Experimental and Model Studies on Continuous Separation of 2‐Phenylpropionic Acid Enantiomers by Enantioselective Liquid–Liquid Extraction in Centrifugal Contactor Separators

Abstract

Multistage enantioselective liquid-liquid extraction (ELLE) of 2-phenylpropionic acid (2-PPA) enantiomers using hydroxypropyl-β-cyclodextrin (HP-β-CD) as extractant was studied experimentally in a counter-current cascade of centrifugal contactor separators (CCSs). Performance of the process was evaluated by purity (enantiomeric excess, ee) and yield (Y). A multistage equilibrium model was established on the basis of single-stage model for chiral extraction of 2-PPA enantiomers and the law of mass conservation. A series of experiments on the extract phase/washing phase ratio (W/O ratio), extractant concentration, the pH value of aqueous phase, and the number of stages was conducted to verify the multistage equilibrium model. It was found that model predictions were in good agreement with the experimental results. The model was applied to predict and optimize the symmetrical separation of 2-PPA enantiomers. The optimal conditions for symmetric separation involves a W/O ratio of 0.6, pH of 2.5, and HP-β-CD concentration of 0.1 mol L(-1) at a temperature of 278 K, where eeeq (equal enantiomeric excess) can reach up to 37% and Yeq (equal yield) to 69%. By simulation and optimization, the minimum number of stages was evaluated at 98 and 106 for eeeq > 95% and eeeq > 97%.

Advances and applications of chiral resolution in pharmaceutical field

“…In addition, the principles of extraction can be classified into three kinds of mechanisms: (1) Complexing extraction separation; (2) Diastereomer‐forming extraction separation; (3) Affinity extraction. More discussions can be seen in previous studies 139–141 …”

“…Based on existing researches, the operational selectivity in one extraction step can be optimized by adjusting the type and volume of the solvents, chiral selector concentration, extraction time, type of buffer, organic solvent, the temperature of the sample solution, and pH. 133,142 Among them, the three mechanisms mentioned above are used to study and establish the process of optimization and prediction of enantiomeric distribution behavior and separation efficiency, 137,140,143 but the clear-out dependency is remained to be expounded clearly. Liquid-liquid extraction is a mature technology which can be easily operated in the multistage countercurrent process approach.…”

Liquid‐Liquid Centrifugal Extractors: Types and Recent Applications – a Review

“…Other enantioselective extractions were researched as well on CINC device, where the enantiomers of oxybutynin [112], metoprolol [113], terbutaline [114], and 2-phenylpropionic acid [115] were separated. Also using ACCs but without specifying which type, reported literature studied the separation of the enantiomers of phenylsuccinic acid [116], ketoconazole [117], amino-(4-nitro-phenyl)-acetic acid [118], 4-nitro-D,Lphenylalanine [119], α-Cyclohexyl-mandelic Acid [120], and pantoprazole [121].…”

Recent Development: Enantio Selective Eextraction in Chiral Separation

“…Fractional reactive extraction for separation of 4-Nitro-D,Lphenylalanine in centrifugal contactor separators was studied by Tang et al [26] study on enantioselective reactive extraction of p-hydroxyphenylglycine enantiomers with metal phosphine complexes was done by Tang et al [27]. Reactive extraction of L-valine using di(2-ethylhexyl) phosphate acid as chiral selector was done by Li et al [28].…”