Experimental and Model Study on Multistage Enantioselective Liquid

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Industrial & Engineering Chemistry Research

1

Experimental and Model Study on Multistage Enantioselective

2

Liquid–Liquid Extraction of Ketoconazole Enantiomers in

3

Centrifugal Contactor Separators

4

Kewen Tang,*,† Xiaofeng Feng,‡ Panliang Zhang,† Shuangfeng Yin,*,‡

5

Congshan Zhou,† Changan Yang†

6

†

Department of Chemistry and Chemical Engineering, Hunan Institute of Science and Technology, Yueyang 414006, Hunan, China

7 ‡

8

College of Chemistry and Chemical Engineering, Hunan University, Changsha 410083, Hunan, China

9

10 11 12 13 14 15 16 17 18 19 20 21

*

Corresponding author. E-mail address: [email protected] (K.W. Tang); [email protected] (S. F. Yin) 1

ACS Paragon Plus Environment


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1

ABSTRACT: This paper reports on the multistage enantioselective liquid-liquid

2

extraction

3

hydroxyphenyl-β-cyclodextrin (HP-β-CD) as hydrophilic chiral selector in centrifugal

4

contactor separators (CCSs). Single-stage and multi-stage extraction experiments

5

were performed to investigate the influence of some important factors. Mathematical

6

model was built to predict the experimental results. The influence of some factors on

7

the multistage separation process, including the extract phase/washing phase ratio

8

(W/O), the concentration of chiral selector, the pH value of aqueous phase, and the

9

number of stages were investigated by experiment and simulation. It was found that

10

experimental results are in good agreement with the model predictions. The model

11

was applied to predict and optimize the symmetrical separation of KTZ enantiomers.

12

The optimal conditions for symmetric separation involves a W/O ratio of 4.5, pH of

13

8.5 and HP-β-CD concentration of 0.1 mol/L at 278K, where eeeq (equal enantiomeric

14

excess) can reach up to 38% and Yeq (equal yield) to 68%. By modeling, the minimum

15

number of stages was evaluated at 72 and 94 for eeeq> 97% and eeeq > 99%,

16

respectively.

17

KEYWORDS: Ketoconazole enantiomers; Multistage extraction; Centrifugal

18

contactor separators; Modeling and optimization

19

1. INTRODUCION

(ELLE)

of

ketoconazole

(KTZ)

enantiomers

using

20

In recent years, chiral separation is still an active field of study, owing to its

21

importance in the industry of fragrance,1 pharmacy,2 and food3. Normally, different

22

enantiomers of a chiral drug may exhibit different biological activity and toxicity

2


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1

profiles in the human body. In most cases, only one enantiomer possesses the

2

pharmaceutical effect and has a very low level of side effects.4 Many governmental

3

agencies, for example, the U.S. Food and Drug Administration stipulated that the

4

pharmaceutical activity and toxicity of the two enantiomers need to be studied and

5

analyzed before a new drug was marked.5 Therefore, it is very necessary to separate

6

the racemates into their constituent single enantiomers. A number of impressive

7

methodologies, such as chromatographic techniques,6 crystallization techniques,7

8

capillary electrophorsis,8,9 and liquid membrane10,11 have been developed. Compared

9

with the methodologies mentioned above, ennatioselective liquid-liquid extraction

10

(ELLE) may be the most promising approach for chiral separation, which is easier to

11

scale up to commercial scale, has higher efficiency and has a broader application

12

range. Recently, a lot of researchers attempted the separation of chiral active

13

substances by ELLE and large

14

appeared.12-21

numbers of research results on ELLE have

15

The centrifugal contactor separator (CCS) is an example of a compact continuous

16

flow equipment that seems perfectly suitable for continuous separation of enantiomers

17

by ELLE. In the CCS equipment, reaction and separation are combined in a single

18

device, and two immiscible phases are contacted efficiently and are subsequently

19

separated. The CCS has been successfully used for production of biodiesel,22 for

20

separation of ionic liquid dispersions and for some other extraction processes.23-25 In

21

recent years, the separation of chiral compounds by multistage ELLE in CCS has

22

attracted increasing attention.14-17 However, there are only a few studies on modeling

3



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and optimization of the multistage ELLE.

2

Hydrophilic β-cyclodextrins has hydrophobic cavities in the molecular structures

3

and can form complexes with guest molecules by their inclusion in the cavities.26

4

Hydroxypropyl-β-cyclodextrins (HP-β-CD), a hydroxyalkyl derivative, is highly

5

soluble in aqueous phase but is insoluble in organic liquids (Figure 1). It has recently

6

been regarded as a promising alternative to traditional chiral selectors due to the

7

unique physical properties and non-toxic side effects. The use of HP-β-CD as chiral

8

selectors has been widely reported. 20, 21, 27

9

Ketoconazole,

cis-l-acetyl-4[4-[2-(2,4-dichlorophenyl)-2-(1H-imidazole-l-

10

ylmethyl)-1,3-dioxolan-4-yl]

methoxyphenyl]

piperazine,

is

widely

used

as

11

antimycotic drug (Figure 2). It has two chiral centres and the absolute configuration of

12

KTZ has been reported.28 It is usually marketed as a racemate, but studies have found

13

that the two enantiomers of KTZ have different pharmacological activity, the

14

pharmacological activity of (-)-KTZ is 2–4 times higher than (+)-KTZ.29 In recent

15

years, several studies attempting to obtain single KTZ enantiomer have been reported,

16

which are mainly achieved by chromatographic methods30-32 and liquid membrane10.

17

Limitation of these methods is their large-scale production. Therefore, it is vital to

18

explore a high-efficiency method for large-scale production of single KTZ

19

enantiomer.

20

In this paper, centrifugal contactor separator devices are used for the multistage

21

separation of KTZ enantiomers by ELLE. In order to obtain high yield and good

22

purity at the minimum number of stages, many process parameters such as the extract

4


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1

phase/washing phase ratio (W/O), the concentration of chiral selector, the pH value of

2

aqueous phase, and the number of stages were investigated. Based on the physical and

3

chemical equilibrium of single-stage system and the law of mass conservation, a

4

multistage countercurrent ELLE equilibrium model for separation of KTZ was set up.

5

The experimental data were modeled by the multistage equilibrium model, and the

6

modle was also applied to further predict and optimize the separation process of KTZ

7

enantiomers.

8

2. EXPERIMENTAL SECTION

9

2.1. Materials. Racemic KTZ was obtained from Spec-Chem Industry Inc.

10

(Nanjing,

China),

with

a

purity>98%.

11

hydroxypropyl-β-cyclodextrin

12

(SBE-β-CD) were all bought from Zhiyuan Biotechnology Co. Ltd (Binzhou, China).

13

Butyl acetate (purity ≥99.0 %), dichloromethane (purity ≥99.5 %), cyclohexane

14

(purity ≥99.5 %), disodium hydrogen phosphate and phosphoric acid were purchased

15

from Huihong Reagent Co. Ltd (Changsha, China). Methanol (HPLC grade) and

16

heptane (purity ≥98.5 %) were supplied by Tianli Chemical Reagent Co. Ltd (Tianjin,

17

China). And heptanol (purity ≥99 %) was bought from Aladdin Industrial Inc.

18

(Shanghai, China).

(HP-β-CD)

and

Hydrophilic

extractants,

sulfobutylether-β-cyclodextrin

19

2.2. Explore the Effect of Organic Solvent by Single-stage Extraction

20

Experiments. The single-stage extraction experiments were carried out in a 15 mL

21

centrifuge tube, settled in a thermostat bath with temperature set at 278 K. In the

22

extraction system, aqueous phase was prepared by dissolving 0.1 mol/L HP-β-CD in

5



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1

0.1 mol/L Na2HPO4/ H3PO4 buffer solution, and organic phase was prepared by

2

dissolving racemic KTZ (1 mmol/L) in organic solvent. Equal volumes (each 3 ml) of

3

the organic and aqueous phase were added into the centrifuge tube. The tube was

4

shaken sufficiently (6 h) before being kept in a water bath at 278 K to reach

5

equilibrium. After separation of the two phases, the aqueous phase was taken and the

6

concentrations of KTZ enantiomers in aqueous phase were ananlyzed by HPLC.

7

Because the total volume of two-phase change in is very small, it can be considered to

8

be negligible. The total amount of each enantiomer in the aqueous phase and organic

9

phase after extracting was consistent with their initial amount. The concentrations of

10

(-)-KTZ and (+)-KTZ in organic phase were calculated from a mass balance.

11

2.3. Multistage Extraction Experiments. As shown in Figure 4, the devices of

12

centrifugal contactor separators were set up in a counter-current cascade. The CCSs

13

were settled in a thermostat bath maintaining a stable temperature of 278 K and the

14

rotational speed was set at 2500 revolutions per minute. The aqueous phase (extract

15

phase) was prepared by dissolving HP-β-CD in 0.1 mol/L Na2HPO4/ H3PO4 buffer

16

solution, and the organic phase (raffinate phase) was pure organic solvent, and

17

racemic KTZ was dissolved in organic phase to obtain the feeding phase. Before the

18

start of extraction experiments, the CCSs had been filled with the heavy phase (in this

19

case it was the aqueous phase). After the aqueous phase outflow from heavy phase

20

outlet, the pump of the light phase (organic phase) was started. Only when the organic

21

phase outflow from light phase outlet, could the feed pump be turned on. After 3

22

hours, samples were collected from the outlet of aqueous phase every 20 minutes until

6


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1

the concentration of (-)-KTZ and (+)-KTZ in aqueous phase outlet was no longer

2

change. The concentration of KTZ enantiomers in aqueous phase outlet was analyzed

3

by HPLC while that in organic phase outlet was calculated from mass balance.

4

2.4. Analytical Method. The quantification of KTZ enantiomers in aqueous outlet

5

was determined by HPLC (Waters e2695 Separation Module), and a UV detector

6

(Waters 2998 Photodiode Array Detector) with UV wavelength set at 225 nm was

7

used. The column was Diamonsil C18 (250 mm × 4.6 mm id., 5 µm) (Dikma

8

Technologies). The mobile phase was methanol: 0.02 mol/L NaH2PO4 aqueous

9

solution (pH = 3.0, adjusted with phosphoric acid) (60:40, V/V) containing 1.0

10

mmol/L SBE-β-CD and 0.02% triethylamine.33 The flow rate was set at 0.7 mL/min

11

and the column temperature was set at 30 oC. The pH of the aqueous phase was

12

measured with a pH meter and a pH electrode (Orion, model 720A). The retention

13

time of the (-)-KTZ was less than that of the (+)-KTZ.

14

3. THEORY AND MODELING

15

3.1 Mechanism of Reactive Extraction. Knowledge of the reactive liquid-liquid

16

extraction mechanism is essential and required for the optimization of an extraction

17

process. In the systems of reactive liquid-liquid extraction, the reactions may take

18

place in the aqueous phase, the organic phase or at the interface. In this work, the

19

extractant HP-β-CD is completely dissolved in the aqueous phase and insoluble in the

20

organic phase. Therefore, the possibility that the reaction takes place in organic phase

21

has been excluded. Depending on the solubility of the solutes of KTZ enantiomers in

22

the aqueous phase and organic phase, the complexation reations will take place either

23

in the aqueous phase or at the interface. It was found that KTZ enantiomers distribute

24

over the organic and aqueous phase. Therefore, the homogeneous aqueous phase 7



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Page 8 of 42

reaction mechanism was applied here and depicted it in Figure 3.

2

The distribution ratios (D) and separation factor (α) are two important parameters to

3

estimate the performance of liquid-liquid extraction system, which can be calculated

4

by the following formulas: all form

5

[A ] [A ]

D- =

6

D+ =

7

α =

-

aq all form

-

org

(1)

all form + aq all form + org

[A ] [A ]

(2)

D+ , assuming D+ >DD-

(3)

8

As depicted in Figure 3, the relations of phase equilibrium and mass balance

9

equations for each stage (j = 1, 2, 3...N) may be modeled. The dissociation constant of

10

11

(+)- and (-)-KTZ in the aqueous phase can be calculated by:

Ka =

[A + ]a q,j [H + ]a q,j [A + H + ]aq,j

=

[A - ]aq,j [H + ]aq,j [A - H + ]aq,j

(4)

12

where [A+H+]aq and [A-H+]aq are the concentrations of the ionic (+)- and (-)-KTZ in the

13

aqueous phase at equilibrium, respectively; [A+]aq and [A-]aq are the concentrations of

14

the free (+)- and (-)-KTZ in the aqueous phase at equilibrium, respectively.

15 16

17

The physical partition coefficient of molecular (+)- and (-)-KTZ can be described as the following: P0 =

[A + ]aq,j [A - ]aq,j = [A + ]org,j [A - ]org,j

(5)

18

among which [A+]org and [A-]org represent the concentrations of the free (+)- and

19

(-)-KTZ in the organic phase at equilibrium, respectively.

20

The physical partition coefficient of ionic (+)- and (-)-KTZ, Pi, can be written as:

8


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1

[A + H + ]aq,j [A - H + ]aq,j Pi = = [A + H + ]org,j [A - H + ]org,j

(6)

2

among which [A+H+]org and [A- H+]org are the concentrations of the ionic (+)-and

3

(-)-KTZ respectively, in organic phase at equilibrium; [A+H+]aq and [A- H+]aq are the

4

concentrations of the ionic (+)-and (-)-KTZ respectively, in aqueous phase at

5

equilibrium.

6 7

8

The complexation equilibrium constants of (+)- or (-)-KTZ with HP-β-CD in aqueous phase can be calculated by: Ki =

[A i C]aq

(7)

[A i ]aq [C]aq

9

among which [C]aq represents the concentration of free HP-β-CD in the aqueous phase

10

at equilibrium; [AiC]aq represents the concentrations of complex A+C or A-C in the

11

aqueous phase at equilibrium, respectively.

12

3.2 The Model of Multistage Counter-current ELLE Equilibrium. A flow

13

diagram of the cascade of centrifugal contact separators for the separation of racemic

14

KTZ into (-)-KTZ and (+)-KTZ is depicted in Figure 4. The racemic KTZ is pumped

15

into the CCSs at the feed stage, indicated with f. The Organic phase is pumped into

16

the CCSs at the first stage. The aqueous phase (containing HP-β-CD and 0.1 mol/L

17

Na2HPO4/H3PO4 buffer solution) is pumped into the CCSs at the last stage, indicated

18

with N. With the complexation constant K+ > K-, the stages f to N form the stripping

19

section, in which A+ (A+ represent (+)-KTZ) is preferentially extracted to the aqueous

20

phase (extract phase). The stages 1 to f-1 form the wash section, in which the

21

co-extracted A- (A- represent (-)-KTZ) is washed out of the extract stream and entered

9



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1

into the organic phase (raffinate phase). Therefore, after multistage centrifugal contact

2

separators for the separation of racemic KTZ, the A+ enantiomer is mainly left in the

3

aqueous phase and the A- enantiomer is primarily remained in the organic phase.

4 5

6

7 8 9

10

11 12

13

The following equations represent component balances for Ai in the feed stage, respectively. F[A i ]0 + W([A i ]aq,f+1 + [A i H + ]aq,f+1 + [A i C]aq,f+1 ) + O([A i ]org,f-1 + [A i H + ]org,f-1 ) = W([A i ]aq,f + [A i H + ]aq,f + [A i C]aq,f ) + (O+F)([A i ]org,f + [A i H + ]org,f )

(8)

Where [Ai]o is the initial concentrations of (+)-KTZ or (-)-KTZ in organic feed. The component balances of A+ or A- for wash section (j = 1, 2, 3…f-1), can be written as follows: O([A i ]org,j-1 + [A i H + ]org,j-1 ) + W([A i ]aq,j+1 + [A i H + ]aq,j+1 + [A i C]aq,j+1 ) = O([A i ]org,j + [A i H + ]org,j ) + W([A i ]aq,j + [A i H + ]aq,j + [A i C]aq,j )

(9)

The component balances of Ai for stripping section (j = f+1, f+2, f+3…N), can be written as follows: (O+F)([A i ]org,j-1 + [A i H + ]org,j-1 ) + W([A i ]aq,j+1 + [A i H + ]aq,j+1 + [A i C]aq,j+1 ) = (O+F)([A i ]org,j + [A i H + ]org,j ) + W([A i ]aq,j + [A i H + ]aq,j + [A i C]aq,j )

(10)

14

The component mass balance of HP-β-CD in aqueous phase is given by Eq. 11.

15

[C]o = [C]aq,j + [A + C]aq,j + [A - C]aq,j = [C]aq,j+1 + [A + C]aq,j+1 + [A - C]aq,j+1

(11)

16

among which [C]o is the initial concentration of HP-β-CD in aqueous phase. (j = 1, 2,

17

3…N-1)

18

The enantiomeric excess (ee) is used as a measure of the optical purity of the

19

raffinate and the extract. The ee of KTZ in the extract and raffinate can be calculated

20

by:

21

eeextract

allforms + aq allforms + aq

[A ] = [A ]

allforms

- [A - ]aq

allforms

+ [A - ]aq

(12)

10


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allforms

1

eeraffinate

[A ] = [A ] -

-

org allforms org

allforms

- [ A + ]org

allforms

+ [ A + ]org

(13)

2

The yield of (+)-KTZ and (-)-KTZ are, respectively, defined as:

3

Yextract =

4

Yraffinate =

5

The model of multistage counter-current ELLE equilibrium was programmed on

6

Matlab. The influence of some factors, including the extract phase/washing phase

7

ratio (W/O), the concentration of chiral selector, the pH value of the aqueous phase,

8

and the number of stages, was modeled.

9

4. RESULT AND DISCUSSION

totalA + extract [mol] totalA + feed

[mol]

totalA - raffinate [ mol] totalA - feed

[mol]

(14)

(15)

10

4.1. Influence of Organic Solvent. The organic solvents have a great influence on

11

the solubility of all solutes and the distribution ratios. The influence of organic

12

solvents on distribution behavior of KTZ enantiomers was investigated in various

13

two-phase systems containing 0.1 mol/L HP-β-CD in aqueous phase and 1 mmol/L

14

KTZ in different organic solvents (Table 1). When 1-heptane is used as solvents, high

15

distribution ratios are obtained but low enantioselectivity is found. When

16

dichloromethane, cyclohexane and 1-Heptanol are used as solvents, very small

17

distribution ratios are obtained with low enantioselectivity. Compared with all the

18

above solvents, suitable distribution ratios and higher enantioselectivity are obtained

19

with butyl acetate as organic solvent. Therefore, butyl acetate is selected as solvent for

20

extraction of KTZ enantiomers.

21

4.2. Exploration of Equilibrium Time. Experimental study on the multistage

11



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Page 12 of 42

1

enantioselective ELLE of KTZ enantiomers by centrifugal contactor separators was

2

performed. The racemic feed was pumped to the cascade at the middle stage (as

3

shown in figure 4). Samples were collected from the extract outlet every 20 minutes

4

and analyzed by HPLC. The CCS cascade was run successfully for 350 min at 278K.

5

As it is depicted in Figure 5, the concentration of KTZ enantiomers increases

6

gradually with time before the 200th minute, and then fluctuates within a narrow

7

range. The experimental results indicate that the time needed for the extraction

8

concentration reaching a steady state is about 200 min. Therefore, it can be suggested

9

that the time needed for physical and chemical equilibrium is relatively short.

10

4.2. Influence of W/O Ratio. In multistage reactive extraction, W/O ratio has a

11

great influence on purity and yield. In order to explore the influence of the W/O ratio

12

on extraction performance, a series of extraction experiments were performed with

13

W/O ratio in the range from 1.0 to 7.0 at W/F = 6, pH = 8.5, [HP-β-CD] = 0.1 mol/L,

14

[A+,-] = 1 mmol/L, T = 278 K, and N = 10 (N represents number of stages). It is clear

15

from Figure 6 that the experimental data of ee and yield are in a good agreement with

16

the model predictions. As it is shown in Figure 6a, with the increase of W/O ratio, the

17

ee decreases in the extract phase (aqueous phase) while increases in the raffinate

18

phase (organic phase). It can also be seen from Figure 6b that the yield in extract

19

phase increases with the increase of W/O ratio, but the yield in raffinate phase

20

decreases. The possible reasons for these may be that with the increase of W/O ratio,

21

co-extraction of the non-preferential enantiomer is enhanced, so the ee in the extract is

22

decreased. While in the reffinate, although the co-extraction of the non-preferential

12


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1

enantiomer is enhanced, the extracted (+)-enantiomer is always more than

2

(-)-enantiimer, so the ee in the raffinate is increased. Furthermore, at a larger W/O

3

ratio, the stripping section has stronger power for extraction of the enantiomers, and

4

more complexes (A+C and A-C) are formed in stripping section, so yield in extract

5

phase increases with the increase of W/O ratio. While in the wash section, less

6

enantiomers are washed back from aqueous phase with the increase of W/O ratio, so

7

yield in raffinate phase decreases. When the W/O ratio is 4.5, there is a crosspoint

8

where ee in the extract phase is equal to those in the raffinate phase, so the yield of

9

both phases does. The crosspoint is the operating point for symmetric separation of

10

KTZ enantiomers and eeeq (equal ee) and Yeq (equal Y) are obtained. As is shown in

11

Table 1, when butyl acetate was used as organic solvent, D- = 0.2127 and D+ = 0.2807

12

is measured. According to literature13, a symmetric separation is achieved if

13

W 1 . In this case, the result W/O = 4.5 is basically consistent with the = O D- D+

14

experimental value:

15

are varied with the change of several process parameters. Thus, the optimal phase

16

ratio is not a constant value, which can be achieved by further optimization.

W 1 = 4.1. However, it should be noted that D- and D+ = O D- D+

17

4.3. Influence of Extractant Concentration. It is crucial to operate at suitable

18

extractant concentration in an industrial production process. Here, the ee and yield of

19

multistage ELLE of KTZ enantiomers were determined with the concentration of

20

HP-β-CD ranging from 0 to 0.14 mol/L. It is clear from Figure 7 that there is a good

21

agreement between model predictions and the experimental results. As shown in

13



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Page 14 of 42

1

Figure 7a, the ee in the extract phase increases obviously when the concentration of

2

HP-β-CD increased from 0 to 0.04 mol/L, and then decreases with a further increase

3

of HP-β-CD concentration. However, the ee in the raffinate keep a rising trend with

4

the increase of HP-β-CD concentration. This peculiar phenomenon can be explained

5

as follows: the solubility of KTZ in aqueous phase is very poor at low HP-β-CD

6

concentration. When the concentration of HP-β-CD is very small, only a few

7

complexes are formed between HP-β-CD and KTZ enantiomers in extract phase. As a

8

result, almost all KTZ enantiomers are in raffinate phase (Figure 7b), and the ee value

9

in the raffinate is very small. With the increase of HP-β-CD concentration, more and

10

more KTZ enantiomers are extracted to aqueous phase (Figure 7b) and

11

enantioselectivity increases rapidly. With a further increase of HP-β-CD concentration,

12

the extractant goes excess, then considerable amount of undesired enantiomer are also

13

extracted to aqueous phase. As a result, the ee in extract phase decreases with a

14

further increase of HP-β-CD concentration.

15

4.4. Influence of pH Value. The pH value is a significant factor for consideration

16

in the separation of enantiomers as it impacts the states of KTZ enantiomers. The

17

influence of pH value on the ee and yield in both streams was studied by varying the

18

pH value from 6.5 to 10.5. Comparison between the experimental data and the

19

simulation of the ee and yield in both streams is shown in Figure 8.

20

It is observed from Figure 8a that the ee in the raffinate phase decreases obviously

21

when the pH value raising from 6.5 to 8.5, and then keeps constant. The ee in the

22

extract phase increases with the rise of pH value (pH < 8.5), and then keeps constant

14


Page 15 of 42

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1

with pH value increasing from 8.5 to 10.5. It is observed from Figure 8b that the yield

2

in the raffinate phase increases with pH value increasing from 6.5 to 8.5, while an

3

opposite tendency is observed for the yield in the extract phase. And the yields in both

4

exit streams reach a plateau at pH greater than 8.5. It can be concluded from Figure 8

5

that the model predictions are in good agreement with the experimental results.

6

The possible reasons for these may be that most of KTZ enantiomers molecules are

7

protonated and dissolved in aqueous phase at low pH value. HP-β-CD mainly has

8

chiral recognition ability and affinity for molecular KTZ, but not for protonated KTZ.

9

With the increase of pH value from 6.5 to 8.5, more protonated KTZ turned into

10

molecular KTZ and enter the raffinate phase, and amount of complexes formed by

11

HP-β-CD and KTZ enantiomers increases. As a result, the yield in the extract phase

12

and the ee in the raffinate phase decrease, while the yield in the raffinate phase and

13

the ee in the extract phase increase. When the pH value was varied from 8.5 to 10.5,

14

KTZ enantiomers mainly exist in the form of neutral molecule, which leads to the ee

15

and the yield keep nearly constant.

16

4.5. Influence of Number of Stages. The number of stages has a significant effect

17

on eeeq and Yeq in the CCS cascade. High enantiomeric purity and yield are desired

18

for the production of chiral drug. As shown in Figure 9, the influence of number of

19

stages on ee and Y is modeled at 10 and 20 stages CCS. The separation experiments of

20

KTZ enantiomers were performed by changing the W/O ratio (W/O = 3, 4.5, 6) at 10

21

and 20 stages CCS, respectively. It is clear from Figure 9 that eeeq and Yeq are obvious

22

increased after the number of stages changed from 10 stages to 20 stages.

15



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Page 16 of 42

1

Experimental results show that the eeeq can reach 38% and the Yeq can reach 68% at N

2

= 20. The results of experiment are basically in conformity with the model predictions.

3

In this paper, the (-)-KTZ is the desired product and is mainly concentrated in

4

raffinate phase. Hence, the (-)-KTZ of higher purity can be obtained by increasing the

5

W/O ratio without the need of increasing the number of stages.

6

5. MODEL PREDICTIONS AND OPTIMIZATION IN THE MULTISTAGE

7

EXTRACTION SYSTEM

8

The results of the above studies show that the cascade of CCS provides a very useful

9

device for multistage enantioselective ELLE. Comparison of the model predictions

10

with experimental results indicates that the established multistage equilibrium model

11

is a good way of predicting the extract performance for separation of KTZ

12

enantiomers over a range of experimental conditions. Thus, we used the model to

13

investigate the influence of various operating conditions on extraction efficiency and

14

optimize the separation process.

15

5.1 Location of Feed Stage. The location of the feed stage is a vital parameter in

16

multistage ELLE. The change of location of the feed stage will lead to the change of

17

the number of stages in the wash section and stripping section, which will obtain a

18

different extraction performance of the symmetric separation. Figure 10 shows the

19

eeeq and Yeq in aqueous phase and organic phase with location of the feed at different

20

stages. It can be seen clearly that the eeeq and the Yeq both reach the maximum when

21

the feed stage is located exactly at the middle stage. Thus, higher eeeq and Yeq can be

22

obtained by using the same number of stages in wash section and stripping section.

16


Page 17 of 42

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1

5.2 Flow Ratio. The ee in the extract phase and raffinate phase are simulated as a

2

function of W/O ratio and W/F ratio (Figure 11). It can be observed from Figure 11

3

that the flow ratios of W/F and W/O have a clear effect on ee. With the increase of

4

W/F and W/O, the purity in the extract decreases, while the ee in the raffinate follow

5

an opposite tendency. In order to obtain the relationship between flow ratios and eeeq

6

at different extractant concentration, the space curve (Figure 12) has been modeled. It

7

can be seen that the extractant concentration has great influence on eeeq. As shown in

8

Figure 12, the purity of KTZ enantiomers can be obvious improved by increasing the

9

concentration of HP-β-CD. The eeeq rises rapidly with the extractant concentration

10

increasing from 0.05 mol/L to 0.1 mol/L. Then the eeeq increases slowly. Therefore,

11

taking economic benefit into account, the extraction concentration of 0.1 mol/L is

12

more appropriate. It can be also seen that the eeeq of different extractant concentration

13

follows a similar tendency with the change of flow ratios. The eeeq increases with the

14

rise of W/F, but decreases with the rise of W/O. Thus, a larger wash flow and a

15

smaller feed flow are required to obtain higher eeeq.

16

5.3 Number of Stages and W/F Ratio. Figure 13 shows eeeq as a function of the

17

number of stages from 10 stages to 100 stages at different W/F ratio. It can be

18

observed from Figure 13 that the eeeq at different W/F ratio follows a similar tendency

19

with the increase of number of stages. The eeeq rises rapidly when the number of

20

stages is less than 50, and then the change is slight with a further increase of the

21

number of stages. From Figure 13, it can also be observed that the eeeq increases

22

greatly when W/F ratio is less than 20, and then the eeeq increases slowly with a

17



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

1

Page 18 of 42

further increase of W/F ratio.

2

For a symmetrical separation, the minimum number of stages needed for

3

eeeq >97% and eeeq >99% was calculated by modeling and optimization at W/F ratio

4

of 40, W/O ratio of 3.3, [HP-β-CD] = 0.1 mol/L, pH = 8.5. As shown in Table 2, the

5

optimized settings for the two cases are listed. When the eeeq is higher than 97%, a

6

cascade of 72 stages is required, whereas for eeeq >99% a minimum of 94 stages is

7

needed.

8

α-cyclohexyl-mandelic acid enantiomers was reported in our previous work.21 The

9

enantioselectivity of the chiral selector, HP-β-CD, towards α-cyclohexyl-mandelic

10

acid enantiomers is 1.95.34 By modeling, the minimum number of stages for eeeq >

11

97% and eeeq > 99% was predicted as 42 and 48, respectively. However, in this paper,

12

the enantioselectivity of the chiral selector towards KTZ enantiomers is moderate

13

(about 1.32), so larger number of stages is required. According to the model

14

prediction, about 72 and 94 stages are required for symmetric separation of KTZ

15

enantiomers with e.e. higher than 97% and 99%. Because the chiral selector can be

16

reused and the centrifugal contactor separator can give high mass transfer coefficient,

17

these may make the process economically viable. In order to reduce the number of

18

stages, the chiral selector should be improved to obtain a higher enantioselectivity.

19

Furthermore, in industrial application, the number of stages can be considerably

20

reduced by asymmetric separation, in which the flow ratios are adjusted to obtain the

21

desired enantiomer with high purity in one phase while the undesired enantiomer is

22

partly enriched in the other phase.

Experiments

and

model

study

on

continuous

extraction

of

18


Page 19 of 42

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1

6. CONCLUSION

2

Multistage enantioselective liquid−liquid extraction was performed for separation of

3

KTZ enantiomers with HP-β-CD as chiral extractant. Experimental results show that

4

the performance of extraction is strongly influenced by the process parameters such as

5

phase ratios (W/O ratio), extractant concentration, the pH value of aqueous phase and

6

the number of stages. Based on the single-stage model of separation of KTZ

7

enantiomers and the law of mass conservation, a multistage ELLE equilibrium model

8

was established. The model was verified experimentally and provides a good means

9

to predict the performance for separation of KTZ enantiomers in multistage

10

centrifugal contactor separators over a range of experimental conditions.

11

The performance of the multistage ELLE process was evaluated using ee and yiled

12

to obtain the optimum conditions. The best conditions are obtained by modeling and

13

optimization at W/O ratio of 4.5, pH of 8.5 and HP-β-CD concentration of 0.1 mol/L

14

at 278k. The optimal operational eeeq of 38% and Yeq of 68% is close to the predicted

15

of 40% and 70%. By modeling, the minimum number of stages for full separation is

16

calculated as 72 and 94 for eeeq > 97% and eeeq > 99% at both stream exits.

17

■ AUTHOR INFORMATION

18

Corresponding Author

19

*Tel.: +86-13762003936; fax: +86-730-8640921.

20

E-mail address: [email protected] (K. W. Tang)

21

Notes

22

The authors declare no competing financial interest.

23

■

24

This work was supported by the National Basic Research Program of China (No.

ACKNOWLEDGMENTS

19



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Page 20 of 42

1

2014CB260407), Hunan Provincial Natural Science Foundation of China (No.

2

2015JJ6045) and Science and Technology Planning Project of Hunan Province

3

(2014GK3108)

4

■

5

KTZ = ketoconazole

6

HP-β-CD = hydroxypropyl-β-cyclodextrin

7

P0 = The physical distribution coefficient of molecular (+)- and (-)-KTZ

8

Pi = The physical partition coefficient of ionic (+)- and (-)-KTZ

9

A+,-= (±)-KTZ

NOTATION

10

A+C = complex of (+)-KTZ with HP-β-CD

11

A-C = complex of (-)-KTZ with HP-β-CD

12

N = number of stages

13

f = location of feed stage

14

ELLE = enantioselective liquid – liquid extraction

15

ee = enantiomeric excess

16

Y = yield

17

[ ] = concentration, mol/L

18

W = flow of aqueous phase (ml/min)

19

O = flow of organic phase (ml/min)

20

F = flow of feeding phase (ml/min)

21

T = temperature (K)

22

Ka = dissociation constant

20


Page 21 of 42

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1

D = distribution ratio

2

α= enantioselectivity

3

K = complexation equilibrium constants

4

Subscripts

5

i = index for -, +

6

j = stage index

7

0 = initial value

8

+ = (+)-KTZ

9

－

= (-)-KTZ

10

aq = aqueous phase

11

org = organic phase

12

extract = the result in extract

13

raffinate = the result in raffinate

14

eq = equal value

15

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11 12

Figure captions

13

Figure 1. Molecular structure of HP-β-CD.

14

Figure 2. Molecular structure of the enantiomers of ketoconazle.

15

Figure 3. Diagram of the mechanism of reactive extraction of KTZ enantiomers by

16

HP-β-CD. Ai = (+)-KTZ or (-)-KTZ, C = HP-β-CD.

17

Figure 4. Flow diagram of the multistage centrifugal counter-current extraction of

18

KTZ enantiomers.

19

Figure 5. Concentration of KTZ enantiomers in extract outlet.

20

Figure 6. Influence of W/O ratio on ee and yield for separation of KTZ enantiomers.

21

Conditions: W/F = 6, pH = 8.5, [HP-β-CD] = 0.1 mol/L, [A+,-] = 1 mmol/L, T = 278 K,

22

N = 10, feed in the middle stage. (a) Influence on ee and (b) Influence on yield.

23

Figure 7. Influence of HP-β-CD concentration on ee and yield for separation of KTZ

26


Page 27 of 42

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1

enantiomers. Conditions: W/O = 4.5, W/F = 6, pH = 8.5, [A+,-] = 1 mmol/L, T = 278

2

K, N = 10, feed in the middle stage. (a) Influence on ee and (b) Influence on yield.

3

Figure 8. Influence of pH value on ee and yield for separation of KTZ enantiomers.

4

Conditions: W/O = 4.5, W/F = 6, [HP-β-CD] = 0.1 mol/L, [A+,-] = 1 mmol/L, T = 278

5

K, N = 10, feed in the middle stage. (a) Influence on ee and (b) Influence on yield.

6

Figure 9. Influence of number of stages on ee and yield for separation of KTZ

7

enantiomers. Conditions: W/F = 6, pH = 8.5，[HP-β-CD] = 0.1 mol/L, [A+,-] = 1

8

mmol/L, T = 278 K, feed in the middle stage. (a) Influence on ee and (b) Influence on

9

yield.

10

Figure 10. Influence of the location of feed stage on eeeq and Yeq for separation of

11

KTZ enantiomers. Conditions: W/O = 4.5, W/F = 6, pH = 8.5, [HP-β-CD] = 0.1 mol/L,

12

[A+,-] = 1 mmol/L, T = 278 K, N = 10.

13

Figure 11. Influence of W/O ratio and W/F ratio on ee for separation of KTZ

14

enantiomers. Conditions: pH = 8.5, [HP-β-CD] = 0.1 mol/L, [A+,-] = 1 mmol/L, T =

15

278 K, N=10, feed in the middle stage. (a) Influence on eeextract and (b) Influence on

16

eeraffinate.

17

Figure 12. Influence of W/O ratio and W/F ratio on eeeq for separation of KTZ

18

enantiomers at different extractant concentration. Conditions: pH = 8.5, [A+,-] = 1

19

mmol/L, T = 278 K, N=10, feed in the middle stage.

20

Figure 13. Influence of number of stage on eeeq for separation of KTZ enantiomers at

21

different W/F ratio. Conditions: pH = 8.5, [A+,-] = 1 mmol/L, T = 278 K, feed in the

22

middle stage.

27



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1

Tables

2

Table 1. Influence of Organic Solvent Type Oranic solvent

D-

D+

Page 28 of 42

α

dichloromethane

0.0148

0.0178

1.20

butyl acetate

0.2127

0.2807

1.32

cyclohexane

0.0760

0.0779

1.03

1-heptane

6.5429

6.6497

1.02

1-heptanol

0.0709

0.0781

1.10

3

Aqueous phase: [HP-β-CD] = 0.1 mol/L, pH = 8.5. Organic phase: [A+,-] = 1.0 mmol/L；T = 278

4

K.

5 6 7 8 9 10 11 12 13 14 15 16 17 18

28


Page 29 of 42

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1

Table 2. Optimized Settings for Symmetrical Separations with [A+,-] = 1 mmol/L, pH = 8.5, T

2

= 278 K Variable

eeextract and eeraffinate > 97% setings

eeextract and eeraffinate > 99% setings

N

72

94

f

37

48

[HP-β-CD](mol/l)

0.1

0.1

W/F

40

40

W/O

3.3

3.3

3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 29



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

1

Page 30 of 42

Figure 1.

2

3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

30


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1

Figure 2.

2

3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

31



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

1

Page 32 of 42

Figure 3.

2

3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 32


Page 33 of 42

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1

Figure 4.

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

33



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

1

Page 34 of 42

Figure 5.

2

3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 34


Page 35 of 42

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1

Figure 6.

2 3

(a)

4 5

(b)

6 7 8 9 10 11 12

35



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

1

2 3 4

5 6

Page 36 of 42

Figure 7.

(a)

(b)

7 8 9 10 11 12 13 36


Page 37 of 42

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1

2 3

4 5 6 7

Figure 8.

(a)

(b)

8 9 10 11 12 13 14 37



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

1

Page 38 of 42

Figure 9.

2

3 4 5

(a)

6 7

(b)

8 9 10 11 12 13

38


Page 39 of 42

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1

Figure 10.

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 39



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

1

Page 40 of 42

Figure 11.

2 3

(a)

4 5

(b)

6 7 8 9 10 11 12

40


Page 41 of 42

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1

Figure 12.

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

41



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

1

Page 42 of 42

Figure 13.

2 3 4

42


Experimental and Model Study on Multistage Enantioselective Liquid

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