Enantioselective Liquid–Liquid Extraction of Racemic Ibuprofen by l

Article pubs.acs.org/jced

Enantioselective Liquid−Liquid Extraction of Racemic Ibuprofen by L‑Tartaric Acid Derivatives Zhongqi Ren,*,† Yong Zeng,† Yutao Hua,‡ Yongqi Cheng,† and Zhimin Guo† †

Beijing Key Laboratory of Membrane Science and Technology, Beijing University of Chemical Technology, Beijing 100029, People’s Republic of China ‡ China National Center for Biotechnology Development, Beijing 100036, People’s Republic of China ABSTRACT: Enantioselective liquid−liquid extraction (ELLE) of racemic ibuprofen enantiomers was studied by using L-tartaric acid derivatives as chiral extractants in the organic phase. The chiral recognition mechanism of two ibuprofen enantiomers with L-tartaric acid esters was preliminarily investigated using density functional theory. The calculated binding energy of the (R)-ibuprofen/L-tartaric acid dihexyl ester complex (−64.32 kJ·mol−1) is higher than that of the (S)-ibuprofen/L-tartaric acid dihexyl ester complex (−39.74 kJ·mol −1 ). The influences of the type and concentration of the L-tartaric acid ester, the type of organic solvent, and the pH of the aqueous phase in the ELLE process were experimentally studied. The results showed that L-tartaric acid dipentyl ester was the best chiral extractant for racemic ibuprofen. The distribution coefficient and separation factor were best with polar organic solvents at low pH. Under the optimum conditions (0.2 mol·L−1 L-tartaric acid dipentyl ester in the organic phase and decanol as the solvent), the maximum enantioselectivity of racemic ibuprofen enantiomers was over 1.2.

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INTRODUCTION Chiral drugs occupy an increasingly larger share in the global medicine market, with over 50% of production and sales in the world’s chemical drugs.1 The differences in the pharmacological activities of chiral enantiomeric drugs result in serious problems in treatment of diseases or other applications using racemates. Since 1992, the U.S. Food and Drug Administration (FDA) has required that chiral drugs be reported only in single-isomer form. Otherwise, the pharmaceutical companies must provide clear pharmacology and toxicity justification for both enantiomers and racemates.2,3 It is very important to get single-enantiomer drugs by resolution methods. At present, there are mainly three ways to get singleenantiomer drugs. Chiral pool synthesis is a cheap way to get enantiopure compounds using natural or biological methods,4 such as fermentation processes.5 However, this method is limited by precursors of natural sources. Asymmetric synthesis is an alternative way to obtain high-purity single enantiomers.6−8 Developing an appropriate path or efficient catalyst for each product is difficult. Recently, racemic resolution to obtain single-enantiomer drugs has gotten more attention, including diastereomeric crystallization,9−11 preferential crystallization,12,13 chromatography,14,15 capillary electrophoresis,16,17 enantioselective liquid−liquid extraction (ELLE),4 and so on. Diastereomeric crystallization is a mature technology that is used for large-scale production of chiral drugs, but the operation is very complex and the yields are poor. Preferential crystallization has been used for the separation of the © XXXX American Chemical Society

enantiomers of racemic conglomerates on large and productive scales. The application of preferential crystallization would widen the potential of typically inexpensive crystallization-based techniques for enantioseparation. Although chromatography and capillary electrophoresis methods have high separation ability and can be widely used and scaled-up successfully, the high cost and low yield obstruct the application of both methods. ELLE, which integrates chiral separation and liquid−liquid extraction, is an attractive industrial technology to get single enantiomers from racemic mixtures in a continuous operation mode.18 The ELLE process has the advantages of easy scale-up, convenient and continuous operation, and low cost. In the ELLE process, the chiral extractant is the key factor. At present, cyclodextrins,19,20 tartaric acid derivatives,21−23 and crown ethers24,25 are considered as chiral extractants. Tartaric acid derivatives may be ideal among those mentioned above because of ease of obtainability and lower cost of industrialization for chiral resolution. The chiral recognition mechanism of ELLE follows the rule of “three-point interaction”.26 Under this rule, a molecule of the chiral extractant (L-tartaric acid derivative) can form different stable complexes with the two ibuprofen enantiomers by hydrogen-bonding, dipole−dipole, π−π, or other weak Received: March 31, 2014 Accepted: June 25, 2014

A

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intermolecular interactions.27 A deep understanding of this mechanism should be obtained in further studies to help experimental and industrial application. 2-(4-Isobutylphenyl)propionic acid (ibuprofen), one of the most effective and widely used nonsteroidal analgesic, antipyretic, and anti-inflammatory agents, belongs to the general category of 2-arylpropionic acids.28 The structure is shown in Figure 1. In the ibuprofen molecule, the α-carbon of

thrice with saturated sodium bicarbonate solution and twice with distilled water for p-toluenesulfonic acid removal. Drying to remove water and vacuum distillation to remove methylbenzene afforded the L-tartaric acid ester. To ensure its purity, the structure of each final product was checked by NMR and Fourier transform IR (FTIR) spectroscopy. 1H NMR data for L-tartaric acid dipentyl ester (600 MHz, DMSO): δ 4.51 (s, 2H), 4.23 (s, 4H), 3.24 (s, 2H), 1.68 (m, 4H), 1.34 (m, 8H), 0.90 (m, 6H). Enantioselective Liquid−Liquid Extraction Process. ELLE experiments were performed by contacting 10 mL of both aqueous and organic phases in a tapered bottle. The aqueous phase was a sodium phosphate buffer salt solution containing ibuprofen racemic mixture. The organic phase was one of the above-mentioned organic solvents containing the Ltartaric acid ester. The whole ELLE process was performed in a bath shaker with a thermostat for 30 min, and then the mixture was left to achieve equilibrium for (1 to 2) h. After extraction, no significant volume change was observed. The mixture was then transferred to a separatory funnel and allowed to settle for at least 30 min to obtain complete phase separation. The sample was obtained from the aqueous phase and filtered with a 0.45 μm water system filtering header to be analyzed by HPLC. All extraction experiments were carried out at least three times. For the ELLE process, the distribution coefficients (D) for the S and R enantiomers were calculated as follows:

Figure 1. Molecular structures of (a) ibuprofen and (b) L-tartaric acid dihexyl ester.

the carboxyl group is chiral. Pharmacological effect research shows that (S)-ibuprofen is 160 times more medically active than the R enantiomer. The side effects or toxicity, such as gastrointestinal problems, are often caused by the R enantiomer.29,30 Thus, it is necessary to find a simple and effective resolution method to get pure (S)-ibuprofen.31−33 In this work, L-tartaric acid ester derivatives were used as chiral extractants. The structure of one such derivative, Ltartaric acid dihexyl ester, is shown in Figure 1. ELLE of racemic ibuprofen enantiomers was experimentally studied. The chiral recognition mechanism of two ibuprofen enantiomers with L-tartaric acid esters was preliminarily investigated by density functional theory (DFT) using Gaussian 03.34 The influences of the type and concentration of L-tartaric acid ester, the type of organic solvent, and the pH of the aqueous phase on the ELLE process were experimentally studied.

DS =

CSorg CSaq

DR =

CRorg CRaq

org

(1)

(2) aq

where C and C denote the concentrations in the organic and aqueous phases, respectively. The enantioselectivity (α) was calculated as

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EXPERIMENTAL SECTION Materials. Ibuprofen racemic mixture and other reagents were of analytical grade and are listed in Table 1. The L-tartaric acid ester derivatives used in the ELLE process were synthesized in our laboratory by esterification between Ltartaric acid and the relevant alcohols with p-toluenesulfonic acid as the catalyst. Methylbenzene was used to dissolve the alcohol, and the temperature of the reaction was 140 °C. After cooling to room temperature, the reaction product was washed

α=

DR DS

(3)

Analytical Methods. The concentrations of the two ibuprofen enantiomers in the aqueous phase were determined by HPLC using a UV detector (SPD-20A, Shimadzu, Japan) at a wavelength of 220 nm. A Chiral-AGP column (100 mm × 4.6 mm × 5.0 μm) and a guard column (10 mm × 4.0 mm × 5.0 μm) from Daicel (Japan) were used. The mobile phase was 0.1

Table 1. Specifications for Chemicals Used

a

chemical name

source

initial mole fraction purity

purification method

final mole fraction purity

analysis method

ibuprofen L-tartaric acid p-toluenesulfonic acid n-hexane octane n-octyl alcohol n-decyl alcohol n-amyl alcohol n-hexanol methylbenzene n-hexane L-tartaric acid esters

TSKF GuangFu Fine Chemical YiLi Fine Chemical Beijing Chemical Works Beijing Chemical Works Beijing Chemical Works Beijing Chemical Works Beijing Chemical Works Beijing Chemical Works Beijing Chemical Works Beijing Chemical Works synthesis

0.99 0.99 0.99 0.99 0.99 0.99 0.99 0.99 0.99 0.99 0.99 0.99

none none none none none none none none none none none none

0.99 0.99 0.99 0.99 0.99 0.99 0.99 0.99 0.99 0.99 0.99 0.99

NMR,a FTIRb

Nuclear magnetic resonance spectroscopy. bFourier transform infrared spectroscopy. B

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mol·L−1 sodium phosphate buffer solution/methanol (98:2 v/ v) at a flow rate of 0.5 mL·min−1. The injection volume was 20 μL. The relative retention time of (R)-ibuprofen was about 8.4 min, and that of (S)-ibuprofen was about 11.2 min. The pH of the aqueous phase was measured with a pH meter (PXS-450, Shanghai Dapu Instruments Co., Ltd., China).

Table 2. Interactions between L-Tartaric Acid Dihexyl Ester and Ibuprofen Enantiomers single molecule or complex (S)-ibuprofen (R)-ibuprofen L-tartaric acid dihexyl ester (S)-ibuprofen/L-tartaric acid dihexyl ester complex (R)-ibuprofen/L-tartaric acid dihexyl ester complex

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RESULTS AND DISCUSSION Calculation Details. All of the calculations were performed using the Gaussian 03 program.32 L-Tartaric acid dihexyl ester was used as the host, and the two ibuprofen enantiomers were used as guests. The initial structures of the host and guests were constructed by using CS Chem3D Ultra. Each structure was fully optimized by DFT at the B3LYP/6-31G* level without any symmetry constraints. The optimized structures of the host and both guests are shown in Figure 2.

energy

BE

kJ·mol−1

kJ·mol−1

−1620898.944 −1620902.613 −2833124.489 −4454063.175

−39.74

−4454091.419

−64.32

complexation process is energetically favorable. Also, the BE of the (R)-ibuprofen/L-tartaric acid dihexyl ester complex (BER = −64.32 kJ·mol−1) is more negative than that of the (S)ibuprofen/L-tartaric acid dihexyl ester complex (BES = −39.74 kJ·mol−1), showing that the interaction of L-tartaric acid dihexyl ester with (R)-ibuprofen is stronger than that with (S)ibuprofen in the enantiomer complexes. The difference between the BEs for the two enantiomers (24.58 kJ·mol−1) represents the energetic contribution to the enantioselectivity. The optimized geometries of the inclusion complexes obtained by DFT calculations are presented in Figure 3. The

Figure 2. Molecular structures of the guests and host.

According to the molecular structures of the host and guests, two hydroxyls, two carbonyls and two ether groups exist in the L-tartaric acid dihexyl ester and one carboxyl group exists in the ibuprofen enantiomer. All of them can form hydrogen bonds, which would lead to chiral recognition interaction. The two hexyls in the L-tartaric acid dihexyl ester and the phenyl in the ibuprofen enantiomers can form steric hindrance, which makes the chiral recognition between L-tartaric acid dihexyl ester and the two ibuprofen enantiomers different. The analysis above was used as the basis for the construction of the initial enantiomer complexes. With the optimized host and guest structures, the models of the enantiomer complexes were built and optimized by DFT at the B3LYP/6-31G* level. All of the optimizations were performed in vacuo. The binding energy (BE) upon complexation between L-tartaric acid dihexyl ester and each ibuprofen enantiomer, which represents the strength of chiral recognition, was calculated for the minimumenergy structure as follows: BE = E(host−guest)opt − [E(host)opt + E(guest)opt ] opt

opt

Figure 3. Optimized geometries of the inclusion complexes: (left) (R)-ibuprofen/L-tartaric acid dihexyl ester; (right) (S)-ibuprofen/Ltartaric acid dihexyl ester.

binding geometries in the two complexes are both affected by host−guest O−H···O interactions. The distances and angles for the O−H···O interactions are less than 3.0 Å and greater than 90°, respectively. The results indicate that the process of chiral recognition between ibuprofen enantiomers and L-tartaric acid dihexyl ester mainly involves hydrogen-bonding interactions. As the number of hydrogen bonds in the (R)-ibuprofen/L-tartaric acid dihexyl ester complex is 2 times that in the (S)-ibuprofen/ L-tartaric acid dihexyl ester complex, the former complex is more stable than the latter. Influence of the Type of L-Tartaric Acid Ester on the ELLE Process. L-Tartaric acid esters with different alkyl chain lengths were synthesized and used as extractants. A sodium phosphate buffer solution containing 80 mg·L−1 ibuprofen racemic mixture at pH 2.5 was used as the aqueous solution. The organic phase was an octane solution containing 0.2 mol· L−1 L-tartaric acid ester. As shown in Table 3, DR is larger than DS for all of the extraction systems containing L-tartaric acid ester in the organic phase. This result indicates that all types of L-tartaric acid esters preferentially recognize (R)-ibuprofen. In the ELLE process, a discriminating force of chiral recognition exists between the two enantiomers with L-tartaric acid ester in

(4)

opt

where E(host−guest) , E(host) , and E(guest) represent the optimized energies of formation of the host−guest complex, free L-tartaric acid ester, and free guest, respectively. The structures of ibuprofen enantiomer/L-tartaric acid dihexyl ester complexes with the lowest binding energies were studied by DFT. The interaction of chiral recognition between the ibuprofen enantiomer and L-tartaric acid dihexyl ester becomes stronger as the magnitude of the BE increases, and the enantiomer complex is more stable. As listed in Table 2, the BEs of the (R)-ibuprofen/L-tartaric acid dihexyl ester and (S)-ibuprofen/L-tartaric acid dihexyl ester complexes are both negative, indicating that both ibuprofen enantiomers can form complexes with L-tartaric acid dihexyl ester and that the C

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Table 3. LLE Data for {(R)-Ibuprofen (1) + (S)-Ibuprofen (2) + L-Tartaric Acid Ester (3) + n-Octane (4)} Systems at pH 2.5, T = 298.15 K, and p = 0.1 MPa Along with Distribution Factors (D) and Enantioselectivities (α)a Caq 1 type of ester dibutyl diisobutyl dipentyl diisopentyl dihexyl dioctyl a

Caq 2 −1

Corg 1 −1

mg·L

mg·L

6.40 5.47 5.37 5.16 5.12 4.85

7.08 5.98 6.17 5.75 5.59 5.47

Corg 2

−1

mg·L

mg·L−1

DR

DS

α

32.92 34.02 33.83 34.25 34.41 34.53

5.25 6.32 6.45 6.75 6.82 7.25

4.65 5.69 5.49 5.96 6.15 6.31

1.129 1.111 1.175 1.133 1.109 1.149

33.60 34.53 34.63 34.84 34.88 35.15

Standard uncertainties u are u(T) = 0.2 K, u(pH) = 0.01, and u(p) = 5 kPa, and the combined standard uncertainty is uc(x) = 0.0013.

the organic phase, which leads to the difference in the distribution coefficients. According to the chiral recognition mechanism31 and the above results of the theoretical calculations, the two enantiomers form complexes with L-tartaric acid ester by hydrogen bonding. However, the stabilities of the two complexes are different because of the steric effect: the complex of (R)-ibuprofen and L-tartaric acid ester is more stable than that of S form. The ELLE process is a competitive extraction process, and the distribution coefficient of (R)-ibuprofen (DR) was larger than that of (S)-ibuprofen (DS). The experimental results are in accordance with the calculated results. It was found that among the L-tartaric acid esters with different alkyl chain lengths, L-tartaric acid dipentyl ester had the strongest recognition ability and the highest enantioselectivity. Influence of L-Tartaric Acid Ester Concentration on the Extraction Resolution. In a competitive extraction process, the concentrations of the host and guest molecules should influence the results of the extraction resolution. The influence of the L-tartaric acid dipentyl ester concentration was investigated. The aqueous phase was a sodium phosphate buffer solution containing 80 mg·L−1 ibuprofen racemic mixture at pH 2.5. The organic phases were octane solutions containing different concentrations of L-tartaric acid dipentyl ester. As shown in Figure 4 and Table 4, the distribution coefficient increases with increasing L-tartaric acid dipentyl ester concentration. As the stabilities of the complexes formed by the chiral resolving agent L-tartaric acid dipentyl ester and the ibuprofen enantiomers are different, the ibuprofen enantiomers are selectively extracted to the organic phase, and the distribution coefficient can be improved by increasing the Ltartaric acid dipentyl ester concentration. When the concentration of the chiral extractant is low, (R)-ibuprofen can be preferentially extracted from the organic phase, as the distribution coefficient of (R)-ibuprofen is bigger than that of (S)-ibuprofen because of the competitive extraction. This result shows that two enantiomers can be separated. However, with increasing L-tartaric acid dipentyl ester concentration, the two ibuprofen enantiomers are extracted to the organic phase to the same degree. The performance of competitive extraction disappears, which results in the decrease in the separation factor. Influence of the Organic Solvent on the Extraction Resolution. In the ELLE process, the type of organic solvent can affect the stability of the diastereomeric compounds formed from the chiral compounds and the chiral extractant. The influence of the organic solvent type on the ELLE process was studied. The organic phases were various organic solvents containing 0.2 mol·L−1 L-tartaric acid dipentyl ester. The

Figure 4. Influence of the concentration of L-tartaric acid dipentyl ester on the distribution coefficient D and separation factor α for ibuprofen enantiomers.

Table 4. LLE Data for {(R)-Ibuprofen (1) + (S)-Ibuprofen (2) + L-Tartaric Acid Dipentyl Ester (3) + n-Octane (4)} Systems at pH 2.5, T = 298.15 K, and p = 0.1 MPa Along with Distribution Factors (D) and Enantioselectivities (α)a Cester mol·L

−1

0.00 0.05 0.10 0.15 0.20 0.25 0.30

Caq 1

Caq 2 −1

mg·L

12.05 9.88 7.81 6.65 5.37 5.12 4.64

mg·L

Corg 1 −1

12.08 10.02 8.14 7.32 6.17 5.53 4.93

−1

mg·L

27.95 30.12 32.19 33.35 34.63 34.88 35.36

Corg 2 mg·L−1

DR

DS

α

27.92 29.98 31.86 32.68 33.83 34.47 35.07

2.32 3.05 4.12 5.02 6.45 6.82 7.62

2.31 2.99 3.91 4.46 5.49 6.23 7.11

1.004 1.019 1.054 1.124 1.175 1.094 1.071

a Standard uncertainties u are u(T) = 0.2 K, u(pH) = 0.01, and u(p) = 5 kPa, and the combined standard uncertainty is uc(x) = 0.0015.

aqueous phase was a sodium phosphate buffer solution containing 80 mg·L−1 ibuprofen racemic mixture at pH 2.5. The type of organic solvent has a significant influence on the ELLE process. In Table 5, polar solvents have higher extraction distribution coefficients than nonpolar ones, which accords with the theory of similarity and intermiscibility. Alcohols used as D

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Table 5. LLE Data for {(R)-Ibuprofen (1) + (S)-Ibuprofen (2) + L-Tartaric Acid Dipentyl Ester (3) + Solvent (4)} Systems at pH 2.5, 0.2 mol·L−1 L-Tartaric Acid Dipentyl Ester in the Organic Phase, T = 298.15 K, and p = 0.1 MPa Along with Distribution Factors (D) and Enantioselectivities (α)a Caq 1 organic solvent n-octanol n-decanol 1,2-dichloroethane n-heptane n-octane a

Caq 2 −1

Corg 1 −1

mg·L

mg·L

1.27 1.02 1.86 5.68 5.37

1.52 1.24 2.16 6.23 6.17

mg·L

Corg 2

−1

38.73 38.98 38.14 34.32 34.63

mg·L−1

DR

DS

α

38.48 38.76 37.84 33.77 33.83

30.53 28.23 20.53 6.04 6.45

25.29 31.23 17.56 5.42 5.49

1.207 1.224 1.169 1.114 1.175

Standard uncertainties u are u(T) = 0.2 K, u(pH) = 0.01, and u(p) = 5 kPa, and the combined standard uncertainty is uc(x) = 0.0013.

the organic solvent have higher separation factors because of their hydroxyl group, which can affect the bonding interactions participating in the formation of the diastereomeric compounds. When decanol was used as the solvent, the separation factor was as high as 1.224. Influence of the pH of the Aqueous Phase on the Extraction Resolution. Ibuprofen has a carboxyl group, which can ionize hydrogen ions. The pH of the aqueous phase should therefore have an effect on the molecular content, which would lead to a change in the distribution coefficient of ibuprofen and consequently affect the separation factor. Thus, the influence of pH on the distribution behavior of ibuprofen enantiomers in the aqueous phase was investigated. As shown in Figure 5 and

Table 6. LLE Data for {(R)-Ibuprofen (1) + (S)-Ibuprofen (2) + L-Tartaric Acid Dipentyl Ester (3) + n-Octane (4)} Systems at T = 298.15 K, p = 0.1 MPa, and Various pH Values Along with Distribution Factors (D) and Enantioselectivities (α)a Caq 1

Caq 2

Corg 1

Corg 2

pH

mg·L−1

mg·L−1

mg·L−1

mg·L−1

DR

DS

α

2.5 4.0 5.5 7.0

5.37 6.20 12.84 19.49

6.17 6.72 13.07 19.68

34.63 33.80 27.16 20.51

33.83 33.28 26.93 20.32

6.45 5.45 2.12 1.05

5.49 4.95 2.06 1.03

1.175 1.100 1.026 1.019

a

Standard uncertainties u are u(T) = 0.2 K and u(p) = 5 kPa, and the combined standard uncertainty is uc(x) = 0.0012.

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CONCLUSIONS The enantioselective liquid−liquid extraction of ibuprofen enantiomers with L-tartaric acid ester derivatives was calculated theoretically and experimentally validated. The interaction of Ltartaric acid esters with (R)-ibuprofen is much stronger than that with (S)-ibuprofen. L-Tartaric acid dipentyl ester was the best chiral extractant for racemic ibuprofen because of the steric effect. The optimum concentration was 0.2 mol·L−1. The distribution coefficient and separation factor were much better with polar organic solvents at low pH. The maximum enantioselectivity of racemic ibuprofen enantiomers was 1.224 using n-decanol as the solvent. The experimental results show that ELLE of ibuprofen enantiomers is a promising alternative method.

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AUTHOR INFORMATION

Corresponding Author

*Tel: +86-10-6442-3628. Fax: +86-10-6442-3628. E-mail: [email protected]. Funding

Figure 5. Influence of pH on the distribution coefficient D and separation factor α.

This work was supported by the National Natural Science Foundation of China (21076011 and 21276012) and the Program for New Century Excellent Talents in University (NCET-10-0210). The authors gratefully acknowledge these grants.

Table 6, the distribution coefficients of ibuprofen enantiomers

Notes

decrease with increasing pH, mainly because the amounts of

The authors declare no competing financial interest.

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ibuprofen ions rise. The ibuprofen molecule mainly exists at low pH, while the ibuprofen carboxylate ions mainly emerge at

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