Process optimization of reactive extraction of clorprenaline enantiomers by experiment and simulation

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 experiment and simulation Wanru Wang, Weifeng Xu, Guilin Dai, Panliang Zhang, Kewen Tang

T

⁎

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: Enantioselective liquid-liquid extraction Clorprenaline enantiomer Tartrate-boric acid system Equilibrium model Simulation

This paper studied the process optimization of reactive extraction of clorprenaline enantiomers (CP) by experiment and simulation. An efficient extraction system was obtained through single stage extraction experiments, where boric acid (BA) in aqueous phase and D-isobutyl tartrate (DT) in organic phase were selected as extractant and 1,2-dichlorethane was selected as organic solvent. The best enantioselectivity (α) with 2.012 was obtained. The extraction mechanism was proposed and thermodynamic constants such as physical partition coefficient and reactive equilibrium constants were obtained. Based on single stage extraction, phase and reactive 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 Clorprenaline, 1-(2-Chlorophenyl)-2-(isopropylamino) ethanol (Fig. 1), which has been confirmed its curative effect and high selectivity towards the β2 receptor agonist, is commonly applied in the treatment of bronchia asthma and bronchitis. However, each enantiomer of racemic drugs shows different pharmacological and toxicological 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 vibration. 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 separation efficiencies, rapid separation, and low consumption of reagents [21]. Unfortunately, its application in chiral separation has been ⁎

severely hindered due to the poor reproducibility, complex instrument, complicated sample pretreatment, and difficult realizing the industrialization [22]. Chiral chromatography has been usually adopted to generate the optically pure compounds in the separation of enantiometric 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 reaction 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) tetracarboxylic acid [32], have successfully used for chiral separations in the systems mentioned above, and β-cyclodextrins and tartarte derivatives

Corresponding author. E-mail address: [email protected] (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.

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Nomenclature

Ka,C Dissociation constant, mol/L KBR Complex equilibrium constant, L/mol KBS Complex equilibrium constant, L/mol KDR Complex equilibrium constant, L/mol KDS Complex equilibrium constant, L/mol KR Complex equilibrium constant KS Complex equilibrium constant N Number of stages O Volume flow rate organic phase, mL/min P0 Physical partition coefficient of molecular clorprenaline Papp Apparent physical partition coefficient SBE-β-CD Sulfobutylether-β-cyclodextrin TD Tartrate derivatives T Temperature, K Y Yield W Volume flow rate aqueous phase, mL/min α Enantioselectivity

Abbreviations AR ARH+ AR-DT AS ASH+ AS-DT BA BA− BDR BDS BR+ BS+ CCSs CM-β-CD CP DR DS DT ee eeeq F f Ka,B

(R)-Clorprenaline Protonated (R)-clorprenaline Supramolecular complex (S)-Clorprenaline Protonated (S)-clorprenaline Supramolecular complex Boric acid Dissociated boric acid Ternary complex formed by DT, BA and (R)-CP Ternary complex formed by DT, BA and (S)-CP Borate ester Borate ester Centrifugal contactor separators Carboxymethyl-β-cyclodextrin Clorprenaline enantiomers Distribution ratios for (R)-clorprenaline Distribution ratios for (S)-clorprenaline D-Isobutyl tartrate Enantiomeric excess Equal enantiomeric excess Volume flow rate feed phase, mL/min Number of feed stages Dissociation constant, mol/L

Subscripts i j aq org eq

Index for CP enantiomers of different optical rotation, i = R or S Stage index Aqueous phase Organic phase Equal value

Centrifugal contactor separator (CCS), which was a device that integrated 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 researchers. 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 support 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 coefficient and reactive equilibrium constants, and ELLE in CCS was utilized for full separation of clorprenaline enantiomers by experiment and simulation. 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 conditions. 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 enantioselectivity (α) can be obtained; (2) it can be applied to ELLE in multistage 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 dispersion and separation, etc. According to the chemical and physical equilibrium of single stage, and mass balance, a multistage equilibrium model of ELLE was established. 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 industrial production.

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 enantiomers. Recently, kinetic study on extraction of clorprenaline enantiomers 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 promising to be scale-up in industry.

Fig. 1. Chemical structure of clorprenaline enantiomer. 142

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2. Materials and methods

2.4. Extraction experiments

2.1. Material

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 aqueous 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 clorprenaline in the organic phase was determined by mass balance.

Clorprenaline (racemate, purity 98%) was purchased from Hubei Kangbaotai Fine-chemicals Co., Ltd, Hubei, China. D-tartaric acid and Ltartaric acid (AR, 99%) were purchased from Shanghai Aladdin Biochem 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). Dand L- tartrate derivatives were synthesized in our laboratory with the purity of 99% according to the reference [44]. Solvents for chromatography were of the HPLC grade.

2.4.2. Multistage extraction experiments Fig. 2 shows the flow diagram of multistage countercurrent extraction of clorprenaline enantiomers using a series of CCSs. The substrate (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.

2.2. Apparatus HPLC (Waters e2695 Separation Module) and An UV/visible detector (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 ultrapure water system (Easy) was purchased from Heal Force Instrument Co., Ltd. (Shanghai, China).

2.5. Determination of physical distribution coefficients P0 and Pi of molecular and ionic clorprenaline pH is adjusted by CH3COONa/CH3COOH buffer solution. The solubility 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 parameters, which are only influenced by temperature. The experimental P0 and Pi will be inaccurate if the concentration of clorprenaline in aqueous phase is saturated. Therefore, the initial concentration of clorprenaline in organic phase is selected as 2 mmol/L. A series of experiments to determine physical distribution coefficient 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

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 (CMβ-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 Rand S- clorprenaline enantiomers were completely separated from each other, with an indication that R-clorprenaline with less affinity to CM-βCD eluted earlier, whereas S-clorprenaline with more affinity to CM-βCD eluted later.

Fig. 2. Flow diagram of the multistage centrifugal counter-current extraction of clorprenaline enantiomers. 143

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water bath at 278.15 K to reach equilibrium. The concentration of clorprenaline in aqueous phase was measured by HPLC. The concentration of clorprenaline in organic phase was determined by a mass balance.

Papp =

1 1 [H+] ⎞ ⎫ [H+] Papp ⎧ + ⎛ =1+ ⎨ ⎬ P P Ka Ka i⎝ ⎠⎭ ⎩ 0

1 ⎛ [H+] 1 1 [H+] ⎞ + 1⎞ = + ⎛ Papp ⎝ Ka P0 Pi ⎝ Ka ⎠ ⎠

In this work, the clorprenaline enantiomers are extracted by a chiral selector of DT and BA. Several papers have reported the research on mechanism of enantioselective extraction of some β-blockers with boric acid and tartrate as chiral selector, which offer important references for this paper to understand the mechanism of reactive extraction of CP enantiomers by DT and BA [45–47]. Herein we describe our assumption on extraction mechanism. Experiments were performed to validate these assumptions. Distribution of CP enantiomers in the organic phase may be through the following three approaches (depicted in Fig. 3): Firstly, for the molecular CP, even without the formation of a complex with the extractant, the physical partitioning of the neutral form of CP between the organic and aqueous phases may take place, which is characterized by the physical partition coefficient, P0:

⎜

KDR =

KDS =

(5)

[AR -DT]org [AR]org [DT]org

(6)

[AS-DT]org [AS ]org [DT]org

(7)

where [DT]org represents the equilibrium concentration of DT in the organic phase; [AR-DT]org represents the equilibrium concentration of 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 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 restricted 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 tartrate derivatives towards the (R)-chlorprenaline and (S)-chlorprenaline.

[Ai]org (1)

[Ai H+]org [Ai H+]aq

⎟

Secondly, the supramolecular interactions between CP enantiomers and DT can take place in organic phase in the absence of BA and this interesting phenomenon has been observed by lots of researchers [47,48]. Assuming a 1:1 supramolecular complex is formed between CP enantiomers and DT, the complexation constants are expressed by the following equations for (R)-CP and (S)-CP, respectively:

where [Ai]org represents the concentrations of R- and S- clorprenaline in the organic phase at equilibrium, and [Ai]aq represents the concentrations 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:

Pi =

(4)

Eq. (4) can be transformed into

3.1. The construction of the model

[Ai]aq

(3)

Therefore, Papp can be derived as

3. Model descriptions

P0 =

[A]W + [AH+]W [A]o + [AH+]o

(2)

+

where [AiH ]org represents the concentrations of the ionic R- and Sclorprenaline in the organic phase at equilibrium, and [AiH+]aq represents 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

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. 144

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Fig. 4. The formation mechanism of ternary complex.

Distribution ratio (D) and enantioselectivity (α) are defined by the following Eqs. (14) to (16):

The acid-base equilibrium of CP in the aqueous phase is characterized by the acid-base dissociation constant:

K a,C =

[AR]aq [H+]aq [AR H+]aq

=

[AS]aq [H+]aq [ASH+]aq

+

DR =

(8)

DS =

KBS =

[BA−]aq [H+]aq [BA]aq

(9)

α=

[AR H+]aq [BA]aq

(10)

[BS+]aq [ASH+]aq [BA]aq

(11) +

where, [BR ]aq and [BS ]aq are the equilibrium concentrations of the borate esters containing (R)-CP and (S)-CP, respectively. Owing to nonselective nature of these reactions, the equilibrium constant KBR is equal to KBS. The equilibrium constants for formation of the ternary complex containing (R)-CP and (S)-CP are defined as follows:

KR =

KS =

DR DS

KBDS =

(15)

(16)

[BDR]org [H+]aq [AR H+]aq [BA]aq [DT]org

(17)

[BDS]org [H+]aq [ASH+]aq [BA]aq [DT]org

(18)

(12)

For wash section (j = 1 … f-1), the component balances for R- and S-clorprenaline can be written as follows: (the subscript, i, represent Ror S-):

(13)

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

[BDS]org [H+]aq [DT]org [BS+]aq

forms [AS]all aq

KBDR =

[BDR]org [H+]aq [DT]org [BR+]aq

forms [AS]all org

Given the above descriptions, the complete mechanism on reactive extraction of CP enantiomers in an aqueous/organic two-phase system is illustrated in Fig. 4. According to the literature report [46], the equilibrium constants for the reactions producing borate esters in aqueous phase i.e. KBR and KBS are very small. Therefore, the equilibrium concentrations of BR+ and BS+ in aqueous phase are actually very small. It is difficult to quantify them through an experimental means and direct determination of KR and KS is basically impossible. To simplify the calculation, we decide to use the product of KBR and KR (KBS and KS), which represents the equilibrium constant of the reaction producing the ternary complex from DT, BA and CP enantiomer.

[BR+]aq

+

(14)

where [AR]org and [AS]org are the total concentrations of (R)-CP and (S)CP in the organic phase, respectively; [AR]aq and [AS]aq are the total concentrations of (R)-CP and (S)-CP in the aqueous phase, respectively. When the R-clorprenaline is preferentially extracted, enantioselectivity (α) is defined as follows:

where, [BA]aq is the equilibrium concentration of molecular BA in aqueous phase; [BA−]aq is the equilibrium concentration of the dissociated BA in aqueous phase; Ka,B is the acid-base dissociation constant. To simplify the notation, the equilibrium constants for the reactions depicted in Fig. 3 are expressed as follows with the abbreviations of the corresponding species:

KBR =

forms [AR]all aq

+

where, [ARH ]aq and [ASH ]aq are the equilibrium concentration of the protonated (R)-CP and (S)-CP in the aqueous phase, respectively; [H+]aq is the equilibrium concentration of hydrogen ion in the aqueous phase; the acid-base dissociation constant Ka,C is the same for both of the enantiomers. The acid-base equilibrium of BA in the aqueous phase:

K a,B =

forms [AR]all org

+ 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 DT reacts preferentially with the borate ester containing (R)-CP, KR is bigger than KS.

= O([Ai ]org,j + [Ai DT]org,j − 1 [BDAi ]org,j ) + W([Ai ]aq,j + [Ai H+]aq,j + [BA +i ]aq,j ) 145

(19)

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Table 1 Influence of organic solvents.

Table 2 Influence of different tartrate derivatives.

Solvent system

DR

DS

α

Extractant

Ethyl acetate/aqueous solution (1:1, v/v) Butyl acetate/aqueous solution (1:1, v/v) Isobutyl acetate/aqueous solution (1:1, v/v) Methyl tert-butyl ether/aqueous solution (1:1, v/v) n-Octanol/aqueous solution (1:1, v/v) Dichloromethane/aqueous solution (1:1, v/v) 1,2-dechlorethane/aqueous solution (1:1, v/v) n-Hexane/aqueous solution (1:1, v/v) Cyclohexane//aqueous solution (1:1, v/v)

0.065 – – 0.033 0.111 0.549 0.308 – –

0.057 – – 0.031 0.109 0.271 0.153 – –

1.156 – – 1.059 1.019 2.025 2.012 – –

D-

cyclohexyl tartrate

LD-

n-octyl tartrate

LD-

isobutyl tartrate

LD-

n-hexyl tartrate

LDL-

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 tartrate. Equilibration temperature: T = 278.15 K. “–” distribution ratio was too little.

n-butyl tartrate

DR

DS

α

0.405 0.246 0.705 0.394 0.308 0.286 0.518 0.344 0.657 0.492

0.241 0.413 0.384 0.718 0.153 0.570 0.715 0.621 0.368 0.970

1.685 1.676 1.834 1.823 2.012 1.989 1.380 1.802 1.787 1.972

Aqueous phase: [BA] = 0.10 mol/L, [clorprenaline] = 2 mmol/L, [CH3COONa] = 0.10 mol/L, pH = 5.0. Organic phase: 1,2-dichlorethane (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: forms forms [AS]all − [AR]all aq aq

eeaq =

forms forms [AS]all + [AR]all aq aq

eeorg =

(23)

forms forms [AR]all − [AS]all org org forms forms [AR]all + [AS]all org org

(24)

Besides the ee, another important parameter is the yield (Y). The yield of R- and S- clorprenaline are, respectively, defined as:

Yaq =

totalAS,aq [mol] totalAS,feed [mol]

(25)

Yorg =

totalAR,org [mol] totalAR,feed [mol]

(26)

Fig. 6. Influence of pH on D (a) and α (b). Aqueous phase: [BA] = 0.10 mol/L, [CH3COONa] = 0.10 mol/L. Organic phase: 1,2-dichlorethane (0.1 mol/L Disobutyl tartrate), [clorprenaline] = 2 mmol/L. Equilibration temperature: T = 278.15 K.

The multistage extraction model was programmed on Matlab (MathWorks, Natick, MA). Influence of some important process parameters including flow ratio (O/W, F/W), the extractant concentration, and how many stages used were modeled.

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.

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; 146

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4. Results and discussions

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 kinetic study of chlorpenaline [20].

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 concentration on the extraction efficiency in single-stage extraction experiments. The extraction efficiency was evaluated by distribution ratio (D) and enantioselectivity (α).

4.1.2. Influence of tartaric acid derivatives Here, the distribution behavior and extracting efficiency for clorprenaline 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 interesting 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. Rclorprenaline 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 tartrate (DT) was used. Therefore, D-isobutyl tartrate was selected to be the best additive.

4.1.1. Influence of organic solvents Table 1 shows the influence of different organic solvent on distribution behavior. As Table 1 shows, distribution ratio and enantioselectivity 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-octanol, n-hexane and cyclohexane are selected as organic solvent. Compared with other organic solvent, when dichloromethane and 1,2dichlorethane 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

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

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

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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 increasing 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 decreased. 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 concentration 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 parameters. Experiments were carried out to study the influence of those parameters on ee and Y, and then the experimental results were compared 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 between 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 depicted 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 extract 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 both phases did. The crosspoint with eeeq and Yeq was selected as the operating point for symmetric separation of clorprenaline enantiomers.

Fig. 8. Influence of O/W ratio on ee and yield for separation of clorprenaline 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 middle stage.

4.3. Application of the model dissociation extraction by Gaikar and co-workers [49–52], the distribution behavior is caused by the differences in the pKa values of chlorprenaline and BA. The predicted pKa of CP is 13.6 ± 0.20, and that of BA is 8.91 ± 0.43. The functions of species distribution on pH are simulated in Fig. 5. From Fig. 5, it is observed that when pH is below 7, CP enantiomers are in their protonated forms, and BA exists in molecular form, which is conducive to form the ternary complexes. 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) systems. As Fig. 5 shows, pH has an important influence on distribution ratios and enantioselectivity. It is observed that when the pH value varies from 4.0 to 5.0, the distribution ratios increase slowly and enantioselectivity increases rapidly. When pH is increased from 5.0 to 7.0, distribution ratios are increased rapidly, while enantioselectivity decreases slowly. The highest enantioselectivity is obtained with pH of 5.0.Therefore, pH of 5.0 is selected for extraction of CP enantiomers.

The above experimental results showed that CCS device was suitable for multistage ELLE. The comparison between the model predictions and the experimental results indicated that the established multistage equilibrium model was a good approach to simulate the extract efficiency for separation of clorprenaline enantiomers in CCSs. Thus, the model could be applied to predict and optimize the effects of various operating parameters on extraction performance in this system. 4.3.1. Location of feed stage The change of the location of the feed stage would lead to a change of the number of stages in the stripping section and wash section, which would make extraction efficiency different. It was observed from Fig. 9 that both eeeq and Yeq increased with the location of the feed stage varied from 2 to 6, and then decreased with the location of the feed stage varied from 6 to 9. Therefore, using the same number of stages in the wash and stripping sections was an efficient solution for symmetrical separation of clorprenaline enantiomers.

4.1.4. Influence of D-isobutyl tartrate concentration and boric acid concentration The impacts of the concentration of lipophilic D-isobutyl tartrate and

4.3.2. The influence of multi factors in ELLE system According to the experiments above, the concentrations of BA and 148

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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, [clorprenaline] = 5 mmol/L, T = 278.15 K, feed in the middle stage, N = 10.

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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), [clorprenaline] = 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.

while there was an opposite tendency of Yorg. Fig. 11 shows the eeeq as a function of BA and DT concentration at different F/W. eeeq decreased with the increase of F/W ratio. Value of 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 efficiency into consideration, a relative low F/W would be selected. Fig. 12 reveals the influence of the flowrate ratio of feed phase amd aqueous phase (F/W) and number of stages on the eeeq. When the number of stages (N) was under 30, the eeeq presented a rapid rise with 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 further decrease. Therefore, a lower F/W and more number of stages were needed to achieve higher eeeq. Additionally, the model could predict the minimum number of stages needed for eeeq > 97% and eeeq > 99%. Table 3 shows the optimized results of the two cases. The number of stages for these two cases will be at least 26 and 33, respectively.

Table 3 Optimized settings for symmetrical separations with [clorprenaline] = 5 mmol/ L, pH = 5.0, T = 278.15 K. Variable

eeeq > 97% settings

eeeq > 99% settings

N f [BA] [D-isobutyl tartrate] F/W O/W

26 13 0.10 0.075 0.125 1.86

33 17 0.10 0.075 0.125 1.87

DT had a great influence on the extraction performance. Fig. 10 shows the influence of concentrations of BA and DT on ee and Y in two phases. As shown in Fig. 10a and b, with the increase of BA and DT concentration, the eeaq increased rapidly at first and then increased slowly, when BA and DT were both in a relatively high concentration, there was a platform of eeaq appearing, in which the eeaq value could be the highest and constant. While the eeorg showed an opposite tendency. The influence on Y in two phases was depicted in Fig. 10c and d. With the increase of BA and DT concentration, the Yaq kept constant at relatively low concentration of BA and DT, and then decreased rapidly,

5. Conclusion 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 result indicated that several process parameters (types of solvent and TD, concentrations of DT and BA, pH of aqueous phase) had greater influence on the extraction effect, mainly manifesting in the following several 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 recognition ability for clorprenaline enantiomer. Thirdly, the formation of ternary complexes was affected by the pH value and the concentrations of DT and BA. Finally, under the explored optimal of circumstances 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 enantiomers 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 experimentally 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.

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