Enantioselective extraction of phenylsuccinic acid in aqueous two-phase systems based on acetone and β-cyclodextrin derivative: Modeling and optimization through response surface methodology

Highlights

• Novel ATPS composed of acetone and β-CD derivative was developed.

• β-CD derivative simultaneously serves as phase-forming agent and chiral selector.

• The calculated TLs data were successfully correlated by several empirical equations.

• Enantioselective extraction conditions for rac-PSA were rapidly and accurately optimized using RSM.

Abstract

A novel aqueous two-phase system (ATPS) composed of β-cyclodextrin (β-CD) derivative and acetone was developed for enantioselective extraction of racemic phenylsuccinic acid (PSA). Binodal curves, tie-lines, and critical points for the investigated ATPS were determined and the experimental tie-lines data were successfully correlated by Othmer-Tobias, Bancroft, and Setschenow-type equations. ATPS containing sulfobutyl ether-β-CD (SBE-β-CD) exhibited better enantioselectivity than that using carboxymethyl-β-CD (CM-β-CD). To optimize enantioselective partitioning conditions of PSA in acetone/SBE-β-CD ATPS, three factors (PSA concentration, pH, and equilibrium temperature) were analyzed by using central composite design in response surface methodology. The calculated equilibrium constants of inclusion complexation are 1638.64 M⁻¹ for SBE-β-CD-(R)-PSA and 835.84 M⁻¹ for SBE-β-CD-(S)-PSA, respectively. Under the optimized conditions, the separation factor of 3.14 and high enrichment efficiency (E_R = 98.06%, E_S = 99.25%) were simultaneously achieved in a single step.

Introduction

Due to more strict regulations for pharmaceutical products, the share of drug containing only single enantiomer has grown dramatically in the past decades [1]. Two different approaches including asymmetric synthesis and enantioseparation of racemates have been well established to produce enantiopure compounds [2]. Among enantioseparation methods, enantioselective liquid-liquid extraction (ELLE) is considered to be a promising process because of its ease of scaling up [3]. Furthermore, another strength of ELLE is that a very high selectivity is not required, but with a moderate selectivity using a multistage process high purity can still be obtained. Nevertheless, the use of a large amount of organic solvent as a single phase might cause the environmental concern. As a result, there is an ongoing search for more environmentally benign extraction systems.

Aqueous two-phase systems (ATPS) can be foreseen as a greener alternative to the traditional organic solvent-water extraction system since their two phases possess a water-rich environment [4]. The utilization of ATPS in enantioseparation was first proposed by Sellergren [5], thereafter, only a limited number of studies have been reported [6], [7], [8], [9], [10]. The realization of chiral recognition for enantiomers in these ATPS merely relied on the introduction of auxiliary chiral selector and the enantioseparation efficiency was still unsatisfactory. Recently, chiral ionic liquid, which simultaneously serves as phase-forming agent and chiral selector, was successfully applied for enantioseparation [11], [12]. Inspired by this encouraging work, we were devoted to developing the novel ATPS by employing the phase-forming agent possessing dual function as chiral selector.

To date, β-cyclodextrin (β-CD) and its derivatives have emerged to be the most widely used chiral selector for resolution of various enantiomers [13], [14], [15]. The formation of inclusion complexes and weak intermolecular forces between analytes and substituted groups cooperatively contribute to their chiral recognition ability. In addition, β-CD derivatives have an enhanced ability to be hydrated due to the existence of large amounts of hydrophilic groups, thus, potentially acting as phase-forming agent in ATPS. On the other hand, acetone is an organic solvent with excellent solvability for numerous organic substances, and miscible with water in the whole composition range. More importantly, acetone has a lower boiling point than water, which leads to the easy recovery. Herein four highly water-soluble β-CD derivatives (methyl-, hydroxypropyl-, carboxymethyl-, and sulfobutyl ether-β-CD) were employed as new phase-forming agent and chiral selector simultaneously to construct ATPS with acetone. And the potential of the proposed ATPS was evaluated using racemic phenylsuccinic acid (PSA, Fig. S1) as a target.

In the conventional optimization process, there is a variation of only one parameter at a time, keeping the other parameters at constant level, and thus, the interactions among various parameters may be ignored. Response surface methodology (RSM) [16] includes useful statistical and mathematical methods for the test of process parameters and their reciprocal interaction. By means of the empirical statistics analysis, RSM not only greatly reduces the number of experimental trials, but also generates a mathematical model to quantify the relationship between the controllable parameters and the responses. Therefore, in this work, RSM was adopted to effectively optimize the parameters for enantioselective extraction of PSA.