Continuous Separation for Propranolol by Fractional Extraction

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Continuous Separation for Propranolol by Fractional Extraction: Symmetric Separation and Asymmetric Separation Pan-Liang Zhang, Weifeng Xu, and Ke-Wen Tang Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00296 • Publication Date (Web): 13 Nov 2018 Downloaded from http://pubs.acs.org on November 14, 2018

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Organic Process Research & Development

Continuous Separation for Propranolol by Fractional Extraction:

Symmetric

Separation

and

Asymmetric

Separation Panliang Zhang, Weifeng Xu, Kewen Tang* Department of Chemistry and Chemical Engineering, Hunan Institute of Science and Technology, Yueyang, China

1

ACS Paragon Plus Environment

Organic Process Research & Development 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

Table of Contents Graphic

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ABSTRACT Symmetric and asymmetric separations for propranolol (PN) enantiomers were performed by fractional extraction with boric acid (BA) and di-cyclohexyl (D)-tartrate (DT) as selector. A phase equilibrium model was constructed on basis of interfacial reaction mechanism and verified to be dependable by experiment. On account of phase equilibrium model and mass conservation, a multistage model was developed to optimize the process parameters. Optimal situations for symmetric separation were obtained, involving CPN of 0.0078 mol/L, CDT and CBA of 0.05 mol/L, F/W of 0.4, O/W of 0.9435, feeding in the centre stage and pH of 6.00. Under the optimal conditions, eeeq and Yeq are up to 0.98 and of 0.99 by symmetric separation of 25 centrifugal contactor separators, respectively. Because S-PN is the desired enantiomer, eeraffinate for S-PN can be up to 0.98 with 10 stages by asymmetric separation under the situations containing CPN of 0.0078 mol/L, CDT and CBA of 0.1 mol/L, F/W of 0.15 and O/W of 0.3534, feeding in the Stage 3 at pH of 6.00. The study shows that the required NTU is greatly decreased for high ee of S-PN by asymmetric separation. KEYWORDS:

symmetric

separation,

asymmetric

enantiomers, chiral extraction, optimization

3


separation,

propranolol


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INTRODUCTION It is necessary to obtain enantiomeric purity compounds in many fields, especially in pharmaceutical industry. To obtain the desired enantiomers, chiral separation has played an important role in separation of racemic mixture.1 Chiral separation

methods

include

as

follows:

enantioselective

crystallization,2,3

chromatography,4–6 membrane-based approaches7–9 and so on. The

above

mentioned techniques have made valuable contributions to the expansion of fields. Among them, crystallization has become the common method, which is applied to industrial unit for chiral drugs production. However, the low versatility of crystallization may limit its widespread use. Chromatography is another frequently used techniques, while the shortcomings impede its further use in industrilization: low sample volume and high cost. For membrane-based approaches, low transfer rate and risk of fouling hinder its scale-up.10 Compared to above technologies, enantioselective liquid-liquid extraction (ELLE) is deemed as a powerful method with potential in high transport rate, in which mass transfer is performed through convection and diffusion.10–14 What’s more, easy operation and scale up in chemical industry make ELLE become more interesting.10 In ELLE, to separate chiral drugs, a chiral environment provided by chiral extractant is the most important factor. According to literatures, some chiral selectors have been explored, such as cyclodextrin derivatives, cinchona alkaloids, crown ethers, tartaric acid derivatives and so on. For resolution of β-amino-alcohols, the enantioselectivities of tartaric acid derivatives reported are significantly enhanced with the presence of

4


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BA.15 For example, bucumolol, alprenolol, propranolol and pindolol were separated and enantioselectivities were increased from 1.60 to 2.90. Nowadays, fractional extraction has been proposed to obtain target produce with high purity. The centrifugal contactor separator (CCS) is introduced to fractional extraction, which is a good equipment for multistage ELLE.10–12,16,17 CCS can sufficiently mix and then rapidly separate two immiscible phases. Comparing to traditional equipment, such as extraction column or mixer-settler, CCS just requires small amount of liquid volume and significantly reduces the host inventory.17,18 Propranolol (PN, Figure 1) is usually used in treatment of various arrhythmias, such as atrial and ventricular premature beats, sinus and supraventricular tachycardia, atrial fibrillation and so on. However, S-PN is more powerful than R-PN in blocking the β-receptor, and it is about 100 times stronger than R-PN.19 Analytical methods for PN enantiomers are often reported, while there is no viable method for continuously producing optically pure PN enantiomers in large scale.20 ELLE shows potential in industrial production of single PN enantiomers. More recently, ELLE of PN enantiomers was studied with enantioselectivity of 2.36, in which di-cyclohexyl (D)-tartrate (DT) acted as chiral selector dissolving in cyclohexane and BA was added into aqueous phase.21

Figure 1. Chemical structure of PN. Here, the study of extraction mechanism is presented and mathematical models 5



were established. Influences of important factors affecting extraction process are modeled. To obtain high optical purity of PN enantiomers, multistage experiments were performed with a cascade of CCSs and the separation process was simulated and optimized by the model. Finally, highly pure PN can be achieved by asymmetric separation or symmetrical separation22

EXPERIMENTAL SECTION Chemicals Racemic PN enantiomers with a purity ≥ 99% were employed. DT was synthesized with tartaric acid of purity ≥ 99% as described in the literature.29 Solvents for chromatography are of HPLC grade. All other chemicals were analytical-regent grade. Analytical method PN enantiomers were quantified by HPLC on Inertsil ODS-3 column at 290 nm and 298 K. The mobile phase was a mixed solution, in which 70 mmol/L n-hexyl L-tartrate was dissolved in methanol and 60 mmol/L BA was added to 15 mmol/L ammonium acetate buffer solution. The volume ratio of methanol and buffer solution was 80 : 20. The flow was set at 0.8 mL/min. With the adjustment of triethylamine, the pH of aqueous phase was 6.50. 20 μL sample was injected. Experimental procedures Extraction experiments BA was dissolved in 0.1 mol/L phosphate buffer solution to obtain aqueous phase. PN enantiomers and DT were dissolved in cyclohexane. Two phases (each 3 ml) were added in a centrifuge tube and fully vibrated to reach equilibrium at 280 K.

6


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PN enantiomers in aqueous phase were quantified by HPLC. Based on material balance, the concentrations of PN enantiomers in the other phase were obtained. Under identical conditions, repeated experiments were performed. Determination of physical distribution coefficient With the absence of BA, water phase was composed of 0.1 mol/L phosphate buffer solution with a range of pH. Without DT, PN enantiomers were dissolved in cyclohexane to obtain organic phase. The experiments were performed at 280 K. The other steps were the same as the extraction experiment. Determination of equilibrium constants for binary complexess With the absence of BA, water phase was composed of 0.1 mol/L phosphate buffer solution. PN enantiomers and DT were dissolved in cyclohexane to achieve organic phase The experiments were carried out at 280 K. The other steps were the same as the extraction experiment. Fractional extraction experiments BA was dissolved in a buffer solution at pH=6.00 to prepare aqueous phase. DT was dissolved in cyclohexane to prepare organic phase. PN enantiomers and DT were dissolved in cyclohexane to prepare feed phase. Fractional extraction was performed in 10 CCSs (Model V02) at 280 K with rotor diameter of 5.1 cm and annulus height of 7 cm (Figure 3). The speed of CCSs was set at 3000 rev. After starting all generators, aqueous phase was pumped into Stage 1. Then organic phase was introduced into Stage 10 of CCS. At last, the feed phase was pumped into the CCS, taking samples every 25 minutes from the aqueous phase outlet.

7



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THEORY Organic phase hardly dissolves BA and water scarcely dissolves DT. Therefore, the reaction will happen in the interface of two phases, and interfacial reaction mechanism is employed.22,23 Figure 2 describes the mechanism. The extraction process is complicated, including physical distribution, ionization balance, ternary complex

and

supramolecular

interaction.

Through

ternary

complex

and

supramolecular interaction, PN enantiomers can be selectively recognized. Through mass balance relations and coupled equilibrium relations, the reactive extraction process can be simulated.22,23

Figure 2. Diagram of extraction mechanism for racemic PN. The distribution ratios (DR and DS) for R- and S-PN are described as follows: DR 

DS 

total C R, org, j

C

total R,aq, j

CS,total org, j C

total S, aq, j





[R  PN]org, j  [DR]org, j  [DBR]org, j [R  PN]aq, j  [R  PNH  ]aq, j

[S  PN]org, j  [DS]org, j  [DBS]org, j [S  PN]aq, j  [S  PNH  ]aq, j

(1)

(2)

where, [R-PN]org,j, [DR]org,j and [DBR]org,j are the concentrations of R-PN, DR and

8


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DBR in organic phase of Stage j, respectively; [R-PN]aq,j and [R-PNH+]aq,j are the concentrations of R-PN and R-PNH+ in aqueous phase of Stage j, respectively. Separation factor (α) is described as: α

DR (assume DR＞DS) DS

Figure 3. A flow scheme of separation of PN enantiomers in CCSs

(3)

.

Separation of PN enantiomers in CCSs by fractional extraction is shown in Figure 3. A model is constructed based on hypothesis that each stage reaches phase equilibrium. Equilibrium equations can also be deduced for each stage. Concentrations of R-PN and S-PN can be determined by MATLAB. Since R-PN is preferably recognized, organic phase is considered as extract phase and aqueous phase is considered as raffinate phase. Enantiomeric excess (ee) of R-PN and S-PN enantiomers are as follows: ee extract 

total total C R, org,1  CS, org,1 total total C R, org,1  CS, org,1

ee raffinate 

total CS,total aq,1  C R,aq,1 total CS,total aq,1  C R,aq,1

(4)

(5)

The yields of R-PN and S-PN are calculated by Eq. 6 and Eq. 7: Yextract 

total (O  F)  C R, org,1

F  C R,0 9


(6)


Yraffinate 

W  CS,total aq, N F  CS,0

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(7)

where, CR,0 and CS,0 are the initial concentration of R-PN and S-PN. Using the mathematical model, ee and yield are simulated as a function of process parameters, such as extractant concentration, volume flow ratio, feed stage and NTU.

RESULTS AND DISCUSSION Parameter regression Physical distribution coefficient (P0) Partition of PN enantiomers in the biphasic system without BA and DT was investigated at different pH to estimate P. Here, the distributition of ionic species in organic phase can be ignored due to very low solubilities of ionic species. The apparent physical distribution coefficient (Papp) can be described as: Papp 

[PN]org, j  [PNH  ]org, j

 x mol  Pmol  x pro  Ppro [PN]aq, j  [PNH  ]aq, j 1  x mol  Pmol  (1  )  P0 pH  pK a,P 1  10

(8)

where, Pmol and Ppro are the physical distribution coefficients of molecular PN and PNH+, respectively; xmol and xpro are the molar fractions of molecular PN and PNH+ in water phase at balance, respectively; pKa,M is the dissociation constant of PN. Papp can be achieved by experiments or by Eq. 8. P0 is estimated by non-linear regression analysis. The total squared residuals (Q) for Papp at different pH are obtained by Eq. 9: n

exp cal 2 Q   (Papp, i  Papp,i ) i

10


(9)

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exp cal where, Papp and Papp are the experimental and calculated Papp, respectively. Figure

4 indicates the comparison of calculation and experiment of Papp. P0 is estimated as 20.22, where Q arrives at minimum.

Figure 4. Influence of pH on Papp. Equilibrium constants for binary complexes Experiments for distribution equilibrium were carried out in the aqueous-organic biphasic system without BA at different pH to determine the equilibrium constants of KDR and KDS, Two binary complexes are achieved in cyclohexane through hydrogen bonds between PN enantiomers and DT.24 Assuming 1:1 complexes of DT and PN enantiomers, the equilibrium constants for R-PN and S-PN can be described: K DR 

K DS 

[DR]org, j [R  PN]org, j[DT]org, j [DS]org, j [S  PN]org, j[DT]org, j

11


(10)

(11)


(a)

(b) Figure 5. Linear fitting of KDR (a) and KDS (b). Both linear relationships of [DR]org,j and [DR]org,j with [R-PN]org,j[DT]org,j can be achieved from Figure 5, which shows that the hypothesis that PN enantiomers and DT form 1:1 complexes is dependable. Then, KDR and KDS are the slopes of the two lines in Figure 5a and b, and is 12.54 L/mol and 10.35 L/mol, respectively, which indicates the intrinsic α is 1.21 without BA. Equilibrium constant for ternary complexes It has been reported that the complexing constants of borate esters in water are very small25. Therefore, the concentrations of BR+ and BS+ are very small in water at

12


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equilibrium. These concentrations are difficultly measured, so it is impossible to directly determine KR and KS. In order to simplify the calculation, the product of KB and KR (KB and KS) is employed, which are the complexing constants of the ternary complexes from DT, BA and PN enantiomers. Eq. 12 and Eq. 13 show the combined complexing constants, KBR and KBS for R-PNH+ and S-PNH+, respectively. K BR  K B  K R 

K BS  K B  K S 

[DBR]org, j[H  ]aq, j [R  PNH  ]aq, j[BA]aq, j[DT]org, j

(12)

[DBS]org, j[H  ]aq, j

(13)

[S  PNH  ]aq, j[BA]aq, j[DT]org, j

From Eq.1, Eq.2, Eq.12 and Eq.13, it is concluded that DR and DS are the function of KBR and KBS, respectively. Eq.14 and Eq.15 reflect the total of squared residuals between experiment and calculation for DR and DS at different extraction conditions, respectively. n

cal 2 U R   (D exp R,i  D R,i )

(14)

i

n

U S   (DS,expi  DS,cali ) 2

(15)

i

KBR and KBS can be achieved when the UR and US reach minimum. KBR and KBS are determined as 5.08×10-4 L/mol and 2.04×10-4 L/mol, respectively (Table 1). Table 2 shows the parameters for process simulations. Table 1. The ternary complexing constants Equilibrium

Sum of squared

Coefficient of determination

residuals

(R2)

0.3121

0.9898

Value constants KBR

5.08×10-4

13



KBS

2.04×10-4

0.1469

Page 14 of 35

0.9692

Table 2. Parameters in the simulations. Parameter

Value

Unit

P0

20.22

dimensionless

KDR

12.54

L/mol

KDS

10.35

L/mol

KBR

5.08×10-4

L/mol

KBS

2.04×10-4

L/mol

pKa,M

9.45 26

dimensionless

pKa,B

9.2427

dimensionless

Experiment and simulation for single-stage extraction Influence of pH pH plays an important role on the form of PN enantiomers in water phase. The form of PN at different pH is indicated in Figure 6. It can be observed that PN nearly exist in the form of protonation at low pH, while high pH mainly exists in the form of molecular states. During enantioselective extraction process, PNH+ enantiomers react with BA to form borate esters. Therefore, it is important to study the influence of pH on D and α.

14


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Figure 6. The state of PN at different pH.

(a)

(b) Figure 7. Effect of pH on D and α. Conditions: Organic phase: CDT = 0.1 mol/L, CPN = 0.005 mol/L; Aqueous phase: CBA = 0.1 mol/L; T = 280 K. Figure 7a describes that both partition coefficints are very small and almost kept 15



constant while pH increases from 3.00 to 5.00 and then rise with the incease of pH from 5.00 to 8.00. With a further rise in pH from 8.00 to 10.00, DR and DS are nearly unchanged. This is because low pH is not conducive to the formation of ternary complexes. And all the PN enantiomers are nearly in the protonated forms at low pH, resulting in less physical distribution and binary complexes. At pH﹥5.00, molecular PN enantiomers, ternary complexes (DBR and DBS) and binary complexes are enhanced, so DR and DS rise. At pH ﹥10.00, PN nearly exists in the molecular state, and then the distribution of PN reaches the limit in the two-phase system. It is also indicated that the separation factor is kept constant in the tested pH(Figure 7b), which is attributed to the formation of ternary complexes (DBR and DBS) and binary complexes (DR and DS). The predictions are identical to the experiment with the average relative deviations of 2.85% for D and 3.14% for α. Influence of DT concentration The effect of CDT on distribution ratios and α was screened in Figure 8. Figure 8a describes that DR and DS are enhanced with the increase of CDT, due to the formation of more DBR, DBS, DR and DS in 1,2-dichloroethane at a higher concentration of DT. Figure 8b also indicates that α is enhanced quickly with the addition of CDT from 0 to 0.005 mol/L and then kept constant. However, when DT reaches a high excess, α is up to its intrinsic maximum. Figure 8 shows that the model predictions are identical to the experiment with the average relative deviations of 1.85% for D and 3.44% for α.

16


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(a)

(b) Figure 8. Effect of CDT on D and α. Conditions: Organic phase: CPN = 0.005 mol/L; Aqueous phase: pH = 6.00, CBA = 0.1 mol/L; T = 280 K. Influence of BA concentration Figure 9 reflects the effect of CBA on D and α. Figure 9a describes that DR and DS rise with addition of CBA. It is due to that more DBR and DBS are formed in cyclohexane at a higher CBA. α is enhanced rapidly with the addition of CBA from 0 to 0.01 mol/L and then remains almost constant (Figure 9b). It is also concluded that the model fits well the experimen with the average relative deviations of 2.59% for D and 2.91% for α.

17



(a)

(b) Figure 9. Effect of CBA on D and α. Conditions: Organic phase: CDT = 0.1 mol/L, CPN = 0.005 mol/L; Aqueous phase: pH = 6.00; T = 280 K. Influence of PN concentration Figure 10 describes that both DR and DS reduce very slowly with the addition of CPN, while α is nearly kept constant. This may be because when CPN rises, the ratio of PN that form binary complexes and ternary complexes reduces and the identical influence for R-PN and S-PN, which results in the reduction of distribution ratios and a constant α.22 It is also indicated that the predictions are in accord with the experiment with the average relative deviations of 3.04% for D and 4.76% for α. 18


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(a)

(b) Figure 10. Effect of CPN on D and α. Conditions: Organic phase: CDT = 0.1 mol/L; Aqueous phase: pH = 6.00, CBA = 0.1 mol/L; T = 280 K. Fractional extraction Influence of volume flow ratio The flow ratios of aqueous phase to organic phase (W/O) and feed phase to organic phase (F/O) have a strong effect on ee and yield. Figure 11 indicates that, at a constant F/O, eeextract is increased with the rise of W/O from 0 to 20, while eeraffinate follows a contrary tendency. However, the Yextract is decreased with the rise of W/O

19



and Yraffinate shows a contrary tendency. It also can been seen from Figure 11 that the predictions are in accord with the experiment with the average relative deviations of 13.58% for ee and 11.03% for Y.

(a)

(b) Figure 11. Relationship between predicted ee (Y) and O/W. Conditions: F/O = 1, CDT = 0.1 mol/L, CPN = 0.0078 mol/L, CBA = 0.1 mol/L, pH = 6.00, T = 280 K, N = 10, f = 5. From Figure 11, excellent accordance of predictions and experiment shows that

20


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the hypothesis of extraction mechanism (chemical and physical equilibrium) in CCSs is reliable. Therefore, the explored model can be utilized to model the enantioselective extraction process. The effect of phase ratios on ee and yield was simulated in Figure 12. Figure 12 indicates that eeextract and eeraffinate can not be up to 0.98 at any flow ratios.

(a)

(b)

21



(c)

(d) Figure 12. Relationship among predicted ee (Y), O/W and F/W. Conditions: CDT = 0.1 mol/L, CPN = 0.01 mol/L, pH = 6.00, CBA = 0.1 mol/L, T = 280 K, f = 5 and N = 10. The ee may be further increased by optimization of the other conditions, such as CDT, CBA, feed stage and NTU. Symmetrical separation can be used to obtain R-enantiomer and S-enantiomer simultaneously, and asymmetric separation can be preferable to achieve the desired enantiomer of R,S-enantiomers.22

22


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Optimization of symmetrical separation process Figure 13 shows eeeq rises with addition of O/W and reduces with rise of F/W. And eeeq increases with addition of CBA and CDT. Here, F/W of 0.4 is chosen for the coming optimization for symmetrical separation. Figure 14 describes that eeeq rises slightly with addition of CBA, but eeeq reduces slightly with addition of CDT. Under these set conditions, eeeq can not be up to 0.98. It is necessary to further optimize the symmetrical separation to achieve higher eeeq. Here, CBA and CDT of 0.05 mol/L were selected for the further simulation.

Figure 13. Relationship among predicted eeeq, O/W and F/W at different CBA and CDT. Conditions: CPN = 0.0078 mol/L, pH = 6.00, T = 280 K, f = 5 and N = 10.

23



Figure 14. Relationship among predicted eeeq, CBA and CDT. Conditions: F/W = 0.4, O/W = 0.9194, CPN = 0.0078 mol/L, pH = 6.00, T = 280 K, f = 5 and N = 10. eeeq can be up to the maximum by feeding in the centre stage.28 NTU is crucial to ensure high eeeq,. As shown in Figure 15, eeeq rises with addition of NTU. And eeeq will be up to 0.98 when NTU is 25.

Figure 15. Relationship between predicted eeeq and extraction stages. Conditions: F/W = 0.4, CDT = 0.05 mol/L, CPN = 0.0078 mol/L, pH = 6.00, CBA = 0.05 mol/L, T = 280 K and feed in middle stage. Optimization of asymmetrical separation process

24


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S-PN shows blocking effects, while R-PN is not active. In a CCSs, the desired S-PN is in aqueous phase outlet. To lower production cost, especially for a small amount of the desired product of S-PN, S-PN with high purity in aqueous phase (eeraffinate) can be obtained by asymmetrical separation. Figure 16 shows that, when CBA and CDT rise from 0 to 0.1 mol/L, eeraffinate is enhanced quickly, but Yraffinate is nearly constant. With a further increase in CBA and CDT, eeraffinate is nearly kept constant, but Yraffinate is reduced fast. Therefore, it is appropriate to choose CBA and CDT of 0.1 mol/L for the coming modeling of asymmetrical separation. We also observe that, at any CBA and CDT, eeraffinate can not be up to 0.98 with 10 stages feeding in the centre position. Then changing the feed position can be a choice to improve eeraffinate. Figure 17 describes that eeraffinate is enhanced with the rise of O/W, and reduces when the feed position is altered from Stage 2 to Stage 9. However, Yraffinate shows a contrary tendency. And when the feed location is Stage 2, Stage 3, Stage 4 or Stage 5, eeraffinate can be up to 0.98 by altering O/W. It can be observed from Table 3 that Yraffinate is the biggest with O/W of 0.3534 feeding in Stage 3.

25



(a)

(b) Figure 16. Relationship among predicted eeraffinate (Yraffinate), CBA and CDT. Conditions: F/W = 0.15, O/W = 0.3, CPN = 0.0078 mol/L, pH = 6.00, T = 280 K, f = 5 and N = 10.

26


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(a)

(b) Figure 17. Relationship among predicted eeraffinate (Yraffinate), O/W and feed position. Conditions: F/W = 0.15, CPN = 0.0078 mol/L, pH = 6.00, T = 280 K and N = 10. Table 3. Optimized settings for asymmetrical separations with eeraffinate= 0.98 Feed position

Stage 2

Stage 3

Stage 4

Stage 5

O/W

0.3295

0.3534

0.3952

0.4907

Yraffinate

0.4152

0.4620

0.4338

0.2883

F/W=0.15, CPN = 0.0078 mol/L, CDT = 0.1 mol/L, pH = 6.00, CBA = 0.1 mol/L, T = 27



280 K, N = 10. Application Experiments for symmetrical separation and asymmetrical separation were carried out under above optimized conditions with 10 stages. Figure 18a indicates HPLC chromatogram of racemic PN, and the retention time for (R)-PN and (S)-PN are 14.05 min and 17.95 min, respectively. Figure 18b shows HPLC chromatogram of PN in aqueous phase outlet after symmetrical separation. The eeeq is calculated as 0.75 from Figure 18b, and the relative deviation is 7.41% compared with prediction (0.81). Figure 18c shows HPLC chromatogram of PN in aqueous phase outlet after asymmetrical separation. The ee of S-PN in aqueous phase is calculated as 0.91 from Figure 18c, and the relative deviation is 7.14% compared with prediction (0.98).

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Figure 18. The HPLC chromatogram of the PN enantiomers. (a) The racemate of (R,S)-PN. (b) The PN in aqueous phase outlet after the multistage extraction of symmetrical separation. Conditions: [PN] = 0.0078 mol/L, [DT] = 0.05 mol/L, [BA] = 29



0.05 mol/L, F/W = 0.4, O/W = 0.9435, pH = 6.00, T = 280 K, f = 5, N =10. (c) The PN in aqueous phase outlet after the multistage extraction of asymmetrical separation. Conditions: [PN] = 0.01 mol/L, [DT] = 0.1 mol/L, [BA] = 0.1 mol/L, F/W = 0.15, O/W = 0.3534, pH = 6.00, T = 280 K, f = 3, N =10.

CONCLUSION Selective extraction of PN enantiomers has been carried out in a aqueous-organic biphasic system. An equilibrium model was explored, and the extraction system was modeled and optimized. Good agreement of predictions with experiment indicates that the explored model can be employed to predict the experimental results for separation of racemic PN. Fractional extraction is utilized to achieve high optical purity of PN. Based on equilibrium model and mass balance, a fractional extraction model was constructed for separation of PN enantiomers. There are strong effects of phase ratios, CDT, CBA, feed position and NTU on separation efficiency. By modeling and optimization, the optimal conditions can be achieved. eeeq can be up to 0.98 by symmetrical separation with NTU of 25 under the conditions involving CPN of 0.0078 mol/L, CDT and CBA of 0.05 mol/L, O/W of 0.9435, and F/W of 0.4, feeding in the centre stage at pH 6.00 and 280 K. The ee of the desired S-PN can be up to 0.98 by asymmetrical separation with NTU of 10 at pH of 6.00 and 280 K under the conditions involving CPN of 0.01 mol/L, CDT and CBA of 0.1 mol/L, F/W of 0.15, O/W of 0.3534 feeding at Stage 3. Both symmetric and asymmetric separations are the powerful methods to obtain optically pure enantiomer, which provides two efficient options to obtain the desired

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enantiomer.

AUTHOR INFORMATION Corresponding Authors *E-mail:

[email protected].

Tel.: +86 730 8846925. Notes The authors declare no competing financial interest.

ACKNOWLEDGEMENTS This work was supported by the National Natural Science Foundation of China (No. 21501057) and Hunan Provincial Natural Science Foundation of China (No. 2012JJ2007).

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