Chiral Separation of Naproxen with Immobilized Liquid Phases

Article pubs.acs.org/OPRD

Chiral Separation of Naproxen with Immobilized Liquid Phases Sandra Corderí,†,‡ Caecilia R. Vitasari,§ Michal Gramblicka,†,∥ Thierry Giard,⊥ and Boelo Schuur*,† †

Sustainable Process Technology Group, Faculty of Science and Technology, University of Twente, P.O. Box 217, 7500 AE Enschede, The Netherlands ‡ Advanced Separation Processes Group, Department of Chemical Engineering, University of Vigo, As Lagoas-Marcosende, 36310 Vigo, Spain § Institute for Sustainable Process Technology, Groen van Prinstererlaan 3, 3818 JN Amersfoort, The Netherlands ∥ Department of Chemical and Biochemical Engineering, Faculty of Food and Chemical Technology, Slovak University of Technology, Radlinského 9, 812 37 Bratislava, Slovakia ⊥ GlaxoSmithKline Vaccines, Rue de l’institut 89, 1330 Rixensart, Belgium S Supporting Information *

ABSTRACT: The use of solvent-impregnated resins (SIRs) as a hybrid technology between liquid extraction and adsorption was investigated for the enantioseparation of naproxen. A chiral recognition system from the enantioselective liquid−liquid extraction from the literature was taken as a starting point, comprising naproxen dissolved in an aqueous solution containing also the chiral selector hydroxypropyl-β-cyclodextrin (HP-β-CD) and an organic phase consisting of L-diisobutyl tartrate (L-IBT) dissolved in 1,2-dichloroethane. As a result of leaching of 1,2-dichloroethane, this solvent is unsuitable for use in a SIR and was replaced by 1-octanol. The effect of the concentrations of the chiral selectors on the equilibrium operational enantioselectivity was studied in the 1-octanol−water system. It was found that HP-β-CD strongly affected the operational selectivity but that LIBT hardly affected the selectivity and could be omitted to reduce the complexity of the system. Enantioseparation of naproxen from aqueous systems using HP-β-CD as the selector with resin technology was investigated for both 1-octanol SIRs and nonimpregnated resins (NIRs) obtained using XAD4 resins. Both equilibrium capacities and uptake rates were studied, and it was found that the capacities were comparable in magnitude but that the uptake rates were remarkably much higher in the SIRs than in the NIRs. When applied in a packed bed, this will result in much shorter mass transfer zones and hence more effective use of the bed.

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INTRODUCTION There are a wide variety of chiral resolution methods, including asymmetric catalysis,1 crystallization,2 chromatographic approaches such as HPLC3 and simulated moving bed,4 and methods based on liquid−liquid partitioning such as liquid− liquid extraction (LLE).5 Crystallization is the most commonly used method, but this technique shows limited versatility, as not all species are able to crystallize out. For the most important alternative, chromatography, the high costs of the existing specific enantioselective adsorbents and the limited capacity are the main drawbacks. Methods based on liquid− liquid partitioning such as enantioselective LLE (ELLE) can be an attractive alternative to crystallization and chromatography because of the possibility to operate on all scales from laboratory separations to bulk-chemical-scale processes in the chemical industry. Recent developments in chiral liquid−liquid partitioning include the use of ionic liquids, 6 liquid membranes,7 chiral centrifugal partition chromatography,8 and solvent impregnated resins (SIRs).9 Liquid−liquid methods seem interesting because of the high capacity obtained. However, they have the drawback that relatively high selectivities are required because of the limited number of theoretical plates that can be made. Therefore, using SIRs in packed columns, which should exhibit a capacity approaching that of LLE but also should be able to achieve a number of theoretical plates that can be much higher than in © XXXX American Chemical Society

LLE, is interesting and could be seen as a hybrid between LLE and chromatography. For example, HPLC processes can yield enantiopure products even when the enantioselectivity is as low as 1.02, while for ELLE a minimum selectivity of 1.5 is given as a rule of thumb.5f As a hybrid between chromatography and LLE, the required selectivity could be estimated as between 1.02 and 1.5 for the SIR method. A SIR consists of a macroporous resin in which a solvent is immobilized. Prerequisites for the solvent are not only high affinity for the resin but also low solubility in water. Figure 1 shows a schematic representation of chromatography, SIRs, and ELLE as chiral separation techniques. To date, only a single study on the topic of chiral SIRs has been reported,9 leaving the technology highly unexplored. The reported study aimed at applying a reported ELLE with a high selectivity of over 10 in a SIR process. One of the directions in which research on ELLE has been reported in recent years is in biphasic recognition ELLE, which is mostly applied to organic acids. These systems are interesting but exhibit only moderate selectivities, and for this reason they appear as an interesting class of chiral separations to be applied in SIRs. Therefore, for this study a system from this class, i.e., 2-(6-methoxynaphth-2Received: January 21, 2016

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DOI: 10.1021/acs.oprd.6b00020 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

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Figure 1. Schematic representation of chiral separation technologies: (a) chromatography; (b) solvent-impregnated resins; (c) enantioselective liquid−liquid extraction.

priate for use in SIR-based processes, and since 1,2-dichloroethane is not an environmentally benign solvent and its solubility in the aqueous phase is too high, 1-octanol was investigated as an alternative solvent. The new ELLE system was studied by liquid−liquid equilibrium experiments in order to investigate the effect of the concentrations of the chiral selectors HP-β-CD and L-IBT. Appropriate conditions were thus found and applied in SIR experiments with XAD4 resin. This resin was selected for this study because of its good combination of capacity, mass-transfer rate, mechanical strength, and selectivity over a fixed-bed column.12 Batch experiments were performed to obtain competitive sorption equilibrium isotherms, and in order to investigate the uptake rate of naproxen enantiomers by the SIRs, the SIRs were applied in zero-length columns (ZLCs). ZLCs are columns with a very shallow layer of particles, omitting any axial dispersion and allowing a high elution rate, thereby reducing the mass-transfer resistance on the outside of the resin particles to negligible values. The measured uptake kinetics in ZLC experiments are thus dependent only on interparticle masstransfer effects.

yl)propionic acid (naproxen), was selected as model racemate to separate. Naproxen is a nonsteroidal anti-inflammatory drug that is widely used to treat osteo-, rheumatoid, and gouty arthritis and to relieve pain and inflammation in sprains, strains, and backache. This drug contains a chiral center that generates two enantiomers with different pharmacological profiles. The pharmacological activity resides in (S)-naproxen, while (R)naproxen can cause some undesired side effects. Hence, it is beneficial to separate (S)-naproxen from racemic naproxen. The chemical structure of this drug is presented in Figure 2.

Figure 2. Chemical structure of naproxen.

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The biphasic recognition system for naproxen10 containing a tartaric acid derivative such as L-diisobutyl tartrate (L-IBT) in the organic phase and hydroxypropyl-β-cyclodextrin (HP-βCD) in the aqueous phase was taken as a benchmark system, exhibiting selectivities ranging from 1.1 to 2.7 for a range of organic acids.11 A schematic representation of this biphasic chiral recognition system is given in Figure 3, and definitions of the parameters in the system are presented in the Supporting Information. In order to separate naproxen with SIR technology, the liquid−liquid equilibria were studied under conditions appro-

EXPERIMENTAL SECTION Materials. Amberlite XAD4 resins were supplied by SigmaAldrich. HP-β-CD with a purity of ≥97% was provided by Acros Organics. L-IBT was synthesized by Syncom BV (Groningen, The Netherlands). Racemic naproxen and optically pure (S)-(+)-naproxen with purities of ≥98% and ≥99%, respectively, were purchased from Tokyo Chemical Industry. The organic solvents 1,2-dichloroethane and 1octanol were provided by Sigma-Aldrich. Monobasic sodium phosphate, NaH2PO4, with a purity of ≥99.0%, was also acquired from Sigma-Aldrich. For HPLC analysis, acetonitrile with ≥99.9% purity was purchased from Sigma-Aldrich. Analytical Method. The aqueous-phase samples were analyzed by HPLC using a UV detector at the UV wavelength of 220 nm to measure the concentration of naproxen enantiomers. The sample was injected into a Varian ProStar HPLC equipped with a 4.6 mm × 250 mm Chiralpak IB column (Daicel, Japan) and a Varian ProStar UV−vis 310 detector. The mobile phase was a 1:3 (v/v) mixture of acetonitrile and sodium phosphate buffer solution (pH 1.5). The flow rate was set at 1 mL·min−1. The injected sample volume was varied from 5 to 45 μL, and the column temperature was T = 293.15 K. These conditions were the result of an optimization process to achieve the best analytical precision. Each experiment was duplicated under identical

Figure 3. Schematic diagram of the resolution of naproxen enantiomers by biphasic chiral recognition extraction. CD and Ta are the enantioselectors HP-β-CD and L-IBT, respectively, and R−CD, S−CD, R−Ta, and S−Ta represent the corresponding complexes with the R and S enantiomers. B



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Figure 4. Schematic representation of the zero-length column setup.

large excess of water. Subsequently, the extra-particle water was removed using vacuum filtration. In this way, the outsides of the particles were devoid of water while their pores were filled with water. The amount of water in the NIRs was determined by weight. Batch Adsorption Experiments with SIRs and NIRs. Batch adsorption equilibrium experiments with SIRs and NIRs were conducted to determine the equilibrium isotherms for resins impregnated with 1-octanol and for nonimpregnated resins. The equilibrium experiments with SIRs and NIRs were carried out in 10 mL glass-stoppered vials in which 5 mL of pH 2.5 buffered 0.01 M HP-β-CD and 1 mM aqueous naproxen solution was mixed with different amounts of SIR or NIR. After 24 h in a temperature-controlled shaking bath at T = 280.2 K, a sample of the aqueous phase was withdrawn with a syringe, filtered, and analyzed by HPLC-UV to determine the concentration of naproxen enantiomers. Preparation and analysis of the samples were the same as for the liquid−liquid experiments. The amounts of (R)- and (S)-naproxen in the resins were calculated from the mass balance for each enantiomer. Zero-Length Column Technology. ZLC experiments are a typical small-scale technology used to determine adsorption kinetics.13 ZLC experiments were prepared by placing a thin layer (8 mm) of adsorbent (SIR or NIR) inside a glass column. An aqueous solution containing the naproxen enantiomers was circulated from the storage vessel over the column with a pump while the concentration of naproxen was measured with the UV detector. The setup consisted of a K-1001 HPLC pump (Knauer GmbH, Berlin, Germany), a K-2600 UV detector (Knauer), an F 25 Julabo water bath, a glass column (volume in mL = 1.7671 × (bed length in cm); Omnifit, Cambridge, U.K.) with two adjustable end pieces, and a water jacket. Figure 4 shows a schematic representation of the ZLC setup. For kinetics adsorption measurements of naproxen enantiomers over the SIR and NIR, the system was operated in recycle mode. In this mode, the inlet and outlet tubes are placed in the same flask, which contains a magnetic stirrer. The non-recycle mode, in which the inlet and outlet tubes are

conditions, and the relative standard deviation was in the range of 3%. Liquid−Liquid Equilibria. LLE experiments were carried out in 2 mL glass-stoppered vials to study the influence of the concentrations of HP-β-CD and L-IBT on the ELLE system. Aqueous 1 mM naproxen solutions were applied in the studies. They were prepared by dissolving the naproxen in a 0.1 M phosphate buffer solution at pH 2.5 and varying the HP-β-CD concentration from 0.01 to 0.20 M. In each experiment, 1.5 mL of aqueous naproxen solution was mixed with 0.3 mL of the organic phase containing L-IBT at a concentration ranging from 0 to 0.25 M. The vials were vigorously shaken and placed in a thermostated shaking bath at T = 280 K for 24 h to ensure equilibrium. Afterward, the phases were allowed to settle, and a sample from the aqueous phase was carefully taken with a syringe, filtered over a 0.45 μm filter, and analyzed by HPLCUV. Each experiment was duplicated. The concentration of naproxen enantiomers in the organic phase was calculated by mass balance, assuming that the volumes of the organic and aqueous phases did not change during the experiment. Impregnation Procedure. The SIRs used in these experiments were prepared using Amberlite XAD4 resins and 1-octanol as the solvent. In the preparation procedure, before their use the Amberlite XAD4 resins were cleaned with water, ethanol, and acetone and then dried under vacuum at T = 323.15 K and p = 2 × 104 Pa overnight. The dry resins were then contacted for at least 3 h with a precalculated amount of 1octanol and a sufficient amount of methanol (used to ensure a homogeneous loading of the particles) so that all of the particles were submerged under a 0.01−0.02 m layer of the methanol−octanol mixture. Afterward, the methanol was slowly evaporated under vacuum at T = 323.15 K and p = 5 × 104 Pa to obtain the octanol impregnated resins. The exact loading of the particles with 1-octanol was determined by measuring the increase in the mass (0.695 mL of 1-octanol per gram of SIR). Nonimpregnated resins were prepared before the experiments by subsequently washing cleaned particles (as explained for SIR preparation) first with methanol (used to facilitate the subsequent loading of particles with water) and then with a C



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placed in two separate flasks, was used for cleaning. After the column was packed with the resins to obtain a bed height of approximately 8 mm, water was pumped over the column in non-recycle mode to stabilize the system. After the equilibration, water was replaced with 150 mL of octanol-saturated aqueous phase containing naproxen, and the system was switched to recycle mode. The conditions of the experiments were chosen in such a way as to reduce the naproxen enantiomer concentration in the aqueous phase at equilibrium to approximately 30% of the initial concentration. The flow rate for each experiment was set at a value of 10 mL·min−1. The column was equipped with a water jacket connected to a circulating water bath at a constant temperature of T = 280 K. Samples were taken at regular intervals and analyzed by HPLCUV to determine the concentration of naproxen enantiomers. The preparation and analysis of the samples were the same as for the liquid−liquid experiments.

Figure 5 shows (a) the distribution coefficients and (b) the enantioselectivities for the series with 0.01 M HP-β-CD and 0.2

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RESULTS AND DISCUSSION 1-Octanol as the Organic Solvent instead of 1,2Dichloroethane. Whereas the enantioseparation system reported in the literature10 made use of 1,2-dichloroethane as the organic solvent, this is not a good solvent for SIR technology because of the non-negligible solubility of 1,2dichloroethane in the aqueous phase and the toxic nature of this solvent. The performance of the more benign 1-octanol was compared with that of 1,2-dichloroethane in biphasic chiral extraction systems containing 1 mM naproxen enantiomers and two different concentrations of HP-β-CD (0.01 and 0.1 M) in 0.1 M phosphate buffer solution at pH 2.5 and 0.1 M L-IBT in the organic solvents. Table 1 presents the obtained results. Table 1. Influence of the Organic Solvents on the Distribution Coefficients kR and kS and the Enantioselectivity αa organic solvent

b

1,2dichloroethane 1-octanol

HP-βCD (M) 0.01 0.10 0.01 0.10

kR 100.40 8.58 299.69 27.24

(0.54) (0.46) (0.65) (0.20)

α

kS 76.28 6.77 202.28 19.88

(0.60) (0.36) (0.85) (0.18)

1.32 1.27 1.38 1.37

(0.04) (0.00) (0.02) (0.01)

a

Standard deviations are shown in parentheses. bContaining 0.1 M LIBT.

When 1,2-dichloroethane was used as the solvent, the distribution coefficients and enantioselectivities were lower than those obtained with 1-octanol. It was also seen that lowering the HP-β-CD concentration strongly increased the distribution coefficients. From these results, it was concluded that the environmentally more benign solvent 1-octanol is perfectly suitable to replace 1,2-dichloroethane as the organic solvent. Influence of the L-IBT Concentration on the Liquid− Liquid Equilibrium. L-IBT was chosen as the chiral selector for naproxen enantiomers in the organic phase on the basis of previous studies of chiral separations reported in the literature.10,11b,14 The effect of its concentration on the distribution coefficients and the enantioselectivities was investigated using two initial concentrations of HP-β-CD (0.01 and 0.2 M) in the aqueous phase (0.1 M phosphate buffer solution, pH 2.5) and 1-octanol as the organic solvent.

Figure 5. (a) Effect of the L-IBT concentration on the distribution coefficients. With 0.01 M HP-β-CD: (▲) kR; (●) kS. With 0.2 M HPβ-CD: (△) kR; (○) kS. (b) Effect of the L-IBT concentration on the enantioselectivity: (■) 0.01 M HP-β-CD; (□) 0.2 M HP-β-CD.

M HP-β-CD as functions of the L-IBT concentration in the organic phase. It follows from Figure 5a that the distribution coefficients are not heavily influenced by the L -IBT concentration, as they show only a slight increase with increasing tartrate concentration. However, the concentration of HP-β-CD has a major impact on the distribution coefficients. For the experiments with 0.01 M HP-β-CD, the distribution coefficients are remarkably high in comparison with those for the series of experiments with 0.2 M HP-β-CD. From Figure 5b it follows that the enantioselectivity is not significantly influenced by the L-IBT concentration, i.e., the D



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addition of tartrate in the organic solvent does not improve the enantioselectivity. Hence, the enantioselectivity in the extraction is mainly provided by the aqueous-phase interaction with the HP-β-CD enantioselector. Next to the concentration of naproxen, the concentration of L-IBT in the aqueous phase was also determined by HPLC-UV using the same conditions as for the naproxen analysis. It was found that leaching of L-IBT into the aqueous raffinate phase was significant, with losses of L-IBT from the organic phase of 2.1−2.3% (for more details, see the Supporting Information). On the basis of the limited effects of L-IBT on the enantioselectivity and the leaching issue, further studies on immobilized solvent systems were carried out without L-IBT. In addition, since the organic phase selector is not necessary, an enantioseparation system consisting of an achiral resin only (nonimpregnated) and an eluting phase containing HP-β-CD as an enantioselector was considered as well as an alternative to the SIR system. Influence of the HP-β-CD Concentration on the Liquid−Liquid Equilibrium. The influence of the HP-β-CD concentration (0.01 to 0.2 M) on the distribution coefficients and the operational enantioselectivity was investigated using an aqueous 0.1 M phosphate buffer solution at pH 2.5, and the results are shown in Figure 6. As illustrated in Figure 6a, the distribution coefficients are strongly influenced by the concentration of HP-β-CD, reaching maximum values at the lowest concentration of the chiral selector. The values of kS are lower than those of kR, which indicates that HP-β-CD preferentially forms complexes with the S enantiomer and that these complexes are retained in the aqueous phase. Although the distributions are strongly affected by the concentration of HP-β-CD, the enantioselectivity is hardly affected, as shown in Figure 6b. Therefore, 0.01 M HP-β-CD seems to be the best choice. Studies of Competitive Sorption Equilibrium Isotherms. The sorption equilibrium isotherms were measured competitively, i.e., in experimental systems where racemic mixtures of (R)- and (S)-naproxen were added to the aqueous phase. Both experiments with SIRs and NIRs were carried out, and the results are illustrated in Figure 7. This figure shows the sorption capacity, q, in millimoles per kilogram of dry particles (i.e., in the case of SIR particles, the mass before impregnation was taken) as a function of the aqueous-phase concentration. The fitted Freundlich isotherms15 are displayed as well. Details of isotherm fitting can be found in the Supporting Information. From Figure 7 it follows that the sorption capacities of SIRs and NIRs are on the same order of magnitude but that at low naproxen concentrations in the aqueous phase the capacity is higher for NIRs than for SIRs. Because of the strong adsorption, very small amounts of the resin had to be contacted with the aqueous naproxen solutions, resulting in some scattering of the data, but the trends are clear. Comparisons of the fitted Freundlich isotherms for SIRs and NIRs in terms of (a) sorption capacity and (b) enantioselectivity of naproxen enantiomers are displayed in Figure 8. As illustrated in Figure 8a, it appears that very strong interactions between the XAD4 functional groups and naproxen enantiomers cause a high level of adsorption even at low aqueousphase naproxen concentrations. In the case of SIRs, the sorption capacity is less at low aqueous-phase naproxen concentrations, but the capacity of SIRs is higher than that of NIRs at increased naproxen concentrations in the aqueous phase. This may be explained by the interactions of the

Figure 6. (a) Effect of the HP-β-CD concentration on the distribution coefficients: (▲) kR for the racemic feed mixture; (●) kS for the racemic feed mixture; (○) kS for enantiopure (S)-naproxen. (b) Effect of the HP-β-CD concentration on the enantioselectivity.

hydroxyl functionality in the solvent 1-octanol with the π systems in the resin, which partly block the active sites for the adsorption of naproxen, while the solubility of naproxen in the octanol solvent causes the higher sorption capacity in SIRs at higher aqueous-phase concentrations. From Figure 8b, it is obvious that the enantioselectivity of naproxen enantiomers in a system with SIRs is much higher than the enantioselectivity in systems with NIRs. Because of the differences in the physicochemical properties of the systems, the overall distributions of the naproxen enantiomers over the bulk aqueous phase with the chiral selector and the achiral solid phase (or the achiral impregnated liquid and solid phases) are E



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Figure 7. Sorption equilibrium isotherms for (a) (R)-naproxen with NIR, (b) (S)-naproxen with NIR, (c) (R)-naproxen with SIR, and (d) (S)naproxen with SIR: (●) experimental; (solid lines) Freundlich.

also different for SIRs and NIRs. In the case of the SIR, 1octanol acts as a buffer between the resin and the naproxen enantiomers. As a result, the SIR shows a higher operational selectivity than the NIR. Furthermore, with the increase in the concentration of enantiomers in the aqueous phase the selectivity decreases, especially at low concentrations of enantiomers. Therefore, it can be concluded that it should be possible to perform a chiral separation of naproxen enantiomers in 1-octanol-impregnated resins because of the combination of greater enantioselectivity for the enantiomers and higher capacity at increased naproxen concentrations in SIR experiments. Zero-Length Column Experiments. ZLC experiments with SIRs and NIRs were carried out to study the rate of extraction of naproxen from the aqueous phase. The experimental data were modeled, and the effective diffusion coefficients were obtained. A description of the dynamic adsorption models that were applied can be found in the Supporting Information. Figure 9 provides the experimental and simulated concentrations of naproxen enantiomers in the aqueous phase as functions of time for the experiments with SIRs and NIRs. As can be observed in the figure, the naproxen enantiomer concentration decreases over time because these are retained by the impregnated particles as well as by the nonimpregnated particles. A clear difference between the experiments with SIRs and NIRs can be seen, as the

equilibrium is approached in 150 min for the experiments with SIRs and in more than 600 min for the experiments with NIRs. For the NIR particles, the effective aqueous-phase diffusion coefficient was found to be Deff,aq = 2.53 × 10−12 dm2· s−1 and for the SIR particles, the effective diffusion coefficient inside the octanol phase was Deffoct = 2.45 × 10−10 dm2·s−1. Therefore, the effective diffusion is 100 times higher in octanol than in water. This difference may be explained by the insolubility of naproxen in water and the fact that naproxen in water almost exclusively appears inside the HP-β-CD. Figure 10 shows a schematic drawing of the concept of a solvent-impregnated resin and a nonimpregnated resin. The size of HP-β-CD is a significantly larger than the size of naproxen molecules, and for the smaller pores in the resin, the size of HP-β-CD is on the same order of magnitude as the pores, resulting in serious mass-transfer limitations. This means that impregnation of the particles with 1-octanol results in a significant improvement in the mass transfer. Thus, the faster chiral separation of naproxen enantiomers in SIRs compared with NIRs could significantly reduce the bed size for quantitative separations.

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CONCLUSIONS The use of a solvent-impregnated resin (SIR) process for enantioseparation of naproxen enantiomers was investigated. The extraction system was characterized using liquid−liquid F



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Figure 9. Experimental and fitted concentrations of naproxen enantiomers in the aqueous phase as functions of time for SIRs and NIRs in the zero-length column experiments: (▲) (R)-naproxen with NIR; (●) (S)-naproxen with NIR; (×) (R)-naproxen with SIR; (+) (S)-naproxen with SIR; (solid lines) simulated concentrations using the dynamic adsorption model.

Figure 8. Comparison of Freundlich isotherms for SIRs and NIRs. (a) Sorption capacity: (solid line) (R)-naproxen with NIR; (dashed line) (S)-naproxen with NIR; (dashed-dotted line) (R)-naproxen with SIR; (dotten line) (S)-naproxen with SIR. (b) Enantioselectivity: (solid line) SIRs; (dashed line) NIRs.

Figure 10. Schematic representation of a solvent-impregnated resin and a nonimpregnated resin.

the complexity of the liquid−liquid system to a single enantioselector in the aqueous phase furthermore allowed the organic solvent to be left out entirely. Competitive sorption equilibrium isotherms for (R)- and (S)-naproxen showed that the sorption capacity was higher for SIRs than for NIRs at high naproxen aqueous-phase concentrations, but this trend was reversed when the naproxen concentration was decreased. In zero-length column experiments it was observed that impregnation with octanol does enhance the mass transfer strongly as a result of the fact that naproxen diffuses freely through 1-octanol at a much higher concentration and in aqueous solutions is contained inside the HP-β-CD, which has a significantly larger diameter, resulting in a much lower effective diffusion coefficient in water. Thus, impregnation of

equilibrium experiments. 1-Octanol was chosen as the organic solvent because of its low solubility in water and more benign properties compared with the chlorinated solvents commonly applied in enantioseparation in liquid−liquid systems. The organic-phase chiral selector L-isobutyl tartrate (L-IBT) did not significantly improve the enantioselectivity but did leach into the aqueous phase, and therefore, it was not applied in a SIR. Instead, only the aqueous-phase chiral selector HP-β-CD was applied, and it was found that the naproxen distribution coefficients were strongly influenced by its concentration, reaching maximum values at the lowest concentration of the chiral selector (0.01 M), while the selectivity for the S enantiomer was hardly affected by the concentration. Reducing G



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R−Ta, S−Ta

the resins can intensify the enantioseparation process significantly, and this may also be applied to other separation processes making use of adsorption.

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ASSOCIATED CONTENT

S Supporting Information *

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel: +31 53 4892891. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS S.C. is thankful to Xunta de Galicia for her predoctoral grant (Plan I2C) and to the University of Vigo for her grant for a stay ́ en Centros de Investigación 2013). This was abroad (Estadias an Institute for Sustainable Process Technology (ISPT) project, ISPT Grant PH-00-01.

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NOMENCLATURE

Abbreviations

SIR NIR HP-β-CD L-IBT ZLC LLE ELLE

solvent-impregnated resin nonimpregnated resin hydroxypropyl-β-cyclodextrin L-diisobutyl tartrate zero-length column liquid−liquid extraction enantioselective liquid−liquid extraction

Symbols

kR and kS α P KA Kaq,R, Kaq,S Korg,R, Korg,S q V

distribution coefficients of (R)- and (S)-naproxen enantioselectivity physical partitioning ratio dissociation equilibrium constant equilibrium complexation constants in the aqueous phase equilibrium complexation constants in the organic phase capacity of SIR (mmol·kg−1) volume (L)

Subscripts

aq org eq o R, S R+, S+ R−CD, S−CD

REFERENCES

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.6b00020. Parameter definitions for the biphasic recognition system for naproxen, influence of the volume ratio (organic/ aqueous) on the liquid−liquid equilibrium, studies of the leaching of L-IBT to the raffinate phase, fit parameters obtained with the Freundlich equation for SIRs and NIRs, and a description of the adsorption dynamic models that were applied for the calculation of the diffusion coefficients in the zero-length column experiments (PDF)

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complexes between (R)- or (S)-naproxen and L-diisobutyl tartrate

aqueous phase organic phase equilibrium initial (R)- and (S)-naproxen enantiomers protonated enantiomers complexes between (R)- or (S)-naproxen and hydroxypropyl-β-cyclodextrin H



Article

(14) Tang, K.; Song, L.; Liu, Y.; Pan, Y.; Jiang, X. Chem. Eng. J. 2010, 158, 411. (15) Freundlich, H. M. F. Z. Phys. Chem. 1906, 57, 385.

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Chiral Separation of Naproxen with Immobilized Liquid Phases

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