Biphasic Recognition Chiral Extraction Research Articles

Enhancement of separation performance for ofloxacin enantiomers by a biphasic recognition chiral extraction system

AbstractDespite greatly improved separation performance towards many mixtures, utilizing biphasic recognition chiral extraction (BRCE) systems in enantiomer separation remains challenging due to inadequate comprehension of chiral recognition and biphasic synergism mechanisms. In this work, using ofloxacin enantiomers as a case study, separation performance of BRCE system is systematically examined from experimental and theoretical aspects. The BRCE system, comprising di‐p‐toluoyl‐l‐tartaric acid and β‐cyclodextrin as hydrophobic and hydrophilic selectors, achieves maximum enantioselectivity and enantiomeric excess values of 2.4 and 26% under optimal conditions. Five‐stage counter‐current extraction and reverse extraction significantly improve the enantiomeric excess value up to 91%. Molecular simulations reveal that to construct an enhanced BRCE system, two chiral selectors should have opposite recognition abilities for target enantiomers and weak interactions between themselves. This work provides guidance on selecting suitable selectors for construction of an enhanced BRCE system not only for separating ofloxacin enantiomers but also other enantiomers.

Deep-eutectic solvents simultaneously used as the phase-forming components and chiral selectors for enantioselective liquid-liquid extraction of tryptophan enantiomers

Two-phase system was widely used for the enantioselective liquid-liquid extraction (ELLE) of various enantiomers. The organic solvents are generally used as the extractants, moreover, the additional chiral selectors should be added to the extraction system. In this study, a biphasic recognition chiral extraction (BRCE) system based on hydrophilic and hydrophobic DESs was developed for the ELLE of tryptophan enantiomers. DESs can be simultaneously used as the phase-forming components and chiral selectors. The hydrophobic/hydrophilic methyl trioctyl ammonium chloride- L(+)-Diethyl L-tartrate/HP-β-CD-L-(−)-Malic Acid (MTAC-DE/HC-MA) system was screened as the optimal extraction system. The molar ratios of hydrogen-bond acceptor (HBA) and hydrogen-bond donor (HBD) in DESs were optimized for the enantioseparation. The other factors of phase volume ratio, initial tryptophan concentration, pH value, and extraction temperature were studied. The maximum enantiomeric excess (e.e.) value of 38.46% was obtained under the optimal conditions by one-step extraction. This BRCE system used for the chiral separation of tryptophan enantiomers has the advantages of environmental friendliness, simple operation, and high efficiency, which has the practical application potentiality in the continuous enantioseparation process.

Biphasic recognition chiral extraction of threonine enantiomers in a two-phase system formed by hydrophobic and hydrophilic deep-eutectic solvents

Recently, deep-eutectic solvents (DESs) were considered as excellent substitutes for conventional organic solvents and ionic liquids (ILs) used in the extraction field. Therefore, the biphasic recognition chiral extraction (BRCE) systems formed by hydrophilic and hydrophobic DESs were developed for the enantioseparation of threonine enantiomers in this study. The chiral selectors of (+)-Diisopropyl L-tartrate (DIPT) and Hydroxylpropyl-β-cyclodextrin (HP-β-CD) were added to the hydrophobic phase and the hydrophilic phase, respectively. The factors influencing the chiral separation effect were investigated, including type of DESs, phase volume ratio, water content in BRCE, chiral selectors concentration, initial threonine concentration, system pH, and extraction temperature. The two-phase system of (−)-Menthol-L(+)-Lactic acid/Choline chloride-Urea (M−LA/ChCl-U) was screened as the optimum BRCE system. The maximum enantiomeric excess (e.e.) value of 31.6% was obtained under the optimized conditions. The enantioseparation of threonine enantiomers can be achieved by a single step extraction, and thus this BRCE based on DESs is simple, efficient, and environmentally friendly.

Equilibrium study on enantioselective distribution of amlodipine besilate enantiomers in a biphasic recognition chiral extraction system

The objective of this paper is to present the enantioselective distribution of amlodipine besilate enantiomers (ADB) in a biphasic recognition chiral extraction (BRCE) system. In the BRCE system, hydrophobic tartrate was added in organic phase and hydrophilic β-cyclodextrins in aqueous phase. Tartrate and β-cyclodextrins preferentially recognize (−)-ADB and (+)-ADB, respectively. Impacts of the type and concentration of chiral selectors, the pH value of the aqueous phase solution as well as temperature on the separation efficiency were investigated. Sulfobutyl ether-β-cyclodextrin (SBE-β-CD) and d-isobutyl tartrate (d-IBTA) were found to be the most suitable chiral selectors. By substituting the monophasic recognition chiral extraction (MRCE, with chiral selector in only one phase) system with BRCE system, the distribution ratios of the ADB enantiomers are remarkably increased with a little increase of enantioselectivity. The optimized conditions that are 5 °C of temperature, 7.2 of pH value, 0.05 mol/L of SBE-β-CD as well as 0.1 mol/L of d-IBTA are identified. The experimental results demonstrated that BRCE with strong chiral separation ability possesses good prospect in separation of enantiomers.

Enantioseparation of Racemic Flurbiprofen by Aqueous Two-Phase Extraction With Binary Chiral Selectors of L-dioctyl Tartrate and L-tryptophan.

A novel method for chiral separation of flurbiprofen enantiomers was developed using aqueous two-phase extraction (ATPE) coupled with biphasic recognition chiral extraction (BRCE). An aqueous two-phase system (ATPS) was used as an extracting solvent which was composed of ethanol (35.0% w/w) and ammonium sulfate (18.0% w/w). The chiral selectors in ATPS for BRCE consideration were L-dioctyl tartrate and L-tryptophan, which were screened from amino acids, β-cyclodextrin derivatives, and L-tartrate esters. Factors such as the amounts of L-dioctyl tartrate and L-tryptophan, pH, flurbiprofen concentration, and the operation temperature were investigated in terms of chiral separation of flurbiprofen enantiomers. The optimum conditions were as follows: L-dioctyl tartrate, 80 mg; L-tryptophan, 40 mg; pH, 4.0; flurbiprofen concentration, 0.10 mmol/L; and temperature, 25 °C. The maximum separation factor α for flurbiprofen enantiomers could reach 2.34. The mechanism of chiral separation of flurbiprofen enantiomers is discussed and studied. The results showed that synergistic extraction has been established by L-dioctyl tartrate and L-tryptophan, which enantioselectively recognized R- and S-enantiomers in top and bottom phases, respectively. Compared to conventional liquid-liquid extraction, ATPE coupled with BRCE possessed higher separation efficiency and enantioselectivity without the use of any other organic solvents. The proposed method is a potential and powerful alternative to conventional extraction for separation of various enantiomers.

Efficient enantioseparation of phenylsuccinic acid enantiomers by aqueous two-phase system-based biphasic recognition chiral extraction: Phase behaviors and distribution experiments

A novel method of aqueous two-phase system (ATPS)-based biphasic recognition chiral extraction has been developed to separate phenylsuccinic acid (PSA) enantiomers. The phase behaviors of ethanol/ammonium sulfate ATPS including phase diagrams, phase volume ratios and phase compositions were studied thoroughly. Based on crucial phase transition points, a modified phase diagram was established experimentally. It was found the phase volume ratios of the system change curves in two parts of ATPS area showed opposite trends, and ideal region with appropriate phase volume ratios and high stability was selected for enantioseparation process. Furthermore, the optimum phase composition for improved enantioseparation was obtained based on two different chiral selector-oriented recognition regions. Then the main system parameters including pH, types of chiral selectors, operational temperature, as well as the PSA enantiomers concentration were also investigated. The maximum separation factor of 4.06 was obtained under the optimized experimental conditions with l-(+)-Tartaric acid diisopropyl ester and Hydroxypropyl-β-cyclodextrin as the biphasic chiral selectors. It is foreseeable that the ATPS-based biphasic recognition chiral extraction could be beneficial to developing efficient enantioseparation methodologies for other racemic compounds.

Host-Guest Inclusion Complexes Between Amlodipine Enantiomers in Biphasic Recognition Chiral Extraction System Using Tartaric Acid and β-Cyclodextrin Derivatives as Positive Confirmation Using of their Enantioselective Extraction

The current work reports an extended theoretical study from our previous experimental work for the enantioselective extraction of amlodipine enantiomers in a biphasic recognition chiral extraction system (BRCES) consisting of hydrophobic D-diisopropyl tartrate dissolved in organic phase (n-decanol) and hydrophilic hydroxypropyl-β-cyclodextrin (HP-β-CD) in aqueous phase (acetate buffer) which preferentially recognize the R-enantiomer and S-enantiomer, respectively. The calculations were simulated using a semi-empirical PM3 method as a part of the Gaussian09 software package and were used to optimize the structures of the hosts, guests, and host-guest complexes in the gas phase without any restrictions. It was found that HP-β-CD has the strongest recognition ability among the three β-CD derivatives studied, namely HP-β-CD, hydroxyethyl-β-cyclodextrin (HE-β-CD), and methylated-β-cyclodextrin (Me-β-CD), due to the large interaction energies (Ecomp = −14.3025 kcal/ mol), while D-diisopropyl tartrate has the strongest ability among the four tartaric acid derivatives studied namely; L-diisopropyl tartrate, D-diisopropyl tartrate, L-diethyl tartrate, and D-diethyl tartrate (Ecomp = −5.9964 kcal/ mol). The computational calculations for the enantioselective partitioning of amlodipine enantiomers rationalized the reasons for the different behaviors for this extraction. The present theoretical results may be informative to scientists who are devoting themselves to developing models for their experimental parts or for enhancing the hydrophobic drug solubility in drug delivery systems.

Biphasic Enantioselective Partitioning of <i>R</i>,<i>S</i>-Omeprazole Enantiomers Using Chiral Extraction

Enantioselective partitioning of racemic omeprazole enantiomers was studied using a biphasic recognition chiral extraction system. Hydrophilic hydroxypropyl-ڂ-cyclodextrin in aqueous phase and hydrophobic D-tartaric acid hexyl ester in organic phase as chiral selectors which preferentially recognize (R)-omeprazole enantiomer and (S)-omeprazole enantiomer, respectively. Different experimental variable parameters could affect the chiral extraction efficiency. The largest distribution coefficientskS,kRand separation factorځwere obtained at concentrations o f 0.1 mol/L HP-ڂ-CD and 0.2 mol/L D-tartaric acid hexyl ester, which were 47.38, 58.65 and 1.24, respectively.kRis always larger thankSwhen using different kinds of tartaric acid derivatives as chiral selectors in organic phase. The present study also reveal the mechanism of biphasic recognition chiral extraction forR,S-omeprazole enantiomers.

Continuous Separation of Pantoprazole Enantiomers by Biphasic Recognition Chiral Extraction in Centrifugal Contactor Separators

Continuous separation of pantoprazole enantiomers by biphasic recognition chiral extraction (BRCE) in a cascade of centrifugal contactor separators was studied. The BRCE system consists of isobutyl d-tartrate (d-IBTA) in the organic phase and hydrophilic-β-cyclodextrin (HP-β-CD) in the aqueous phase. The effect of W/O ratio, extractant d-IBTA concentration, and number of stages on the purity and yield of the product was investigated. A higher d-IBTA concentration and a smaller W/O ratio result in a higher purity in the raffinate phase and lower in the extract phase. More stages are required to obtain higher purities in both product streams. The desired enantiomer can be obtained by asymmetric separation, i.e., by varying the phase ratio, without the need of increasing the number of stages. The optimal conditions for symmetric separation involves a W/O ratio of 5 and 0.1 mol/L d-IBTA, which can make the eeeq up to 48% and Yeq to 68%. The technology is potentially applicable to scale production.

Selective Enantioseparation of Racemic Amlodipine by Biphasic Recognition Chiral Separation System

The biphasic recognition chiral extraction process was developed and applied to separate amlodipine enantiomer. The chiral extraction system contained tartaric acid derivatives in the organic phase and β-cyclodextrin derivatives in the aqueous phase. The effect of extraction equilibrium time and the influence of different types of tartaric acids, types of β-cyclodextrin derivatives, organic solvents, and buffer pH were investigated. The results indicated that hydroxypropyl-β-cyclodextrin (HP-β-CD) showed a higher recognition ability toward (S)-amlodipine than (R)-amlodipine while dibenzoyl-D-tartrate demonstrated the strongest ability among tartaric acid derivatives to bind with (R)-amlodipine. The distribution ratios for (S)-amlodipine (kS) and (R)-amlodipine (kR) gave optimum values at pH 5.0 of 16.54 and 0.78, respectively. Biphasic chiral recognition extraction has great significance for preparative separation of (S)-amlodipine. It can also be used to design and apply the enantioseparation process.

Biphasic recognition chiral extraction — novel way of separating pantoprazole enantiomers

AbstractThis paper presents a biphasic recognition chiral extraction system developed as a new chiral separation technology for the separation of pantoprazole enantiomers, combining a hydrophilic β-CD derivative in the aqueous phase and a hydrophobic tartaric acid in the organic phase which preferentially recognise the (R)-enantiomer and (S)-enantiomer, respectively. In this study, a number of factors which influence the efficiency of the extraction were investigated including types of organic solvents, β-CD and tartaric acid esters and their concentrations, pH and temperature. As a result, enantioselectivity for pantoprazole enantiomers can be improved up to 1.42 under optimised conditions; in addition, it is clear that the combined action of β-CD and tartaric acid esters leads to formation of the biphasic chiral extraction system with a stronger separation capacity than a monophasic chiral extraction system.

Kinetic Study for Biphasic Recognition Chiral Extraction of Naproxen Enantiomers with Hydrophobic L-iso-butyl Tartrate and Hydrophilic Hydroxypropyl-β-Cyclodextrin

The kinetics of biphasic recognition chiral extraction of naproxen (HA) enantiomers was investigated to determine the extraction mechanism, with hydrophobic L-iso-butyl tartrate (L-IBTA) in the organic phase and hydrophilic hydroxypropyl-β-cyclodextrin (HP--CD) in the aqueous phase. The two-phase homogeneous reaction model was selected over the interfacial reaction model, because there is a clear physical solubility of naproxen enantiomers in both the aqueous phase and the organic phase. The reactions between the HA enantiomers and L-iso-butyl tartrate in a stirred cell fall in Regime 3; the extraction is accompanied by two fast chemical reactions in the diffusion film. The reactions have been found to be first order with respect to HA enantiomers and second order with respect to L-IBTA. The forward rate constants for S-HA and R-HA are 1.26 × 10−4 mol−2 m6 s−1 and 2.52 × 10−4 mol−2 m6 s−1, respectively. With the increase of HP--CD concentration in the aqueous phase, high enantioselectivity was obtained, but the extraction rates decreased. These data will be useful in the design of extraction processes.

Kinetic study on biphasic recognition chiral extraction for separation of α‐cyclohexyl‐mandelic acid enantiomers

AbstractBACKGROUND: Chiral solvent extraction is a potentially attractive chiral separation technique. It is essential to know the intrinsic complexation kinetics for selection, design and operation of reactive extraction equipment and for reliable scale‐up. The objective of this research is to study the kinetics of biphasic recognition chiral extraction of α‐cyclohexyl‐mandelic acid (α‐CHMA) enantiomers using a modified Lewis cell.RESULTS: The experimental results demonstrate that the extraction reaction kinetics is fast, and the reactions are first order with respect to α‐CHMA and second order with respect to D‐IBTA, with forward rate constants of 6.54 × 10−4 mol−2 m6 s−1 for S‐α‐CHMA and 6.84 × 10−4 mol−2 m6 s−1 for R‐α‐CHMA. With increase of HP‐β‐CD concentration in aqueous phase, enantioselectivity increases, while the overall mass transfer coefficients decrease.CONCLUSIONS: Sufficient enantioselectivity and fast kinetics of extraction can be obtained in the BRCE system at HP‐β‐CD concentration of 0.1 mol L−1 and D‐IBTA concentration of 0.2 mol L−1. These data will be useful in the design of extraction processes. Copyright © 2012 Society of Chemical Industry

Enantioselective partitioning of 2-phenylpropionic acid enantiomers in a biphasic recognition chiral extraction system

This work reports enantioselective partitioning of 2-phenylpropionic acid enantiomers in a biphasic recognition chiral extraction (BRCE) system combining hydrophobic L- iso-butyl tartrate in organic phase and hydrophilic hydroxypropyl-β-cyclodextrin in aqueous phase which preferentially recognize S-enantiomer and R-enantiomer, respectively. In BRCE system, the concentrations of the extractants and 2-phenylpropionic acid enantiomers, the types of organic solvents and extractants, pH and temperature all exert a considerable influence on the biphasic recognition process. The two-dimensional interpolation method is utilized to explore the influence of the concentrations of selectors and enantiomers on distribution ratios and separation factors in single stage BRCE systems. High separation factors are obtained at low pH value under condition that the concentrations of HP-β-CD and L- iso-butyl tartrate are about 0.1 mol/L and 0.2 mol/L, respectively. BRCE is of strong chiral separation ability. From monophasic recognition chiral extraction (MRCE) system into BRCE system, the separation factor increases from 1.08 to 1.69.

Determination of Kinetics in Biphasic Recognition Chiral Extraction for Separation of Phenylsuccinic Acid Enantiomers

This paper reports on the determination of the intrinsic kinetics in biphasic recognition chiral extraction of phenylsuccinic acid enantiomers (H2A) by L-IBTA and HP-β-CD in a modified Lewis cell. The two-phase homogeneous reaction model was selected, because there is a finite physical solubility of phenylsuccinic acid enantiomers in both the aqueous phase and the organic phase. The regime analysis was split up in three parts: a regime analysis on the aqueous phase reaction in the absence of organic phase reaction, a regime analysis of the organic phase reaction in the absence of the aqueous phase reaction, and a regime analysis of reactions in both phases. The reactions have been found to be first order with respect to H2A and second order with respect to L-IBTA and HP-β-CD. Competitive extraction of H2A enantiomers with HP-β-CD and L-IBTA has great influence on the extraction process. With increase of HP-β-CD concentration, high enantioselectivity was obtained, but the extraction rate decreases.

Separation of flurbiprofen enantiomers by biphasic recognition chiral extraction

Based on our previous work, this paper reports enantioselective partitioning of flurbiprofen enantiomers in a biphasic recognition chiral extraction (BRCE) system combining a hydrophobic l-tartrate in organic phase and hydrophilic β-cyclodextrin derivative in aqueous phase which preferentially recognize R-enantiomer and S-enantiomer, respectively. The studies performed involve an enantioselective extraction in a biphasic system, where flurbiprofen enantiomers form four complexes with β-cyclodextrin derivative and l-tartrate, respectively. In these biphasic resolutions, the concentrations of the extractants and flurbiprofen enantiomers, the types of organic solvents and extractants, pH and temperature all exert a considerable influence on the biphasic recognition process. The maximum enantioselectivity for flurbiprofen enantiomers is 1.24 at the pH of 2.5, 5 °C, the flurbiprofen initial concentration of 0.0001 mol/L and the ratio of 2:1 of [ l- iso-butyl tartrate] to [TM-β-CD]. By changing the monophasic recognition chiral extraction (MRCE) system into BRCE system, the enantioselectivities are greatly improved. Biphasic recognition chiral extraction is of strong chiral separation ability, and can be hopeful for separations of various enantiomers at a large-scale.

Enantioselective Partitioning of Racemic Ibuprofen in a Biphasic Recognition Chiral Extraction System

AbstractEnantioselective partitioning of ibuprofen enantiomers in a biphasic recognition chiral extraction system was studied. A combination of hydrophobic L‐isobutyl tartrate in organic phase and hydrophilic β‐cyclodextrin derivative in aqueous phase is necessary to establish a biphasic recognition chiral extraction system. The studies performed involve an enantioselective extraction in a biphasic system, where ibuprofen enantiomers form four complexes with the β‐cyclodextrin derivative in aqueous phase and the D(L)‐isobutyl tartrate in organic phase, respectively. In these biphasic resolutions, the types and the concentrations of the extractants, pH and temperature all exert a considerable influence on the biphasic recognition process. Good enantioselectivities for ibuprofen enantiomers were obtained at pH≦2.5 and a ratio of 2:1 of [L‐isobutyl tartrate] to [HP‐β‐CD]. Biphasic recognition chiral extraction is of strong chiral separation ability, and may be very helpful to optimize the extraction systems and realize the large‐scale production of enantiomers.

Enantioselective separation of R,S-phenylsuccinic acid by biphasic recognition chiral extraction

A new process has been developed to separate phenylsuccinic acid (H2A) enantiomers, based on the oppositely preferential recognition of hydrophobic and hydrophilic chiral selectors in organic and aqueous phases, respectively, which is named as biphasic recognition chiral extraction (BRCE). BRCE system is established by adding hydrophobic l-iso-butyl tartrate in organic phase and hydrophilic β-cyclodextrin (β-CD) derivative in aqueous phase, which preferentially recognize S-H2A and R-H2A, respectively. The studies performed involve two enantioselective extractions in a biphasic system, where H2A enantiomers form four complexes with β-CD derivative in aqueous phase and l-iso-butyl tartrate in organic phase, respectively. Here it is shown that the efficiency of the extraction depends, often strongly, on a number of process variables, including the types of organic solvents and β-CD derivatives, iso-butyl tartrate configurations, the concentrations of the extractants and H2A enantiomers, pH and temperature. Phase-equilibria in BRCE systems is governed by the complex chemical equilibria in both the organic and aqueous phases. By changing the monophasic recognition chiral extraction (MRCE) system into BRCE system, the enantioselectivity increases from 1.501 to 2.862. The maximum enantioselectivity for H2A enantiomers is obtained at pH≤2.5 and the ratio of 2:1 of [l-(+)-iso-butyl tartrate] to [HP-β-CD]. The experimental results show that BRCE is of much stronger chiral separation ability than MRCE, which is due to utilization of the separation abilities of both tartrate and β-CD derivative. It may be very helpful to optimize the extraction systems and realize the large-scale production of pure enantiomers.

Biphasic recognition chiral extraction: A novel method for separation of mandelic acid enantiomers

This article reports a new chiral separation method-biphasic recognition chiral extraction for the separation of mandelic acid enantiomers. Distribution behavior of mandelic acid enantiomers was studied in the extraction system with O,O'-di-benzoyl-(2S,3S)-4-toluoyl-tartaric acid (D-(+)-DTTA) in organic phase and beta-CD derivatives in aqueous phase, and the influence of the types and concentrations of extractants and pH on extraction efficiency was investigated. Hydroxypropyl-beta-cyclodextrin (HP-beta-CD), hydroxyethyl-beta-cyclodextrin (HE-beta-CD), and methyl-beta-cyclodextrin (Me-beta-CD) have stronger recognition abilities for S-mandelic acid than those for R-mandelic acid, among which HP-beta-CD has the strongest ability. D-(+)-DTTA preferentially recognizes R-mandelic acid. pH and the concentrations of extractants have great effects on chiral separation ability. A high enantioseparation efficiency with a maximum enantioselectivity of 1.527 is obtained at pH of 2.7 and the ratio of 2:1 of [D-(+)-DTTA] to [HP-beta-CD]. The obtained results indicate that the biphasic recognition chiral extraction is of stronger chiral separation ability than the monophasic recognition chiral extraction. It may be very helpful to optimize the extraction systems and realize the large-scale production of pure enantiomers.

Resolution of Zopiclone enantiomers by biphasic recognition chiral extraction

This paper reports a new chiral separation technology—biphasic recognition chiral extraction for the racemic separation of zopiclone, which was selected, as a case study, due to its enantiomers diverse properties. The studies performed involve an enantioselective extraction in a biphasic system, where zopiclone complexes with β-cyclodextrin derivative in aqueous phase and complexes with d( l)-tartaric acid esters present in organic phase, respectively. Factors affecting the extraction mechanism were analysed, namely the influence of the concentrations of the extractants and zopiclone enantiomers, the types of the extractants, pH and temperature. Experimental results show that, in the biphasic recognition chiral extraction system containing hydroxypropyl-β-cyclodextrin and l-isobutyl tartrate, the maximum enantioselectivity is 1.51, which is larger than that in the monophasic recognition chiral extraction system containing only l-isobutyl tartrate in organic phase. Biphasic recognition chiral extraction is of strong chiral separation ability, and has great significance for preparative separation of racemic compounds. It may also be very helpful to optimize the extraction systems and realize the large-scale production of enantiomer.