Enantioselective transport of L-propranolol through a bulk liquid membrane containing complex of(S, S)-di-n-dodecyltartrate and boric acid

F. P. Jiao^1,2, X. Q. Chen¹, Z. Wang and Y. H. Hu²

¹ School of Chemistry & Chemical Engineering,
² School of Minerals Processing & Bioengineering, Central South University, Changsha 410083, China
jiaofp@163.com

Abstract — A method of bulk liquid membrane using complex of (S, S)-di-n-dodecyltartrate and boric acid was developed for the enantioselective transport of racemic propranolol. It was shown that l - propranolol can be effectively transported. The enantioselectivity of the complex for a specific propranolol enantiomer in BLM systems is mainly based on kinetics and is not thermodynamically driven. The effects of the concentration ratio of propranolol to chiral carrier and the buffer pH were studied, respectively. An appropriate choice for such concentration ratio and the pH in the aqueous solution result to be 1 : 20 and 5, respectively. The developed method is helpful for optimizing the transport of bulk liquid membrane systems and realizing the large-scale production of pure enantiomer.

Keywords — Bulk Liquid Membrane. Enantioselective Transport. Propranolol. Complex of (S, S)-di-n-dodecyltartrate. Boric Acid.

I. INTRODUCTION

Liquid membranes are liquid phases, existing in either supported or unsupported form, serving as selective barriers between liquid or gas phases, and have shown great potential for use in chiral separations (Way et al., 1982). Bulk liquid membrane (BLM) is one of the types of liquid membranes (Ma et al., 2002, León and Guzmán, 2005). In a BLM, a relatively thick layer of immiscible fluid is used to separate the feed and strip phases; there is no means of support for the membrane phase and it is kept apart from the external phases only by means of its immiscibility. A recent development in liquid membranes is the incorporation of selective carriers within the liquid membrane phase, facilitating chemically the transport of a specific compound across the membrane. With chiral carriers, it is possible to stereoselectively transport optical isomers (Huang et al., 2006; Jiao et al., 2006; 2007a; 2007b). The type of chiral carrier is evidently a very important parameter when designing an experiment.

For resolution of racemic mixtures it is necessary to design and synthesize specific carriers with ability to recognize selectively the desired enantiomer. Hydrophobic (R, R)- and (S, S)-di-n-dodecyltartrate (DDT) have shown to have the property of forming a non polar organic soluble complex with boric acid, preferentially with the corresponding enantiomer of propranolol (PPL), which belongs to the family of β-blocker and served as a model in this study (Coelhoso et al., 2000). The recognition mechanism of PPL is graphically sketched in Fig. 1. The chiral carrier diffuses from the BLM phase to the feed-membrane interface, where ions PPL⁺ are exchanged for H⁺. Due to the high interfacial reactivity of DDT, a tetrahedral complex between the enantiomer of PPL, boric acid and DDT is formed. The formed complex diffuses through the membrane to the membrane-product interface, where, by reversing the described reaction, H⁺ ions are exchanged for PPL⁺ ones, which are released into the product phase. Though the presence of boric acid in the product phase, because the concentration of the PPL enantiomer in the product phase is very low, the reversibility of the transport process is very weak or impossible. So the chiral carrier is regenerated, thus beginning a new separation cycle. The enantioselective transport of l-PPL through a BLM containing complex of DDT and boric acid is illustrated in Fig. 2.

No further discussion on the enantioselective transport PPL enantiomer by complex of DDT and boric acid, through a BLM, has been carried out (Ferreira et al., 2006). Based on previous results (Coelhoso et al., 2000), this work presents more extensive results on the resolution method of BLM. The influence of the buffer pH and the concentration ratio of DDT to PPL were in particular investigated.

Fig. 1. Enantioselective association of l-PPL with DDT by formation of a borate.

Fig. 2. Coupled transport mechanism for the extraction and re-extraction of PPL in a BLM with a complex of DDT and boric acid

II. MATERIALS AND METHODS

A. Chemicals

Racemic PPL was obtained from ACROS ORGANICS (USA). DDT (FT-IR spectra given in Fig. 3) with a purity higher than 98% was prepared in our laboratory from (S, S)-tartaric acid and n-dodecanol using benzene sulfonic acid as a catalyst (Heldin et al., 1991). All chemicals were of analytical reagent grade.

B. Analysis

Chiral capillary zone electrophoresis was performed using a P/ACE MDQ system equipped with a diode array detection system (Beckman Coulter, Fullerton, CA, USA). The system was computer-controlled, with an integrated P/ACE Station Software (32 Karat TM Version 7.0) package. The dimensions of the capillary were 60.2 cm × 50 μm i.d. with the detection window at the distance of 10 cm from the capillary outlet. The injection mode was hydrodynamic (5 s, 0.3 Pa pressure). Efficient chiral separation was achieved with 17 mmol/l HP-β-CD in 50 mmol/l Na₂HPO₄/ H₃PO₄ buffer pH 3, operated at 24 kV (20 ± 0.1 °C) and detection wavelength of 210 nm. The d-PPL was found to migrate first in the buffer system (Fig. 4) (Chetana et al., 1998).

C. Procedure

The experimental studies were carried out applying the BLM technique (Fig. 5) (León and Guzmán, 2005). The left aqueous feed solutions (40 ml) consisted of PPL of different concentration and 100 mmol/l H₃BO₃ solution. The strip solution (40 ml), which consisted of a 100 mmol/l H₃BO₃ solution, was located in the right part of the vessel. The organic membrane phase (160 ml), prepared by dissolving DDT of different concentration in chloroform, was added under the water phases. The contact area between the feed and the membrane and the membrane and the strip phases of the single BLM system were all 3.14 cm². The experiments were carried out at 25°C by using a thermostated apparatus. The desired pH in the aqueous solution were adjusted using a NaH₂PO₄-NaOH solution. pH measurements were made with a pH meter using a combined glass electrode. The feed solution, the membrane phase and the strip solution were stirred at 300 rpm.

Fig. 3. FTIR spectra of DDT

Fig. 4. Resolution of PPL by capillary zone electrophoresis

The average flux (J) of each enantiomer was calculated by (León and Guzmán, 2005):

(1)

where t is the time over which the concentration difference, ΔCs, is measured in the strip, Vs is the strip volume and A is the effective membrane area. This quantity represents the average flux from the start of the experiment till time t. The enantioselectivity was calculated in terms of the separation factor (α) and the percentage enantiomeric excess (ee, %):

(2)

Fig. 5. Transport cell of bulk liquid membrane

(3)

III. RESULTS AND DISCUSSON

A. Variation of separation factor with transport time

The variation of enantioselectivity over transport time for the BLM was studied at pH 5, the concentration ratio of PPL to DDT of 1:20 and the concentration of 100 mmol/l DDT (Fig. 6). The separation factor decreases sharply during the initial induction period, then begins to decrease slowly and approximately equals 1. This means that any enantioselectivity of complex of DDT and H₃BO₃ for a specific PPL enantiomer in the BLM system is mainly due to kinetics and it is not thermodynamically driven. This suggests that the complexation reaction is slow and that it is unlikely to occur unless the driving force, i.e. the concentration gradient, remains strong enough. There is a bigger concentration gradient across the membrane between the feed and strip phases when the transport is in the initial induction period. The separation factor decreases with the decreasing concentration gradient; when the equilibrium is reached between the feed and the strip phases, which would occur as both the feed and strip phases have the same PPL concentration, then the separation factor approximately equals 1 and the transport process will come to an end.

Fig. 6. Variation of the separation factor with time for PPL

B. Influence of the concentration ratio of PPL to DDT on flux and enantioselectivity

The influence of the concentration ratio of PPL to DDT on flux and enantioselectivity was studied at pH 5 and PPL concentration of 5 mmol/l (Table 1). The l form enantiomer, comparing to the d form, had a slightly higher flux. This means that the complex preferentially recognizes the l-PPL enantiomer with respect to the d form. The flux and enantioselctivity decrease with transport time in the experiment. This is probably due to the loss of chiral carrier from the liquid membrane, leading to reduced enantioselectivities and lower fluxes owing to facilitated transport. The flux and enantioselctivity increase with the variation of the concentration ratio of PPL to DDT from 1:10 to 1:40. This was expected, as more carrier was available with the variation of the concentration ratio, thus increasing the transport rate of both enantiomers. The further variation of concentration ratio did not significantly affect the enantioselectivity. This would imply that the same amount of chiral carrier would perform the required upgrading of the racemic mixture regardless of the initial concentration, thereby minimizing the amount and hence the cost of chiral carrier required for the process. However, the time required to achieve the extraction equilibrium increases with a variation in concentration ratio. In order to obtain a higher enantioselective extraction rate in all the extraction processes, the concentration ratio of 1:20 was selected as the best experimental conditions.

C. Influence of pH in queous phase on flux and enantioselectivity

The influence of pH in aqueous solutions on flux and enantioselectivity was studied at the concentration ratio of PPL to DDT of 1:20 and a concentration of DDT of 100 mmol/l (Table 2). The racemic PPL mixture in aqueous phase and DDT carrier in chloroform have shown a strong dependence of the enantioselectivity with the pH of the aqueous phase. By lowering the pH the concentration of H⁺ ions increases; then, the PPL is easily displaced for its charged form, which favours the selective extraction and re-extraction between the two phases, thus increasing the enantioselectivity. By increasing the pH, the uncharged form of PPL is favoured and thus the non-selective transport of PPL by simple partition between the two phases is enhanced, increasing the flux and decreasing the enantioselectivity of the process. For this reason the choice of pH 5 in aqueous solutions was found to be appropriate.

IV. CONCLUSIONS

Liquid membranes are a unique tool for selective transport of desired solutes from complex mixtures. The industrial future of liquid membranes will depend very strongly on the ability to design and synthesize selective carriers or receptors with the potential to achieve recognition of individual solutes. Therefore, the trend will be the development of supramolecular chemistry with the aim of obtaining very selective carriers, in some cases with the ability for chiral recognition.

Table 1 Effect of concentration ratio of PPL to DDT in the organic phase on flow J (×10³ mol•cm^-2 •h⁻¹) and enantioselectivity

Table 2 Effect of pH on flow J (×10³ mol•cm^-2• h⁻¹) and enantioselectivity for PPL

In this work a complex of DDT and boric acid was used as chiral carriers for the enantioselective transport of racemic PPL. It was shown that l-PPL can be effectively transported. This paper discussed the variation of the separation factor with transport time, which indicates that any enantioselectivity of complex of DDT and H₃BO₃ for a specific PPL enantiomer in BLM systems is mainly based on the kinetics and is not thermodynamically driven. This paper also discussed the influence of the concentration ratio of PPL to DDT on flux and enantioselectivity and the influence of pH in the aqueous phase on flux and enantioselectivity, leading to the choice of a concentration ratio of 1:20 and pH 5 in aqueous solutions as the best experimental conditions.

ACKNOWLEDGEMENTS
We wish to acknowledge the support given to this work by the National Natural Science Foundation of China (project No. 20776162) and by the Postdoctoral Science Foundation of Central South University.

REFERENCES
1. Chetana, P., J.M. Philip and D.C. Peter, "Enantiomeric separation of propranolol and selected metabolites by using capillary electrophoresis with hydroxypropyl-β-cyclodextrin as chiral selector" J. Chromatogr. A, 793, 357-364 (1998).         [ Links ]
2. Coelhoso, I.M., M.M. Cardoso and R.M.C. Viegas, "Transport mechanisms and modelling in liquid membrane Contactors", Sep. Purif. Technol., 19, 183-197 (2000).         [ Links ]
3. Ferreira, Q., I.M. Coelhoso and N. Ramalhete, "Resolution of Racemic Propranolol in Liquid Membranes Containing TA-β-cyclodextrin" Sep. Sci. Technol., 41, 3553-3568 (2006).         [ Links ]
4. Jiao, F.P., K.L. Huang and F.R. Ning, "Chromatographic separation of naproxen enantiomers using hydroxypropyl-β-cyclodextrin as chiral mobile phase additive", Sep. Sci. Technol., 41, 1893-1906 (2006).         [ Links ]
5. Jiao, F.P., X.Q. Chen and W.G. Hu, "Enantioselective extraction of mandelic acid enantiomers by L-dipentyl tartrate and β-cyclodextrin as binary chiral selectors", Chem. Pap.-Chem. Zvesti., 61, 326-328 (2007a).         [ Links ]
6. Jiao, F.P., X.Q. Chen and W.G. Hu, "Enantioselective Transport of R-Clenbuterol through a Bulk Liquid Membrane containing O,O'-Dibenzoyl-(2S, 3S)-tartaric acid", J. Braz. Chem. Soc., 18, 804-809 (2007b).         [ Links ]
7. Heldin, E., K.J. Lindner and C. Petterson, "Tartaric acid derivatives as chiral selectors in liquid chromatography", Chromatographia, 32, 407-416 (1991).         [ Links ]
8. Huang, K., F. Jiao and S. Liu, "Enantioselective extraction of ketoprofen enantiomers using ester alcohol R, R-di-tartarates or S, S-di-tartarates as chiral selector", Lat. Am. Appl. Res., 36, 187-191 (2006).         [ Links ]
9. León, G. and M.A. Guzmán, "Kinetic study of the effect of carrier and stripping agentconcentrations on the facilitated transport of cobalt through bulk liquid membranes", Desalination, 184, 79-87 (2005).         [ Links ]
10. Ma, M., D.S. He and S.H. Liao, "Kinetic study of l-isoleucine transport through a liquid membrane containing di (2-ethylhexyl) phosphoric acid in kerosene" Anal. Chim. Acta., 456, 157-165 (2002).         [ Links ]
11. Way, J.D., R.D. Noble and T.M. Flynn, "Liquid membrane transport: a survey", J. Membr. Sci., 12, 239-259 (1982).         [ Links ]

Received: July 25, 2007.
Accepted: November 10, 2007.
Recommended by Subject Editor Walter Ambrosini.