Chemical Engineering & Processing: Process Intensification 134 (2018) 141–152

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Chemical Engineering & Processing: Process Intensification

journal homepage: www.elsevier.com/locate/cep

Process optimization of reactive extraction of clorprenaline enantiomers by T

experiment and simulation
⁎
Wanru Wang, Weifeng Xu, Guilin Dai, Panliang Zhang, Kewen Tang
Department of Chemistry and Chemical Engineering, Hunan Institute of Science and Technology, Yueyang, 414006, Hunan, China

A R T I C LE I N FO A B S T R A C T

Keywords: This paper studied the process optimization of reactive extraction of clorprenaline enantiomers (CP) by ex-
Enantioselective liquid-liquid extraction periment and simulation. An efficient extraction system was obtained through single stage extraction experi-
Clorprenaline enantiomer ments, where boric acid (BA) in aqueous phase and D-isobutyl tartrate (DT) in organic phase were selected as
Tartrate-boric acid system extractant and 1,2-dichlorethane was selected as organic solvent. The best enantioselectivity (α) with 2.012 was
Equilibrium model
obtained. The extraction mechanism was proposed and thermodynamic constants such as physical partition
Simulation
coefficient and reactive equilibrium constants were obtained. Based on single stage extraction, phase and re-
active equilibrium as well as the law of mass conservation, a model describing the fractional extraction process
was acquired. The process of symmetrical separation of CP was optimized by the model. The optimal conditions
including flow rate ratio (O/W) of 1.5, pH of 5.0, CH3COONa/CH3COOH solution of 0.1 mol/L, clorprenaline
concentration of 5 mmol/L, BA concentration of 0.10 mol/L and DT concentration of 0.075 mol/L were obtained.
Under this case, equal enantiomeric excess (eeeq) could reach up to 67% by 10 stages. The simulated results
revealed that the minimum series for eeeq > 97% and eeeq > 99% were 26 and 33, respectively. The results will
provide guides for scale up and design.

1. Introduction severely hindered due to the poor reproducibility, complex instrument,

Clorprenaline, 1-(2-Chlorophenyl)-2-(isopropylamino) ethanol
(Fig. 1), which has been confirmed its curative effect and high se-
lectivity towards the β2 receptor agonist, is commonly applied in the
treatment of bronchia asthma and bronchitis. However, each en-
antiomer of racemic drugs shows different pharmacological and tox-
icological properties, only R-enantiomers of clorprenaline is effective
component [1], ironically, the S-enantiomers of clorprenaline is of low
therapeutic efficiencies and even unwanted side effects, resulting in
headache, palpitations, nausea, stomach discomfort, and finger vibra-
tion. Therefore, it is highly desired for developing an efficient method
for the separation of clorprenaline enantiomers.
Separation methods for racemic drugs include crystallization [2,3],
chromatography [4,5], membrane separation [6–8] enantioselective
liquid-liquid extraction (ELLE) [9–12] and so on [13,14]. Nowadays,
the existing separation methods for clorprenaline enantiomers include
as follows: capillary electrophoresis (CE) [15–17], chromatography
[18], ELLE [19,20]. CE technique is recognized as a useful technique for
chiral separation of clorprenaline with the advantages of its high se-
paration efficiencies, rapid separation, and low consumption of re-
agents [21]. Unfortunately, its application in chiral separation has been
complicated sample pretreatment, and difficult realizing the in-
dustrialization [22]. Chiral chromatography has been usually adopted
to generate the optically pure compounds in the separation of en-
antiometric compounds. However, chromatography suffers from low
capacity and high capital costs [23]. Most recently, ELLE has gained
more and more attention because of its great advantages to overcome
those difficulties.
ELLE, which has been known in enantioseparation since 1959 [24],
is one of the most mature and widely used techniques. ELLE, developed
over many decades, has possessed several advantages such as more
mature theoretical guidance, lower energy consumption and wider
range of application in industrial processes. In ELLE experiments,
mainly two extraction models were applied, for instance homogeneous
reaction model and interfacial reaction model. The homogeneous re-
action model consists of single-phase recognition model and biphase
recognition model. Several chiral selectors, including β-cyclodextrins
derivatives [25,26], tartarte derivatives [27,28], naproxen derivatives
[29], fluorinated derivatives [30], cinchona alkaloid derivatives [10],
cellulose and amylose derivatives [31], (+)-(18-crown-6) tetra-
carboxylic acid [32], have successfully used for chiral separations in the
systems mentioned above, and β-cyclodextrins and tartarte derivatives

⁎
Corresponding author.
E-mail address: tangkewen@sina.com (K. Tang).

https://doi.org/10.1016/j.cep.2018.10.021
Received 19 September 2018; Received in revised form 21 October 2018; Accepted 30 October 2018
Available online 05 November 2018
0255-2701/ © 2018 Elsevier B.V. All rights reserved.
W. Wang et al. Chemical Engineering & Processing: Process Intensification 134 (2018) 141–152

Nomenclature Ka,C Dissociation constant, mol/L

KBR Complex equilibrium constant, L/mol
Abbreviations KBS Complex equilibrium constant, L/mol
KDR Complex equilibrium constant, L/mol
AR (R)-Clorprenaline KDS Complex equilibrium constant, L/mol
ARH+ Protonated (R)-clorprenaline KR Complex equilibrium constant
AR-DT Supramolecular complex KS Complex equilibrium constant
AS (S)-Clorprenaline N Number of stages
ASH+ Protonated (S)-clorprenaline O Volume flow rate organic phase, mL/min
AS-DT Supramolecular complex P0 Physical partition coefficient of molecular clorprenaline
BA Boric acid Papp Apparent physical partition coefficient
BA− Dissociated boric acid SBE-β-CD Sulfobutylether-β-cyclodextrin
BDR Ternary complex formed by DT, BA and (R)-CP TD Tartrate derivatives
BDS Ternary complex formed by DT, BA and (S)-CP T Temperature, K
BR+ Borate ester Y Yield
BS+ Borate ester W Volume flow rate aqueous phase, mL/min
CCSs Centrifugal contactor separators α Enantioselectivity
CM-β-CD Carboxymethyl-β-cyclodextrin
CP Clorprenaline enantiomers Subscripts
DR Distribution ratios for (R)-clorprenaline
DS Distribution ratios for (S)-clorprenaline i Index for CP enantiomers of different optical rotation,
DT D-Isobutyl tartrate i = R or S
ee Enantiomeric excess j Stage index
eeeq Equal enantiomeric excess aq Aqueous phase
F Volume flow rate feed phase, mL/min org Organic phase
f Number of feed stages eq Equal value
Ka,B Dissociation constant, mol/L

are more widely applied, relatively. Metal complexes and metalloids as
reactive extractant are generally applied in the interfacial reaction
system [33–35]. Moreover, Yoshihiro et al. [36] reported the extraction
separation of β-blockers using tartrate derivatives in the organic phase
with boric acid in the aqueous phase in 1994, and the selectivity of
propranolol was improved to 2.71 with this system. There also are
many examples of the improved separation results of enantiomers with
tartrate-boric acid system [37,38].
In the past, sulfobutylether-β-cyclodextrin (SBE-β-CD) was used as
chiral selector in ELLE, the optimized enantioselectivity was 1.25 [19].
However, it will need many stages to separate clorprenaline en-
antiomers. Recently, kinetic study on extraction of clorprenaline en-
antiomers was performed with isobutyl (D)-tartrate (DT) and boric acid
(BA) as chiral selector [20]. With chiral selector, the enantioselectivity
can reach up to 2.012. The rate constants had been found to be
2.476 × 10−4 L1.53/(mol1.2 s) for (R)-CP and 1.349 × 10−4 L1.53/
(mol1.2 s) for (S)-CP. The reaction order was evaluated as 0.6, 0.8 and
0.8 separately with respect to BA, CP and DT, and the reaction was “fast
reaction” [20], which indicates that the explored extraction is pro-
mising to be scale-up in industry.
Centrifugal contactor separator (CCS), which was a device that in-
tegrated mixing, reaction and separation of liquid-liquid systems and as
such was an interesting example of process intensification [39,40].
Recently, the studies providing the approaches for application of ELLE
in multistage processes have drawn more and more attention from re-
searchers. Factors affecting the multistage processes are numerous and
complicated, it will be a high consumption for studying the relationship
of these factors on the separation performance in multistage extraction
process. Therefore, establishing a mathematical model to simplify the
research fascinates researchers [41–43]. The established model can be a
useful means for predicting the extraction performance and optimizing
the separation process and will provide theoretical guidance and sup-
port for separation of enantiomers in industrial production.
In this paper, reactive extraction equilibrium was further studied to
achieve the thermodynamic constants such as physical partition coef-
ficient and reactive equilibrium constants, and ELLE in CCS was utilized
for full separation of clorprenaline enantiomers by experiment and si-
mulation. The extraction system was screened firstly to obtain the
suitable organic solvent, tartrate derivative, concentrations of tartrate
and boric acid, pH value of aqueous phase and other operational con-
ditions. Organic solvent was an fundamentally important factor in the
extraction process. The suitable organic solvent should meet following
requirements: (1) suitable disstribution ratios (D) and high enantios-
electivity (α) can be obtained; (2) it can be applied to ELLE in multi-
stage process with a relative high boiling point; (3) two phases should
be nearly immiscible, and the viscosity and interfacial tension of two
phases should be low, which would be beneficial to the phase disper-
sion and separation, etc.
According to the chemical and physical equilibrium of single stage,
and mass balance, a multistage equilibrium model of ELLE was estab-
lished. Multistage extraction experiments were carried out to verify the
model. The verified model was applied to simulate and optimize the
separation process, which could provide theoretical direction for in-
dustrial production.

Fig. 1. Chemical structure of clorprenaline enantiomer.

142
W. Wang et al.
2. Materials and methods
2.1. Material
Clorprenaline (racemate, purity 98%) was purchased from Hubei
Kangbaotai Fine-chemicals Co., Ltd, Hubei, China. D-tartaric acid and L-
tartaric acid (AR, 99%) were purchased from Shanghai Aladdin Bio-
chem Technology Co., Ltd, shanghai, China. Boric acid (BA, AR,
99.9%), isobutyl acetate (AR, 99%), and methyl tert-butyl ether (AR,
99%) were purchased from Shanghai Titan chem Co., Ltd, shanghai,
China. Ethyl acetate (AR, 99%), butyl acetate (AR, 99%), n-octanol (AR,
99%), 1,2-dichloroethane (AR, 99%) and dichloromethane (AR, 99.5%)
were supplied by Hunan Huihong Reagent Co., Ltd. (Hunan, China). D-
and L- tartrate derivatives were synthesized in our laboratory with the
purity of 99% according to the reference [44]. Solvents for chromato-
graphy were of the HPLC grade.
2.2. Apparatus
HPLC (Waters e2695 Separation Module) and An UV/visible de-
tector (Waters 2998 Photodiode Array Detector)) were supplied by
Waters Corporation (USA), and pH Meter (PHS-3 F) was purchased from
Shanghai Instrument Scientific Instrument Co., Ltd. (Shanghai, China).
Thermostatic oscillator (SHA-2) was purchased from Pu Dong Physical
Optical Instrument Co., Ltd. (Shanghai, China) and CCS (Model V02)
was supplied by Yaskawa Electric Co., Ltd. (China). Pump (TBP 5002)
for constant flow was purchased from Tong Tian Biotechnology Co.,
Ltd. (Shanghai, China). Thermostat bath (DC-1030) was purchased
from Ningbo scientz thermostat Co. Ltd. (China). ASTM Type I ultra-
pure water system (Easy) was purchased from Heal Force Instrument
Co., Ltd. (Shanghai, China).
2.3. Analytical method
The determination of clorprenaline concentrations in the aqueous
phase was performed by HPLC. The quantitive analysis was performed
by UV–vis adsorption detector at the wavelength of 220 nm. An Inertsil
ODS-3 column, with a 5 μm particle size of packing material, 4.6
nm × 250 mm I.D. (Dikma Technologies) was employed. The mobile
phase was methanol-water (pH = 5.0, adjusted with glacial acetic acid)
(18:82, v/v), containing 8 mmol/L carboxymethyl-β-cyclodextrin (CM-
β-CD) and 0.05% triethylamine. The flow rate was set at 1.0 mL/min
and the column temperature was set at 30 °C. It was observed that R-
and S- clorprenaline enantiomers were completely separated from each
other, with an indication that R-clorprenaline with less affinity to CM-β-
CD eluted earlier, whereas S-clorprenaline with more affinity to CM-β-
CD eluted later.
Fig. 2. Flow diagram of the multistage centrifugal counter-current extraction of clorprenaline enantiomers.
143
Chemical Engineering & Processing: Process Intensification 134 (2018) 141–152
2.4. Extraction experiments
2.4.1. Single-stage extraction experiments
In the liquid-liquid extraction systems, the aqueous phase was
prepared by dissolving boric acid (BA) and clorprenaline in aqueous
solution, and the organic phase was prepared by dissolving tartrate
derivatives (TD) in one organic solvent. The extraction experiments
were carried out as follows: equal volume (3 mL) of organic and aqu-
eous phases were added into the 15 mL centrifuge tube. After capping,
the tube was stirred vigorously for 10 h, and then stewed for 5 h to
reach equilibrium at 278.15 K. The concentration of clorprenaline in
the aqueous phase was measured by HPLC. The concentration of clor-
prenaline in the organic phase was determined by mass balance.
2.4.2. Multistage extraction experiments
Fig. 2 shows the flow diagram of multistage countercurrent ex-
traction of clorprenaline enantiomers using a series of CCSs. The sub-
strate (clorprenaline racemate) was fed to the multistage system
through a constant flow pump at the feed stage (f). The aqueous phase
was a sodium acetate buffer solution with BA and the sodium acetate
concentration was maintained at 0.1 mol/L. The aqueous phase was
transported into the multistage system at the last stage. In the current
system, 1,2-dichlorethane was used as organic phase. The organic phase
was transported into the system from the first stage. In the overall
multistage extraction system, Stages 1 to f were the wash section and
Stages f+1 to N were the stripping section. Through the countercurrent
extraction process, S-clorprenaline and R-clorprenaline were enriched
separately in the aqueous and the organic phases.
2.5. Determination of physical distribution coefficients P0 and Pi of
molecular and ionic clorprenaline
pH is adjusted by CH3COONa/CH3COOH buffer solution. The so-
lubility of clorprenaline in water is less than that in 1,2-diclorethane, so
clorprenaline is dissolved in organic phase. Increasing the amount of
clorprenaline in organic phase, the concentration of clorprenaline in
aqueous phase can be increased. However, the saturated concentration
will happen in aqueous phase if the amount of clorprenaline in organic
phase is excessive. Theoretical P0 and Pi are thermodynamic para-
meters, which are only influenced by temperature. The experimental P0
and Pi will be inaccurate if the concentration of clorprenaline in aqu-
eous phase is saturated. Therefore, the initial concentration of clor-
prenaline in organic phase is selected as 2 mmol/L.
A series of experiments to determine physical distribution coeffi-
cient P0 and Pi of molecular and ionic clorprenaline in two phases were
carried out. The organic phase was prepared by dissolving 2 mmol/L
clorprenaline in 1,2-diclorethane. The aqueous phases were 0.1 mol/L
CH3COONa/CH3COOH solutions with a series of pH values in the range
of 5.0–9.0. Equal volume (3 mL) of organic and aqueous phases were
placed together, and shaken vigorously (10 h) before being kept in a
W. Wang et al. Chemical Engineering & Processing: Process Intensification 134 (2018) 141–152

water bath at 278.15 K to reach equilibrium. The concentration of [A]W + [AH+]W

Papp =
clorprenaline in aqueous phase was measured by HPLC. The con- [A]o + [AH+]o (3)
centration of clorprenaline in organic phase was determined by a mass
Therefore, Papp can be derived as
balance.
1 1 [H+] ⎞ ⎫ [H+]
Papp ⎧ + ⎛ =1+
3. Model descriptions ⎨ P Pi⎝ Ka ⎠⎭⎬ Ka (4)
⎩ 0

3.1. The construction of the model Eq. (4) can be transformed into

1 ⎛ [H+] 1 1 [H+] ⎞
In this work, the clorprenaline enantiomers are extracted by a chiral + 1⎞ = + ⎛ ⎜ ⎟

Papp ⎝ Ka ⎠ P0 Pi ⎝ Ka ⎠ (5)
selector of DT and BA. Several papers have reported the research on
mechanism of enantioselective extraction of some β-blockers with boric Secondly, the supramolecular interactions between CP enantiomers
acid and tartrate as chiral selector, which offer important references for and DT can take place in organic phase in the absence of BA and this
this paper to understand the mechanism of reactive extraction of CP interesting phenomenon has been observed by lots of researchers
enantiomers by DT and BA [45–47]. Herein we describe our assumption [47,48]. Assuming a 1:1 supramolecular complex is formed between CP
on extraction mechanism. Experiments were performed to validate enantiomers and DT, the complexation constants are expressed by the
these assumptions. following equations for (R)-CP and (S)-CP, respectively:
Distribution of CP enantiomers in the organic phase may be through
[AR -DT]org
the following three approaches (depicted in Fig. 3): KDR =
Firstly, for the molecular CP, even without the formation of a [AR]org [DT]org (6)
complex with the extractant, the physical partitioning of the neutral
[AS-DT]org
form of CP between the organic and aqueous phases may take place, KDS =
which is characterized by the physical partition coefficient, P0: [AS ]org [DT]org (7)

[Ai]org where [DT]org represents the equilibrium concentration of DT in the

P0 =
[Ai]aq
where [Ai]org represents the concentrations of R- and S- clorprenaline in
the organic phase at equilibrium, and [Ai]aq represents the concentra-
tions of R- and S- clorprenaline in the aqueous phase at equilibrium.
The value of P0 is the same for both of the enantiomers.
The physical partition coefficient of ionic R- and S- clorprenaline is
defined as:
[Ai H+]org
Pi =
[Ai H+]aq
+
where [AiH ]org represents the concentrations of the ionic R- and S-
clorprenaline in the organic phase at equilibrium, and [AiH+]aq re-
presents the concentrations of the ionic R- and S- clorprenaline in the
aqueous phase at equilibrium. The value of Pi is the same for both of the
enantiomers.
The apparent partition coefficients (Papp) is determined at different
pH values. Since both the molecular and ionic clorprenaline distribute
between the organic and aqueous phases, Papp is given by
organic phase; [AR-DT]org represents the equilibrium concentration of
(1)
the supramolecular complex formed by DT and (R)-CP in the organic
phase and [AS-DT]org has a similar definition.
Thirdly, the CP enantiomers are selectively extracted mainly by
formation of a ternary complex among DT, BA and CP enantiomers.
There exists an acid-base equilibrium for CP in the aqueous phase, and
the protonated CP and neutral form of CP are in equilibrium. Formation
of the ternary complex contains two important steps (Fig. 4). In Step 1:
the protonated CP enantiomers react with boric acid in aqueous phase
producing a borate ester. In Step 2: the borate ester then reacts with DT
(2)
to form a ternary complex. The reaction in Step 2 has enantioselectivity,
namely DT reacts preferentially with the borate ester containing (R)-CP.
It is found that BA is hardly dissolved in organic phase while DT is
hardly dissolved in aqueous solution. Therefore, the reaction is re-
stricted at the aqueous-organic interface and the ternary complex is
dissolved in organic phase. Here, boric acid has no enantioselectivity,
and it plays a role of bridging between chlorprenaline enantiomers and
tartrate derivatives, which strengthens the enantioselectivities of tar-
trate derivatives towards the (R)-chlorprenaline and (S)-chlorprenaline.

Fig. 3. Scheme of the enantioselective complexation of clorprenaline.

Ai: (R)/(S)-clorprenaline, BA: boric acid, DT: D-isobutyl tartrate, AiH+: protonated (R) or (S)-clorprenaline, Ai-DT: supramolecular complex. i: (R) or (S), BDR or BDS :
ternary complex.

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W. Wang et al. Chemical Engineering & Processing: Process Intensification 134 (2018) 141–152

Fig. 4. The formation mechanism of ternary complex.

The acid-base equilibrium of CP in the aqueous phase is char- Distribution ratio (D) and enantioselectivity (α) are defined by the
acterized by the acid-base dissociation constant: following Eqs. (14) to (16):
[AR]aq [H+]aq [AS]aq [H+]aq [AR]all
org
forms
K a,C = = DR =
[AR H+]aq [ASH+]aq (8) [AR]all forms
aq (14)
+ +
where, [ARH ]aq and [ASH ]aq are the equilibrium concentration of
the protonated (R)-CP and (S)-CP in the aqueous phase, respectively; [AS]all
org
forms
DS =
[H+]aq is the equilibrium concentration of hydrogen ion in the aqueous [AS]all
aq
forms
(15)
phase; the acid-base dissociation constant Ka,C is the same for both of
where [AR]org and [AS]org are the total concentrations of (R)-CP and (S)-
the enantiomers.
CP in the organic phase, respectively; [AR]aq and [AS]aq are the total
The acid-base equilibrium of BA in the aqueous phase:
concentrations of (R)-CP and (S)-CP in the aqueous phase, respectively.
[BA−]aq [H+]aq When the R-clorprenaline is preferentially extracted, enantioselec-
K a,B =
[BA]aq (9) tivity (α) is defined as follows:

where, [BA]aq is the equilibrium concentration of molecular BA in DR

α=
aqueous phase; [BA−]aq is the equilibrium concentration of the dis- DS (16)
sociated BA in aqueous phase; Ka,B is the acid-base dissociation con-
Given the above descriptions, the complete mechanism on reactive
stant.
extraction of CP enantiomers in an aqueous/organic two-phase system
To simplify the notation, the equilibrium constants for the reactions
is illustrated in Fig. 4. According to the literature report [46], the
depicted in Fig. 3 are expressed as follows with the abbreviations of the
equilibrium constants for the reactions producing borate esters in
corresponding species:
aqueous phase i.e. KBR and KBS are very small. Therefore, the equili-
[BR+]aq brium concentrations of BR+ and BS+ in aqueous phase are actually
KBR =
[AR H+]aq [BA]aq (10) very small. It is difficult to quantify them through an experimental
means and direct determination of KR and KS is basically impossible. To
[BS+]aq simplify the calculation, we decide to use the product of KBR and KR
KBS =
[ASH+]aq [BA]aq (11) (KBS and KS), which represents the equilibrium constant of the reaction
+ +
producing the ternary complex from DT, BA and CP enantiomer.
where, [BR ]aq and [BS ]aq are the equilibrium concentrations of the
borate esters containing (R)-CP and (S)-CP, respectively. Owing to non- [BDR]org [H+]aq
KBDR =
selective nature of these reactions, the equilibrium constant KBR is equal [AR H+]aq [BA]aq [DT]org (17)
to KBS.
The equilibrium constants for formation of the ternary complex [BDS]org [H+]aq
KBDS =
containing (R)-CP and (S)-CP are defined as follows: [ASH+]aq [BA]aq [DT]org (18)
[BDR]org [H+]aq For wash section (j = 1 … f-1), the component balances for R- and
KR =
[DT]org [BR+]aq (12) S-clorprenaline can be written as follows: (the subscript, i, represent R-
or S-):
[BDS]org [H+]aq
KS = O([Ai ]org,j − 1 + [Ai DT]1 [BDAi]org,j − 1)
[DT]org [BS+]aq (13)
+ W([Ai ]aq,j + 1 + [Ai H+]aq,j + 1 + [BA +i ]aq,j + 1)
where, [BDR]org and [BDS]org are the equilibrium concentrations of the
ternary complexes containing (R)-CP and (S)-CP, respectively. Because = O([Ai ]org,j + [Ai DT]org,j − 1 [BDAi ]org,j )
DT reacts preferentially with the borate ester containing (R)-CP, KR is + W([Ai ]aq,j + [Ai H+]aq,j + [BA +i ]aq,j ) (19)
bigger than KS.

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W. Wang et al. Chemical Engineering & Processing: Process Intensification 134 (2018) 141–152

Table 1 Table 2
Influence of organic solvents. Influence of different tartrate derivatives.
Solvent system DR DS α Extractant DR DS α

Ethyl acetate/aqueous solution (1:1, v/v) 0.065 0.057 1.156 D- cyclohexyl tartrate 0.405 0.241 1.685
Butyl acetate/aqueous solution (1:1, v/v) – – – L- 0.246 0.413 1.676
Isobutyl acetate/aqueous solution (1:1, v/v) – – – D- n-octyl tartrate 0.705 0.384 1.834
Methyl tert-butyl ether/aqueous solution (1:1, v/v) 0.033 0.031 1.059 L- 0.394 0.718 1.823
n-Octanol/aqueous solution (1:1, v/v) 0.111 0.109 1.019 D- isobutyl tartrate 0.308 0.153 2.012
Dichloromethane/aqueous solution (1:1, v/v) 0.549 0.271 2.025 L- 0.286 0.570 1.989
1,2-dechlorethane/aqueous solution (1:1, v/v) 0.308 0.153 2.012 D- n-hexyl tartrate 0.518 0.715 1.380
n-Hexane/aqueous solution (1:1, v/v) – – – L- 0.344 0.621 1.802
Cyclohexane//aqueous solution (1:1, v/v) – – – D- n-butyl tartrate 0.657 0.368 1.787
L- 0.492 0.970 1.972
Aqueous phase: [BA] = 0.10 mol/L, [clorprenaline] = 2 mmol/L,
[CH3COONa] = 0.10 mol/L, pH = 5.0. Organic phase: 0.10 mol/L D-isobutyl Aqueous phase: [BA] = 0.10 mol/L, [clorprenaline] = 2 mmol/L,
tartrate. Equilibration temperature: T = 278.15 K. “–” distribution ratio was too [CH3COONa] = 0.10 mol/L, pH = 5.0. Organic phase: 1,2-dichlorethane
little. (0.1 mol/L TD). Equilibration temperature: T = 278.15 K.

For the feed stage, the component balance for Ai is defined as:

O([Ai]org,f − 1 + [Ai DT]org,f − 1 + [BDAi]org,f − 1)

+ W([Ai]aq,f + 1 [AiH+]aq,f + 1 + [BA +i ]aq,f + 1) + F[Ai ]0
= (O+ F)([Ai ]org,f [Ai DT]org,f + [BDAi]org,f ) (20)
Where, [Ai]0 is the initial concentration of R- and S-clorprenaline in
the feed stream.
The component balances for Ai in stripping section (j = f+1, f+2…
N), can be written as follows:

( O+ F)([Ai]org,j − 1 + [AiDT]org,j − 1 + [BDAi]org,j − 1)

+ W([Ai]aq,j + 1 + [Ai H+]aq,j + 1 + [BA +i ]aq,j + 1)
= ( O+ F)([Ai]org,j + [Ai DT]org,j + [BDAi]org,j )
+ W([Ai]aq,j + [Ai H+]aq,j + [BA +i ]aq,j ) (21)
The overall component mass balances for the enantiomers Ai is
defined as:
Fig. 5. The distribution curves of CP and BA with different existing forms.
F[Ai ]0 = (O+ F)([Ai ]org,N + [Ai DT]org,N + [BDAi]org,N ) +W([Ai]aq,1
+ [Ai H+]aq,1 + [BA +i ]aq,1) (22)
The enantiomeric excess (ee) is used as a measure of the optical purity
of the raffinate and the extract. The ee of clorprenaline in the extract
and raffinate can be calculated by:

[AS]all
aq
forms
− [AR]all
aq
forms
eeaq =
[AS]all
aq
forms
+ [AR]all
aq
forms
(23)

[AR]all
org
forms
− [AS]all
org
forms
eeorg =
[AR]all
org
forms
+ [AS]all
org
forms
(24)
Besides the ee, another important parameter is the yield (Y). The
yield of R- and S- clorprenaline are, respectively, defined as:
totalAS,aq [mol]
Yaq =
totalAS,feed [mol] (25)

totalAR,org [mol]
Yorg =
totalAR,feed [mol]
The multistage extraction model was programmed on Matlab
(MathWorks, Natick, MA). Influence of some important process para-
meters including flow ratio (O/W, F/W), the extractant concentration,
and how many stages used were modeled.
3.2. Thermodynamics constants
According to the methods described in previous work of Zhang et al.
[28], Physical partition coefficient (P0) was 12.05 and Pi was 0;
Fig. 6. Influence of pH on D (a) and α (b). Aqueous phase: [BA] = 0.10 mol/L,
(26) [CH3COONa] = 0.10 mol/L. Organic phase: 1,2-dichlorethane (0.1 mol/L D-
isobutyl tartrate), [clorprenaline] = 2 mmol/L. Equilibration temperature:
T = 278.15 K.
equilibrium constants for the supramolecular interactions between CP
enantiomers and DT (KDR and KDS) was 168 and 151, respectively;
equilibrium constants for the reaction producing ternary complex from
DT, BA and MT enantiomers (KR and KS) was 7.11 × 10−4 and
3.59 × 10-4, respectively.

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4. Results and discussions
4.1. The construction of liquid-liquid extraction system
In order to construct an efficient extraction system, we explored the
influence of organic solvents, tartaric acid derivatives, pH of aqueous
phase and tartaric acid derivatives concentration and boric acid con-
centration on the extraction efficiency in single-stage extraction ex-
periments. The extraction efficiency was evaluated by distribution ratio
(D) and enantioselectivity (α).
4.1.1. Influence of organic solvents
Table 1 shows the influence of different organic solvent on dis-
tribution behavior. As Table 1 shows, distribution ratio and enantios-
electivity are affected obviously by the type of the organic solvent.
Results indicate that the distribution ratios are low and the extractant
nearly has no recognition ability toward CP enantiomers when ethyl
acetate, butyl acetate, isobutyl acetate, methyl tert-butyl ether, n-oc-
tanol, n-hexane and cyclohexane are selected as organic solvent.
Compared with other organic solvent, when dichloromethane and 1,2-
dichlorethane were chosen, the effects of extraction separation were
better. When dichloromethane was selected, the largest α (α = 2.025)
was obtained with suitable distribution ratios. And α (α = 2.012) was
obtained with suitable distribution ratios when 1,2-dichlorethane was
selected. The reasons for these are as follows: CP and the ternary
complexes have strong polarities; increasing the polarity of organic
Fig. 7. Influence of different concentration of BA and D-isobutyl tartrate on D and α. Aqueous phase: [CH3COONa] = 0.10 mol/L, pH = 5.0. BA is dissolved into
aqueous phase. Organic phase: 1,2-dichlorethane (D-isobutyl tartrate), [clorprenaline] = 2 mmol/L. Equilibration temperature: T = 278.15 K.
147
Chemical Engineering & Processing: Process Intensification 134 (2018) 141–152
solvent, the physical distribution of CP will increase, and the solubility
of ternary complexes will be enhanced, which will lead to the increase
of distribution ratios of CP; among the tested organic solvents, the
polarities of dichloromethane and 1,2-dichlorethane are relatively
strong. Considering the low boiling point of dichloromethane, it could
not be used in CCSs, so we would choose 1,2-dichlorethane as the best
suitable organic solvent. 1,2-Dichlorethane was also applied to the ki-
netic study of chlorpenaline [20].
4.1.2. Influence of tartaric acid derivatives
Here, the distribution behavior and extracting efficiency for clor-
prenaline enantiomers were measured in different extraction systems
containing 0.10 mol/L BA in the aqueous phase and 0.1 mol/L TD in
1,2-dichlorethane (Table 2). As shown in Table 2, it follows an inter-
esting rule as follows: D-tartarte derivatives show strong recognition
abilities toward R-clorprenaline enantiomer, while L-tartarte derivatives
show strong recognition abilities toward S-clorprenaline enantiomer. R-
clorprenaline enantiomer is the desired enantiomer. Comparing with
other tartrate derivatives, suitable distribution ratios and the highest
enantioselectivity (α) of 2.012 could be obtained when D-isobutyl tar-
trate (DT) was used. Therefore, D-isobutyl tartrate was selected to be the
best additive.
4.1.3. Influence of pH of aqueous phase
Enantioselective extraction of CP enantiomers are realized through
formation of the ternary complex. According to classical work on
W. Wang et al. Chemical Engineering & Processing: Process Intensification 134 (2018) 141–152

hydrophilic BA on D and α of clorprenaline enantiomers are graphically

revealed in Fig. 7. It was easily found in Fig. 7a and b that with in-
creasing the concentration of BA and D-isobutyl tartrate (more than 0),
the D always increased within the range of the study. As seen in Fig. 7c,
when the concentration of D-isobutyl tartrate was 0.05 mol/L and the
concentration of BA was more than 0.125 mol/L, the α slightly de-
creased. When the concentration of D-isobutyl tartrate was more than
0.075 mol/L, the change of α was little or almost constant. When the
concentration of D-isobutyl tartrate was more than 0.125 mol/L, the α
always decreased. Moreover, as the concentration of D-isobutyl tartrate
was 0.075 mol/L and the concentration of BA was 0.10 mol/L, the
maximum α (α = 2.012) was obtained, and then slowly reduced with
the further increasing BA concentration. Thus, the optimal concentra-
tion of BA and D-isobutyl tartrate for the 1,2-dichlorethane/aqueous
solution system were about 0.10 mol/L and 0.075 mol/L, respectively.

4.2. The verification of the multistage extraction model

In the multistage extraction process, the O/W ratio, concentration of

extractant and the number of the stages were very important para-
meters. Experiments were carried out to study the influence of those
parameters on ee and Y, and then the experimental results were com-
pared with the model prediction, which were used to verify the model.
In this paper, the eeeq (equal enantiomeric excess) and Yeq (equal yield)
were used as the objection. If high eeextract or eeraffinate was used as the
objection, Yextract or Yraffinate would be very low, and it would be large
consumption. When the eeeq was used as the objection, a trade-off be-
tween product purity and yield would be met.
In order to investigate the influence of the O/W ratio on extraction
performance, a series of extraction experiments were performed with
O/W ratio in the range from 0 to 3. This process was also simulated by
the established model. The experimental and simulated results are de-
picted in Fig. 8. It could be observed that the experimental data of ee
and Y were in good consistent with the model predictions. As shown in
Fig. 8a, with the increase of O/W ratio, the ee decreased gradually in
the raffinate phase, while an opposite tendency was observed for the ee
in the extract phase. From Fig. 8b, the yield of R-clorprenaline in the
raffinate phase increased while the yield of S-clorprenaline in the ex-
tract phase decreased with the increase of O/W ratio. When the O/W
ratio was about 1.5, there was one crosspoint where the ee in the
aqueous phase was equal to those in the organic phase, so the yield of
Fig. 8. Influence of O/W ratio on ee and yield for separation of clorprenaline
both phases did. The crosspoint with eeeq and Yeq was selected as the
enantiomers. (a) Influence on ee. (b) Influence on yield. Condition: F/
W = 0.16, [clorprenaline] = 5 mmol/L, T = 278.15 K, N = 10, feed in the
operating point for symmetric separation of clorprenaline enantiomers.
middle stage.
4.3. Application of the model

dissociation extraction by Gaikar and co-workers [49–52], the dis-

The above experimental results showed that CCS device was sui-
tribution behavior is caused by the differences in the pKa values of
table for multistage ELLE. The comparison between the model predic-
chlorprenaline and BA. The predicted pKa of CP is 13.6 ± 0.20, and
tions and the experimental results indicated that the established mul-
that of BA is 8.91 ± 0.43. The functions of species distribution on pH
tistage equilibrium model was a good approach to simulate the extract
are simulated in Fig. 5. From Fig. 5, it is observed that when pH is
efficiency for separation of clorprenaline enantiomers in CCSs. Thus,
below 7, CP enantiomers are in their protonated forms, and BA exists in
the model could be applied to predict and optimize the effects of var-
molecular form, which is conducive to form the ternary complexes.
ious operating parameters on extraction performance in this system.
Fig. 6 shows the influence of pH on distribution behavior by varying the
pH from 4.0 to 7.0 in the 1,2-dichlorethane/aqueous solution (1:1, v/v)
4.3.1. Location of feed stage
systems. As Fig. 5 shows, pH has an important influence on distribution
The change of the location of the feed stage would lead to a change
ratios and enantioselectivity. It is observed that when the pH value
of the number of stages in the stripping section and wash section, which
varies from 4.0 to 5.0, the distribution ratios increase slowly and en-
would make extraction efficiency different. It was observed from Fig. 9
antioselectivity increases rapidly. When pH is increased from 5.0 to 7.0,
that both eeeq and Yeq increased with the location of the feed stage
distribution ratios are increased rapidly, while enantioselectivity de-
varied from 2 to 6, and then decreased with the location of the feed
creases slowly. The highest enantioselectivity is obtained with pH of
stage varied from 6 to 9. Therefore, using the same number of stages in
5.0.Therefore, pH of 5.0 is selected for extraction of CP enantiomers.
the wash and stripping sections was an efficient solution for symme-
trical separation of clorprenaline enantiomers.
4.1.4. Influence of D-isobutyl tartrate concentration and boric acid
concentration 4.3.2. The influence of multi factors in ELLE system
The impacts of the concentration of lipophilic D-isobutyl tartrate and According to the experiments above, the concentrations of BA and

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Fig. 9. Influence of the location of feed stage on eeeq and Yeq for separation of clorprenaline enantiomers. Rectangle: represents Yeq; represents eeeq. O/W = 1.5, F/
W = 0.16, N = 10.

Fig. 10. Influence of BA and DT concentration on ee and Y for separation of clorprenaline enantiomers. Condition: O/W = (0.01, 10), F/W = 0.16, [clorprena-
line] = 5 mmol/L, T = 278.15 K, feed in the middle stage, N = 10.

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W. Wang et al. Chemical Engineering & Processing: Process Intensification 134 (2018) 141–152

Fig. 11. Influence of BA and DT concentration on eeeq for separation of clorprenaline enantiomers at different F/W. Condition: O/W = (0.01, 10), [clorprena-
line] = 5 mmol/L, T = 278.15 K, feed in the middle stage, N = 10.

Fig. 12. Influence of number of stage on eeeq for separation of clorprenaline enantiomers at different F/W ratio. Condition: O/W = (0.01, 10), [clorprenaline] =
5 mmol/L, T = 278.15 K, feed in the middle stage.

Table 3 while there was an opposite tendency of Yorg.

Optimized settings for symmetrical separations with [clorprenaline] = 5 mmol/ Fig. 11 shows the eeeq as a function of BA and DT concentration at
L, pH = 5.0, T = 278.15 K. different F/W. eeeq decreased with the increase of F/W ratio. Value of
Variable eeeq > 97% settings eeeq > 99% settings eeeq could reach up to 0.75 when F/W set at 0.2, but the increase in eeeq
was slight when F/W was further decreased. Taking the economical
N 26 33 efficiency into consideration, a relative low F/W would be selected.
f 13 17
Fig. 12 reveals the influence of the flowrate ratio of feed phase amd
[BA] 0.10 0.10
[D-isobutyl tartrate] 0.075 0.075 aqueous phase (F/W) and number of stages on the eeeq. When the
F/W 0.125 0.125 number of stages (N) was under 30, the eeeq presented a rapid rise with
O/W 1.86 1.87 the rising of N, while the increase tendency was relatively small with
the stages continuing to increase. When F/W decreased from 1 to 0.25,
the eeeq could increase rapidly, while it increased slowly with F/W
DT had a great influence on the extraction performance. Fig. 10 shows further decrease. Therefore, a lower F/W and more number of stages
the influence of concentrations of BA and DT on ee and Y in two phases. were needed to achieve higher eeeq.
As shown in Fig. 10a and b, with the increase of BA and DT con- Additionally, the model could predict the minimum number of
centration, the eeaq increased rapidly at first and then increased slowly, stages needed for eeeq > 97% and eeeq > 99%. Table 3 shows the op-
when BA and DT were both in a relatively high concentration, there was timized results of the two cases. The number of stages for these two
a platform of eeaq appearing, in which the eeaq value could be the cases will be at least 26 and 33, respectively.
highest and constant. While the eeorg showed an opposite tendency.
The influence on Y in two phases was depicted in Fig. 10c and d.
5. Conclusion
With the increase of BA and DT concentration, the Yaq kept constant at
relatively low concentration of BA and DT, and then decreased rapidly,
The method of liquid-liquid reaction extraction separation of

150
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clorprenaline was successfully established using TD in the organic
phase with BA in the aqueous phase. An ELLE system was studied which
obtained the highest α in single-stage extraction experiments. The re-
sult indicated that several process parameters (types of solvent and TD,
concentrations of DT and BA, pH of aqueous phase) had greater influ-
ence on the extraction effect, mainly manifesting in the following sev-
eral aspect. Firstly, besides dichloromethane and 1,2-dichlorethane,
clorprenaline enantiomers were not extracted into other solvents.
Second, complexes formed by different TD with BA had different re-
cognition ability for clorprenaline enantiomer. Thirdly, the formation
of ternary complexes was affected by the pH value and the concentra-
tions of DT and BA. Finally, under the explored optimal of circum-
stances which involved 1,2-dichlorethane as organic phase, 0.10 mol/L
BA in aqueous phase, 0.075 mol/L D-isobutyl tartrate and pH of 5.0 at
278.15 K, the best α with 2.012 was obtained. The experimental results
obtained provide a theoretical and practical guidance for other en-
antiomers separation.
A multistage model on the resolution of clorprenaline enantiomers
was established, based on combination of single stage extraction model,
mass conservation law. This multistage model was verified experi-
mentally and proved to be a good means for fast optimization of the
operational conditions. The model was applied to predict and optimize
the symmetrical separation of clorprenaline enantiomers.
Conflict of interest
None.
Acknowledgement
This work was supported by the National Science Foundation of
China (No. 21376071).
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