DOI 10.1002/chir