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Equilibrium and Kinetics of Reactive Extraction of Ibuprofen Enantiomers from Organic Solution by Hydroxypropyl-β-cyclodextrin Kewen Tang,*,† Jian Cai,‡ and Panliang Zhang† † ‡
Department of Chemistry and Chemical Engineering, Hunan Institute of Science and Technology, Yueyang, 414006, China College of Chemical Engineering, Xiangtan University, Xiangtan, 411105, China ABSTRACT: This paper reports on the equilibrium and kinetics of the reactive extraction of hydrophobic ibuprofen (IBU) enantiomers from the organic phase to the aqueous phase by hydroxypropyl-β-cyclodextrin (HP-β-CD). The modeling and experimental data of extraction performance factors were investigated to obtain the optimal extraction conditions. The best conditions identified involve the use of an HP-β-CD concentration of 0.03 mol/L and pH value of 2.5 at 10 °C. The theory of extraction accompanied by chemical reactions was used to obtain the intrinsic kinetics of the extraction of IBU enantiomers by HPβ-CD. The effects of process parameters, including the agitation speed, interfacial area, initial concentration of IBU enantiomers, initial concentration of extractant, and pH value of aqueous phase, on the initial extraction rate were separately studied. The reactions are first order in IBU and second order in HP-β-CD with forward rate constants of 7.21 104 m6/(mol2 3 s) for S-IBU and 4.58 104 m6/(mol2 3 s) for R-IBU, respectively.
1. INTRODUCTION There is a growing demand for optically pure compounds in the chemical industries, because the left- and right-handed enantiomers of chiral, bioactive compounds often exhibit different physiological effects on pharmacological activity, the metabolism process, and toxicity when ingested by living organisms.1,2 Enantioselective chemical production can be achieved either by using enantioselective processes to generate only one enantiomer or by enantioselective methods to separate racemic mixtures. The most common technique for obtaining enantiopure compounds is the separation of enantiomers. Various separation methods including crystallization,3 chromatography,4 liquid membrane,5 etc., have been developed, but the methods are not always applicable for most racemic mixtures. Chiral solvent extraction is a potentially attractive technique which is cheaper and easier to scale up to commercial scale and has a large application range. Many researchers have attempted the separation of optically active compounds by chiral solvent extraction in recent years.631 Although ample literature is available for enantioselective extraction, only a few studies provide fundamental insights in the reaction engineering mechanisms.2629 Enantioselectivity (α) is the most important parameter for chiral extraction. Enantioselectivity (operational selectivity) is defined by the ratio of the distribution ratios. Its upper limit is the intrinsic selectivity aint, which is the ratio of the complexation constants. For example,7 for a 99% pure product (R/S = 100) about 190 theoretical stages are required for an enantioselectivity of 1.05, a number decreasing to approximately 30 when α increases to a value of 1.20. There are several chiral extractants, such as tartaric acid derivatives,611,27 crown ethers,1216,28 cinchona alkaloids,1720,29 etc.2126 However, the enantioselectivities of the chiral extractants are somewhat low, and a large number of theoretical stages are required in the chiral solvent extraction process. Furthermore, the studies on chiral extraction deal with enantioselective extraction of a hydrophilic species from an aqueous phase to an organic phase, which is not suitable for r 2011 American Chemical Society
Figure 1. Chemical structure of ibuprofen.
separation of hydrophobic enantiomers.629 Enantioselective extraction toward aqueous phases is extremely rare. Enantioselectivities for extraction of some aromatic acid enantiomers have been improved greatly by hydrophilic β-cyclodextrins (CDs) in recent work.8,9,11 CDs show negligible solubilities in organic solvents and can be modified to achieve a high solubility in water. Hydrophilic β-CDs are promising for use as ideal hydrophilic selectors in extraction of hydrophobic drug enantiomers from an organic phase to an aqueous phase. An economically feasible reactive extraction system requires not only high enantioselectivity but also sufficiently fast kinetics. It is essential to know the intrinsic complexation kinetics for selection, design, and operation of reactive extraction equipment and for a reliable scale-up. At present, the studies on chiral extraction mainly focus on extraction equilibrium,614,1629 but study of the kinetics is a largely unexplored topic in the field of enantioselective extraction. Recently, Steensma et al. reported on the reaction kinetics in reactive extraction for chiral separation of amines, amino acids, and amino alcohols.15 Ibuprofen (2-(4-isobutylphenyl)propionic acid, IBU; Figure 1) is commonly used as a nonsteroidal anti-inflammatory drug with high hydrophobility, which is still sold as a racemic mixture. Recent studies show that S-ibuprofen is the active form, which Received: September 5, 2011 Accepted: November 15, 2011 Revised: November 12, 2011 Published: November 15, 2011 964
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OJ-RH column (Daicel Chemical Industries Ltd., Japan). The mobile phase was a 20:80 (v/v) mixture of methanol and 0.5 mol/L NaClO4/HClO4 buffer solution (pH 2.0). The flow rate was set at 0.5 mL/min. 2.3. Equilibrium Experiments. Equilibrium experiments were carried out in a temperature-controlled shaker bath at a fixed temperature of 10 °C. HP-β-CD was dissolved in a buffer solution of 0.1 mol/L NaH2PO4/H3PO4 to prepare aqueous phases, and racemic IBU was dissolved in cyclohexane to prepare organic phases. Equal volumes of organic phase and aqueous phase were placed together and shaken sufficiently to reach equilibrium. The equilibrium concentrations of IBU enantiomers were analyzed by HPLC. 2.4. Determination of Extraction Kinetics. The kinetic experiments were carried out in a modified Lewis cell which was manufactured at the glass shop of the Hunan Institute of Science and Technology. The structure of the Lewis cell was the same as shown elsewhere.3941 The cell was a glass cylinder of inside diameter 6.8 cm and height 7.5 cm which was divided into two halves by an acrylic circular disk with a circular hole in the middle. The actual interface of the two phases could be changed by using different disks with holes of different diameters in the middle. To maintain a uniform temperature in the cell, the cell was equipped with a thermo jacket through which water of constant temperature (10 °C) was circulated. When an experiment was carried out, 110 mL of aqueous phase was first introduced into the cell, and then an equal volume of organic phase was placed carefully on the top of the aqueous phase without disturbing the interface. The stirrers in the organic and the aqueous phases rotated at the same speed in opposite directions. Samples of 0.1 mL were taken from the aqueous phase at specified time intervals. 2.5. Data Treatment. The outcome of a Lewis cell experiment is a plot of the concentration of the extracted component in the aqueous phase as a function of time. For extraction assuming the two-film model, the concentration of R-IBU in the cell as a function of time can be found from ! ! Vorg dCR, org Vaq dCR, aq ¼ ð1Þ ER ¼ A dt dt A
Figure 2. Chemical structure of HP-β-CD.
is 28 times more physiologically potent than the R-enantiomer, while R-ibuprofen can cause gastrointestinal toxicity, water sodium retention, and kidney perfusion and increase allergic reactions and other side effects.32,33 The single enantiomer product has a greater commercial value than the racemic mixture. The resolutions of ibuprofen enantiomers were solved by diastereomeric crystallization,34 supercritical carbon dioxide extraction,35 and enzymatic resolutions36 as well. However, crystallization is usually inflexible and involves solid-phase handling with a yield of no more than 50%, supercritical extraction requires rigorous operation conditions, and enzymatic resolution is still restricted due to low efficiency.37,38 Therefore, an efficient enantioselective extraction technique would be very interesting. This paper reports the equilibrium and kinetic study on enantioselective extraction of IBU enantiomers from the organic phase to the aqueous phase by hydrophilic hydroxypropylβ-cyclodextrin (HP-β-CD). A homogeneous aqueous phase complexation model has been developed for reactive extraction of R,S-IBU with HP-β-CD, involving the physical distribution of IBU, the dissociation of IBU, and complexation between HPβ-CD and IBU. The modified Lewis cell was selected as a model reactor to investigate the intrinsic kinetics of the extraction of IBU enantiomers from organic phase to aqueous phase to establish the chiral extraction mechanism.
where ER is the extraction rate of R-IBU; A is the interfacial contact area taken as the area of the disk; Vaq and Vorg are the volumes of the bulk aqueous phase and organic phase, respectively. To avoid problems due to the reversibility of the reaction between extractant and enantiomers, a reversible reaction is often studied by measuring the initial extraction rate which is only governed by the forward reaction. For a precise determination of the initial extraction rate, it is desirable to use the complete experimental concentration-in-time profile. The initial extraction rate ER,0 was calculated from experimental data by using the following equation: ! ! Vorg dCR, org Vaq dCR, aq ¼ ð2Þ ER, 0 ¼ A dt dt A
2. MATERIALS AND METHODS 2.1. Materials and Apparatus. Hydrophilic extractant (HPβ-CD; substitution degree of 5.00, Figure 2) was bought from Qianhui Fine Chemical & Co. Inc. (Shandong, China). Ibuprofen (IBU; racemate, purity g 99.5%) was purchased from Juhua Group Corp. (Zhejiang, China). The solvent for chromatography was of HPLC grade. All other chemicals were of analytical reagent grade and were bought from different suppliers. 2.2. Analytical Method. The quantification of IBU eantiomers was performed by HPLC using an Agilent LC 1200 series apparatus (Agilent Technologies Co. Ltd., USA). An UV detector operated at 230 nm was applied. The column was a CHIRALCEL
t¼0
t¼0
where (dCR,aq/dt)t=0 is the initial slope of the curve representing concentration in the aqueous phase (CR,aq) versus time (t). The values of ER,0 are determined under various experimental conditions to assess the probable effect of the pertinent variables and to draw inferences on the appropriate kinetic model. Equations 1 and 2 can be defined for S-IBU in the same way. 965
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Table 1. Classical Limiting Regimes for Irreversible Reaction Assuming Constant Volume regime
a
description
stirring
[solute]
[CD]
HaA
µ[CD]
2
4
instantaneous
µ
µ
none
m
n
none µ[CD]
2
reaction
By combining eqs 36, the distribution coefficients for R-IBU and S-IBU, PR and PS, can be written as a complex function of a series of important equilibrium constants and process variables. The performance factor (pf) is introduced in this paper to evaluate the extraction performance and facilitate optimization of reactive extraction systems. A high performance factor indicates conditions where the given enantiomer can be purified to high purity with maximum yield. The extraction performance factor can be expressed in terms of distribution ratios by the following equation:
Figure 3. Diagram of the mechanism of reactive extraction.
3. THEORY 3.1. Equilibrium. A scheme of physical and chemical equilibrium for reactive extraction of IBU enantiomers with HP-β-CD is shown in Figure 3. As shown in Figure 3, IBU enantiomers (R and S) distribute over the organic and aqueous phases, but free HP-β-CD (CD) and the complexes of HP-β-CD with IBU enantiomers (RCD and SCD) remain in the aqueous phase because of the high hydrophilicity of HP-β-CD. The main reactions for enantioselective extraction of IBU enantiomers by HPβ-CD are restricted to the aqueous phase. Therefore, a homogeneous reaction model is used to study the reactive extraction of IBU enantiomers by HP-β-CD. The equilibrium of the reactive extraction system depicted in Figure 3 can be described by a series of coupled equilibrium relations and mass balance equations, as follows. The physical partition coefficient of R-IBU and S-IBU, P0, can be written as follows:
P0 ¼
½Raq ½Saq ¼ ½Rorg ½Sorg
CS
CR 1 1 1 þ 1 þ PS PS PR pf ¼ CR P S þ 1 CS 1 þ 1 1 þ 1 þ PS PR
where CR and CS are the total concentrations of R-IBU and S-IBU in all forms, respectively. Therefore, the performance factor can be predicted as a function of pH and HP-β-CD concentration through eqs 37. 3.2. Kinetics. As shown in Figure 3, the reaction between the solute R (or S) and the extractant HP-β-CD (CD) is reversible and R (or S) has a finite equilibrium concentration in the bulk, so the driving force needs to be modified by incorporating the equilibrium concentration. The extraction involves the partitioning of R (or S) available in the organic phase to the aqueous phase.
ð3Þ
where [R]org and [S]org are the concentrations of free R-IBU and S-IBU in the organic phase at equilibrium, respectively; [R]aq and [S]aq are the concentrations of free R-IBU and S-IBU in the aqueous phase at equilibrium, respectively. The dissociation constant of R-IBU and S-IBU is Ka ¼
½R aq ½Hþ ½Raq
¼
½S aq ½Hþ ½Saq
R org T R aq
½S - CDaq ½Saq ½CDaq
ð8Þ
It is known from equilibrium measurements that only R (or S) partitions between the aqueous phase and the organic phase and that CD and RCD (or SCD) remain in the aqueous phase, so the reaction only takes place in the aqueous phase. The solute R present in the aqueous phase combines with the aqueous extractant CD, according to
ð4Þ
where [R]aq and [S]aq are the concentrations of ionic R-IBU and S-IBU in the aqueous phase at equilibrium. The complexation equilibrium constants of HP-β-CD with IBU enantiomoers in the aqueous phase can be written as follows: KS ¼
R aq þ CDaq T R -CDaq
KR ¼
½Raq ½CDaq
ð9Þ
It is assumed that the rate equation can be defined according to the law of mass action as an (m, n) reaction
ð5Þ
rR ¼ km, n ½Rm ½CDn km, n ½R - CD
½R - CDaq
ð7Þ
ðmol=m3 =sÞ
ð10Þ
According to the physicochemical and hydrodynamic parameters, four limiting regimes of extraction accompanied by complex reactions can be identified for an irreversible (m, n) reactive extraction. Table 1 lists the information on the regimes. Analytical solutions exist for these “limiting regimes”, in which specific conditions apply. The dimensionless Hatta number (Ha) can be used to characterize these regimes. HaR is given by eq 11 for an
ð6Þ
where [SCD]aq and [RCD]aq represent the concentrations of complexes SCD and RCD in the aqueous phase at equilibrium, respectively; [CD]aq represents the concentration of free HP-β-CD in the aqueous phase at equilibrium. 966
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Table 2. Influence of Organic Solvent Typea PR
PS
α
dichloromethane
0.19
0.20
1.05
1,2-dichloroethane
0.27
0.29
1.07
cyclohexane
3.00
3.79
1.26
n-heptane
7.19
8.14
1.13
n-octanol
0.07
0.07
1.00
n-heptanol
0.04
0.04
1.00
organic solvent
a
Aqueous phase: [HP-β-CD]0 = 0.1 mol/L, pH 2.5. Organic phase: [IBU]0 = 1 mmol/L; temperature 10 °C.
(m, n) reaction taking place in the aqueous phase. rffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi 2 km, n ½Rm 1 ½CDn DR m þ 1 HaR ¼ KL, aq
ð11Þ
Figure 4. Calculated performance factors for IBU as a function of pH and HP-β-CD concentration. [IBU]0 = 1 mmol/L, temperature 10 °C.
The hydrodynamic factors are unimportant in regimes 1 and 3, whereas the speed of agitation affects the rate of extraction in regimes 2 and 4.42 The expressions for the rate of extraction for various regimes were given by Doraiswamy and Sharma.42 The expression for regime 3, extraction accompanied by a fast general order chemical reaction, ER, is given in eq 12: rffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi 2 km, n ½Rm 1 ½CDn DR ER ¼ ½R ð12Þ m þ 1 Equations 812 can be defined for S-IBU in the same way.
4. RESULTS AND DISCUSSION 4.1. Extraction Equilibrium. To identify a suitable solvent for chiral reactive extraction, the distribution behavior of S-IBU and R-IBU was investigated in various two-phase systems containing 0.1 mol/L HP-β-CD in aqueous phases and 1.0 mmol/L IBU in different organic solvents (Table 2). It is observed from Table 2 that the nature of the organic solvent has an clear influence on distribution coefficients and enantioselectivity. Because of the polar carboxyl group and the large hydrophobic group in IBU molecule, solvents with weak polarity such as halohydrocarbon and alcohol have very good dissolving ability for IBU. With halohydrocarbon and alcohol as organic solvents, IBU mainly distributes in the organic phase and the distribution coefficients are therefore very low. Furthermore, hydrogen bonding between the alcohol and the carboxyl group makes the distribution coefficients lower with alcohol than with halohydrocarbon. Because only a small amount of IBU enantiomers are recognized by HPβ-CD, the enantioselectivity is very low when halohydrocarbon and alcohol are used as organic solvents. With alkane as organic solvent, IBU enantiomers can distribute into the aqueous phase more easily than with other organic solvents and help the recognition of IBU enantiomers in the aqueous phase. Therefore, the distribution coefficients and the enantioselectivities are relatively high. HP-β-CD can include n-heptane within the hydrophobic interior more easily than cyclohexane because of the higher hydrophobicity and lower steric hindrance, which will weaken the recognition ability of HP-β-CD. Therefore, enantioselectivity is lower with n-heptane than with cyclohexane. The highest enantioselectivity with suitable distribution coefficients is achieved
Figure 5. Performance factor as a function of pH. Solid lines: model predictions. Symbols: experimental data. [IBU]0 = 1 mmol/L, [HPβ-CD]0 = 0.1 mol/L, temperature 10 °C.
with cyclohexane as organic solvent. Therefore, cyclohexane was selected as the optimal organic solvent. To obtain the optimal conditions for reactive extraction of IBU enantiomers, we utilized the model to explore the influence of various operating conditions on extraction efficiency in a single stage. Figure 4 shows the performance factor calculated as a function of pH and HP-β-CD concentration. It is observed from Figure 4 that the performance factor is strongly influenced by pH and HP-β-CD concentration. Relatively high pf values will be obtained at pH 4) more nonselective partitioning of anions (R or S) is occurring. At pH e4, IBU molecules hardly dissociate, and the amount of molecules (R or S) in the aqueous phase is much larger than that of anions (R or S). With the further increase of pH (pH >4), more and more molecular IBU enantiomers are dissociated into ionic IBU enantiomers in the aqueous phase, which leads to partitioning of more molecular IBU enantiomers from the organic phase to the aqueous phase. 4.2.4. Order with Respect to IBU. The effect of initial concentration of IBU in the organic phase on the initial extraction rates was investigated by varying the initial concentration of IBU from 1 to 3 mmol/L. As shown in Figure 10, the extraction rates of R-IBU and S-IBU are linearly proportional to the concentrations. A regression analysis of the data yielded m = 1 (as per eq 12). Thus, the two reactions are first order with respect to R-IBU and S-IBU.
HaR ¼
qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi Daq, R k1, 2, R ½CD2 KL, aq, R
ð18Þ
To verify that the result of the kinetic data complied with regime 3, the values of the parameter Ha were evaluated by eqs 17 and 18. Since KL,aq,S and KL,aq,R were both calculated as 7.94 106 m/s, HaS and HaR were calculated as 10.28 and 8.19, respectively, which are the condition for the validity of regime 3. The above results reflect the intrinsic kinetics of the extraction process. 4.2.7. Model Predictions for Reactive Extraction of IBU. From the obtained forward rate constants and equilibrium constants, 969
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’ AUTHOR INFORMATION Corresponding Author
*E-mail:
[email protected].
’ ACKNOWLEDGMENT This work was supported by the National Natural Science Foundation of China (No. 20976041) the Program for New Century Excellent Talents in University, Hunan Provincial Natural Science Foundation of China (No. 10JJ1004), and the Aid program for Science and Technology Innovative Research Team in Higher Educational Instituions of Hunan Province.
Figure 12. Variations of the concentrations of R-IBU and S-IBU versus time. [IBU]0 = 1 mmol/L, [HP-β-CD]0 = 0.1 mol/L, A = 9.62 cm2, N = 75 rev/min, pH 2.5, temperature 10 °C.
the backward reaction rate constants of k1,aq,S and k1,aq,R were estimated as 3.67 105 s1 and 2.93 105 s1, respectively. For an irreversible (1, 2) reactive extraction, the following two rate equations for R-IBU and S-IBU can be deduced according to eq 10: rR ¼ ð4:58 104 Þ½R½CD2 ð2:93 104 Þ½R - CD ðmol=m3 =sÞ
ð19Þ
rS ¼ ð7:21 104 Þ½S½CD2 ð3:67 105 Þ½R - CD ðmol=m3 =sÞ
ð20Þ
A simulated extraction course for IBU enantiomers can be established to describe the flux over the interface. A comparison of the experimental values with the model predictions is shown in Figure 12. The dashed lines represent the equilibrium concentrations as obtained from equilibrium experiments. It is shown from Figure 12 that the model predictions are in good agreement with the experiment, and the difference between experimental and simulated equilibrium is small. Thus, the model is suitable to describe the extraction course.
5. CONCLUSION The equilibrium for the reactive extraction of IBU enantiomers by HP-β-CD from the organic phase to the aqueous phase was investigated by modeling and experiment. The optimal conditions for reactive extraction of IBU enantiomers were obtained based on experimental data and model simulation. The theory of extraction accompanied by chemical reaction has been used to obtain kinetics of the extraction in a modified Lewis cell. The reactions between IBU enantiomers and HPβ-CD are found to be the fast reaction. The reactions have been found to be first order dependent on IBU enantiomers and second order with respect to HP-β-CD. HaS and HaR are 10.28 and 8.19, respectively, which indicates the condition for the validity of regime 3, and the extraction is accompanied by a fast chemical reaction in the diffusion film. The model predictions are in good agreement with the experiment. The results obtained in this paper will be useful for the design and operation of reactive extraction equipment.
’ NOTATION A = interfacial area, cm2 a = specific area (A/V), m1 C = concentration, mol/L C/R,aq = concentration of R-IBU in the aqueous phase at equilibrium CR,aq = concentration of R-IBU in the aqueous phase at time t D = diffusivity, m2/s ER = extraction rate of R-IBU, mol/(m2 3 s) Ha = Hatta number HP-β-CD (CD) = hydroxypropyl-β-cyclodextrin IBU = ibuprofen K = complexation constants KL = physical mass transfer coefficient, m/s km,n = rate constant for a reaction that is mth order in IBU and nth order in species HP-β-CD km,n = backward reaction rate constant N = stirring speed, rev/min P = distribution coefficient P0 = physical partition coefficient pf = performance factor R = R-ibuprofen RCD = complex of R-enantiomer with HP-β-CD (CD) S = S-ibuprofen SCD = complex of S-enantiomer with HP-β-CD (CD) t = time V = volume of the bulk phase, cm3 [CD]aq = HP-β-CD concentration in aqueous phase, mol/L [R]aq = concentration of R-IBU in aqueous phase, mol/L [R]org = concentration of R-IBU in organic phase, mol/L Greek Symbol
α = enantioselectivity Subscripts
aq = aqueous phase org = organic phase 0 = initial value m = order of reaction with respect to IBU n = order of reaction with respect to HP-β-CD 1 = backward reaction R = R-enantiomer S = S-enantiomer
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dx.doi.org/10.1021/ie202016g |Ind. Eng. Chem. Res. 2012, 51, 964–971
