Enantioselective Extraction Research Articles

Dextrin-assisted gel electromembrane extraction of chiral drugs: Improving the extraction efficiency and investigation of enantioselectivity of extraction

The present study investigates the use of dextrins (maltodextrin, β-cyclodextrin, and hydroxypropyl-β-cyclodextrin) to improve the efficiency of the agarose-based gel electromembrane extraction technique for extracting chiral basic drugs (citalopram, hydroxyzine, and cetirizine). Additionally, it examines the enantioselectivity of the extraction process for these drugs. To achieve these, dextrins were incorporated into either the sample solution, the membrane, or the acceptor solution, and then the extraction procedure was performed. Enantiomers were separated and analyzed using a capillary electrophoresis device equipped with a UV detector. The results obtained under the optimal extraction conditions (sample solution pH: 4.0, acceptor solution pH: 2.0, gel membrane pH: 3.0, agarose concentration: 3 % w/v, stirring rate: 1000 rpm, gel thickness: 4.4 mm, extraction voltage: 62.3 V, and extraction time: 32.1 min) indicated that incorporating dextrins into either the sample solution, membrane or the acceptor solution enhances extraction efficiency by 17.3–23.1 %. The most significant increase was observed when hydroxypropyl-β-cyclodextrin was added to the acceptor solution. The findings indicated that the inclusion of hydroxypropyl-β-cyclodextrin in the sample solution resulted in an enantioselective extraction, yielding an enantiomeric excess of 6.42–7.14 %. The proposed method showed a linear range of 5.0–2000 ng/mL for enantiomers of model drugs. The limit of detection and limit of quantification for all enantiomers were found to be < 4.5 ng/mL and <15.0 ng/mL, respectively. Intra- and inter-day RSDs (n = 4) were less than 10.8 %, and the relative errors were less than 3.2 % for all the enantiomers. Finally, the developed method was successfully applied to determine concentrations of enantiomers in a urine sample with relative recoveries of 96.8–99.2 %, indicating good reliability of the developed method.

Enantioseparation via Chiral Supramolecular Gels Comprising Ambidextrous Gelators Based on β-Peptide-type Primary Amines.

While β-peptides have been paid attention due to their diverse secondary structures, their application to the design of low-molecular-weight gelators (LMWGs) is less explored. In this work, chiral cyclic β-amino acid-based β-peptides were developed as ambidextrous LMWGs, wherein multiple hydrogen bonds between the amide moieties led to high gelation ability. Their molecular assembly was elucidated using spectroscopies, microscopy, and X-ray analysis. Further, the supramolecular gel was used as a platform for the enantioselective extraction of (S)-naproxen from its racemate under optimized conditions. These findings have expanded the utility of β-peptides and shown the potential of supramolecular gels as a distinct dynamic medium for enantiomer separation.

Evaluation of chiral dehydroabietic acid-terminated tetra-arm PEG as an assisted phase-forming polymer and chiral selector for the enantioseparation of propranolol racemate in aqueous two-phase systems

In this work, we successfully synthesized a chiral dehydroabietic acid-terminated tetra-arm PEG (4-arm PEG-DHAA) and utilized it to construct a chiral aqueous two-phase system (ATPS) alongside PEG2000 and (NH4)2SO4. The 4-arm PEG-DHAA served as both an assisted phase-forming polymer and a chiral selector. This ATPS can be employed for chiral recognition and liquid–liquid enantioselective extraction of the propranolol enantiomers. The effects of four primary factors, namely initial rac-propranolol concentration, extraction temperature, system pH, and the concentration of 4-arm PEG-DHAA on enantioseparation, were thoroughly evaluated. Furthermore, the optimization of extraction conditions was conducted using the response surface methodology. The results indicated that the chiral ATPS has better and higher enantioselectivity, with a one-step chiral extraction achieving an e.e. up to 57% and a yield exceeding 73% for S-isomers under the optimized conditions. In addition, the chiral ATPS can be regenerated through simple back-extraction with diethyl ether and reused at least five times, achieving similar enantioselective extraction results. This research presents a valuable enantioseparation approach for propranolol enantiomers via liquid–liquid enantioselective extraction using the chiral ATPS.

Assessment of the properties of natural-based chiral deep eutectic solvents for chiral drug separation: insights from molecular dynamics simulation.

The structural and physicochemical properties of chiral deep eutectic solvents (DESs) consisting of racemic mixtures of menthol and acetic acid (DES1), racemic mixtures of menthol and lauric acid (DES2), and racemic mixtures of menthol and pyruvic acid (DES3) for enantioselective extraction processes are investigated. Structural results, such as the radial distribution function (RDF) and the combined distribution function (CDF), indicate that the hydroxyl hydrogen of menthol has a dominant interaction with the carbonyl oxygen of the acids in the considered DESs. The number of hydrogen bonds and non-bonded interaction energies formed between S-menthol and HBDs are larger than those with R-menthol, resulting in the self-diffusion coefficient of S-menthol being larger than that of R-menthol. Therefore, it can be said that the proposed DESs are good candidates for the separation of drugs with S chirality. The effects of acid type on the density and isothermal compressibility of DESs show the behaviour of DES2 > DES3 > DES1 and DES1 > DES3 > DES2, respectively. Our results provide a better perspective on new chiral DESs at the molecular level for enantioselective processes.

Eutectic solvents formed by (+)-DTTA and L-menthol as novel chiral recognition and separation media for enantioselective extraction of valsartan enantiomers

The enantioseparation of valsartan enantiomers using chiral eutectic solvents (ESs) as extractants was initially studied. The hydrophobic ESs (LM-DTTA) formed by L-menthol and (+)-Di-p-toluoyl-D-tartaric acid is a suitable chiral medium for the enantioselective extraction of R- and S-valsartan. Four principal parameters affecting chiral extraction, such as phase volume ratio, initial rac-valsartan concentration, extraction temperature, and system pH, were evaluated. The results showed that LM-DTTA has better and higher enantioselectivity levels, and one-step chiral extraction achieved an ee value of S-valsartan up to 91% under the optimized conditions. In addition, this chiral medium can be recycled through simple back-extraction with sodium bicarbonate solution and reused at least five times, giving similar results. This work provides a clear example of enantioseparation of the rac-valsartan via liquid–liquid enantioselective extraction using the LM-DTTA as a novel chiral recognition and separation medium. As a result, the established enantioselective extraction method can efficiently separate the R- and S-enantiomer and promote sustainable development for the production of S-valsartan.

Remarkable enantioselectivity enhancement of the extractors with nonaxial chirality in liquid-liquid extraction of underivatized amino acids by introducing t-butyl group.

A class of carbonyl extractors, (R)-3, (R)-4, and (R)-5, with nonaxial chirality containing asymmetric carbons has been synthesized and studied for their efficiencies in enantioselective liquid-liquid extraction for underivatized amino acids. The bulky t-butyl ketone extractors, (R)-4 and (R)-5, showed the stereoselectivities ranging 5.4-9.4 of l/d ratio much better than those of the aldehyde extractor, (R)-3, ranging 2.4-5.2. The imine formation rates and yields of the t-butyl ketones were not significantly affected by their bulkiness and even in the absence of resonance-assisted hydrogen bond. This work confirms that a bulky t-butyl ketone can be a good choice in the development of an extractor not only with axial chirality but also with nonaxial chirality for the enantioselective extraction of unprotected amino acids.

Deep Eutectic Solvents Formed by (+)-Dtta and L-Menthol as Novel Chiral Recognition and Separation Media for Enantioselective Extraction of Valsartan Enantiomers

Deep Eutectic Solvents Formed by (+)-Dtta and L-Menthol as Novel Chiral Recognition and Separation Media for Enantioselective Extraction of Valsartan Enantiomers

Recent Development: Enantioselective Extraction in Chiral Separation

This paper discusses the recent development of enantioselective extraction methods. There are several methods in this field. The principles of all of enantioselective extraction methods are presented a focus on twophase extractions, in these methods used a chiral compound that named chiral selector, this compound distinguishes between two chiral isomers in complexation process, then one isomer more captured by chiral selector, and separation processes happen. The chiral selector should dissolve in on phase. In these methods, typical performance data are reported major emphasis on distribution ratio and enantioselectivity value or selectivity factor. In this paper, we introduce types of enantioselective extraction method, and discuss about them with several examples.

Recent Development: Enantio Selective Eextraction in Chiral Separation

This paper discusses the recent development of enantioselective extraction methods. There are several methods in this field. The principles of all of enantioselective extraction methods are presented a focus on twophase extractions, in these methods used a chiral compound that named chiral selector, this compound distinguishes between two chiral isomers in complexation process, then one isomer more captured by chiral selector, and separation processes happen. The chiral selector should dissolve in on phase. In these methods, typical performance data are reported major emphasis on distribution ratio and enantioselectivity value or selectivity factor. In this paper, we introduce types of enantioselective extraction method, and discuss about them with several examples.

Enantioselective extraction of unprotected amino acids coupled with racemization

Scalable and economical methods for the production of optically pure amino acids, both natural and unnatural, are essential for their use as synthetic building blocks. Currently, enzymatic dynamic kinetic resolution (DKR) underpins some of the most effective processes. Here we report the development of enantioselective extraction coupled with racemization (EECR) for the chirality conversion of underivatized amino acids. In this process, the catalytic racemization of amino acids in a basic aqueous solution is coupled with the selective extraction of one enantiomer into an organic layer. Back-extraction from the organic layer to an acidic aqueous solution then completes the deracemization of the amino acid. The automation of the EECR process in a recycling flow reactor is also demonstrated. Continuous EECR is made possible by the sterically hindered chiral ketone extractant 5, which prevents the coextraction of the copper racemization catalyst because of its nonplanar geometry. Furthermore, the extractant 5 unexpectedly forms imines with amino acids faster and with greater enantioselectivity than less bulky derivatives, even though 5 cannot participate in intramolecular resonance-assisted hydrogen bonding. These features may allow EECR to challenge the preponderance of enzymatic DKR in the production of enantiomerically enriched amino acids.

Dispersive solid-phase extraction of racemic drugs using chiral ionic liquid-metal-organic framework composite sorbent.

Nowadays, enantioseparation of racemic pharmaceuticals in preparations is a prime concern by drug authorities across the globe. In the present work, it was attempted to develop novel enantioselective extraction method for five clinicallyused drugs (atenolol, propranolol, metoprolol, racecadotril, and raceanisodamine in their tablets) as racemates. The enantioselective solid-liquid extraction of these racemic drugs was carried out successfully by the use of chiral ionic liquid (CIL) in combination with a metal organic framework (MOF) for the first time. The composite CIL@MOF was synthesized from tropine based chiral ionic liquids with L-proline anion ([CnTr][L-Pro], n=3-6) and HKUST-1 type MOF, which was comprehensively characterized before being used as sorbent for enantioselective dispersive solid-liquid extraction. Preliminary selection of appropriate CIL was carried out on thin layer chromatography (TLC); under the joint participation of copper ion in the developing reagent, [C3Tr][L-Pro] ionic liquid showed better resolution performance with ΔRf value of 0.35 between the enantiomers was obtained for racemic atenolol. Moreover, the effect of copper salt dosage, amount of CIL, soli-liquid ratio and extraction time were investigated. The optimal conditions were obtained after thorough investigations; i.e. sample solution: ethanol, elution solvent: methanol, solid-liquid ratio: 12.5 mg:50 mL, amount of copper salt: 8 mg L-1, amount of impregnated CIL: 30% and extraction time of 30 min. As a result, enantiomeric excess values are 90.4%, 95%, 92%, 81.6% and 83.2% for atenolol, propranolol, metoprolol, racecadotril and raceanisodamine, respectively. The developed enantioselective method was validated following ICH guidelines and it was proved to be simple, effective and enantioselective way for separation of racemic pharmaceuticals with similar behaviors.

Highly Enantioselective Extraction of Phenylglycine by a Chiral Macrocyclic Receptor Based on Supramolecular Interactions.

Using supramolecular interactions, a novel macrocyclic receptor is able to selectively extract zwitterionic phenylglycine from neutral aqueous solutions into chloroform with up to 91.8% ee. Modeling studies, nuclear magnetic resonance experiments, and X-ray diffraction analysis were carried out to explain the high enantioselectivity observed.

Chiral separation of methadone using solid membrane extraction based on chiral selector, solid membrane: sheep skin leather

A new, green, and without solvent extraction method and chiral separation system effective in separation of racemic methadone is presented. We have used sheep leather as the membrane in enantioselective extraction for chiral separation of methadone. In this work, chiral (2-hydroxypropyl)-β-cyclodextrin (OHP-β-CD) was used as a versatile chiral selector. The influences of various conditions on the separation performance were studied. Results showed, the selectivity in one separation step is related to the thickness of leather, chiral selector concentration, pH and temperature of sample solution. At optimum conditions (0.3 mm for thickness of leather, 5 g/L of chiral selector concentration, pH of sample equal to 4.3 and temperature equal to 20 °C), the distribution ratio of R- and S-methadone was 19.4 and 1.6, respectively, and the enantioselectivity value of 12.1 was found at best condition.

Enantioselective Extraction of Phenylalanine Enantiomers Using Environmentally Friendly Aqueous Two-Phase Systems

(1) Background: The environmentally friendly choline-amino acid ionic liquids (ChAAILs) and deep eutectic solvents (DESs) have been used as excellent alternatives to volatile organic compounds (VOCs) and ionic liquids (ILs) in recent years; (2) Methods: Thus, ChAAILs/salt and DESs/salt aqueous two-phase systems (ATPSs) were developed for the chiral extraction of phenylalanine enantiomers. The optimum ATPS of [Ch][L-Pro]/K3PO4 was chosen, and the influencing parameters were investigated, including ChAAILs concentration, salt concentration, chiral selector concentration, extraction temperature, phenylalanine concentration, and system pH; (3) Results: The phenylalanine enantiomers were mainly extracted into the top phase (ChAAIL-rich phase), meanwhile, the (S)-phenylalanine [(S)-Phe)] was preferentially recognized by the chiral selector in the top phase. The maximum separation factor (α) of 2.05 was obtained under the optimal conditions; and (4) Conclusions: This ATPS that was used for the chiral extraction of enantiomers is much more environmentally friendly, simple, and rapid, and has the potential to be used in the enantioselective extraction of other enantiomers.

Synthesis of imprinted styrene-maleic acid functionalized resin for enantio-selective extraction of R-amphetamine

This article presents the development of an enantio-selective polymeric resin based on cross-linked styrene-maleic acid copolymer for chiral recognition of R-amphetamine and efficient optical resolution of (±)-amphetamine racemate. In the beginning, a polymerizable R-amphetamine-maleimide derivative was synthesized and investigated using elemental analysis, FTIR, and NMR spectroscopy to affirm the chemical structure. The chiral maleimide derivative was then copolymerized with styrene and divinylbenzene via free radical polymerization and the obtained polymeric resin was agitated with sodium hydroxide followed by HCl to expel the R-amphetamine template molecules out of the polymer texture. The obtained molecularly imprinted polymer was characterized using SEM, FTIR and EDX spectra then evaluated for selective removal of R-amphetamine under various conditions. The results indicated that the maximum uptake was achieved at pH 7 and the adsorption was performed in accordance with the Langmuir model with a maximum capacity of 210 ± 1 mg/g. In addition, the optical separation was carried out using a column and the results indicated approximate enantiomeric excess values of 76.5% and 56.5% within both supernatant and eluant solution referring to S- and R-amphetamine approximately, respectively.

Modelling studies of enantioselective extraction of an amino acid derivative in slug flow capillary microreactors

This work shows that enantioselective liquid–liquid extraction in microreactors is attractive for chiral separation. A precise control over the residence time in microreactors results in high enantiopurities and low host inventories. Mathematical modelling has been presented to describe the experimental results on the enantioselective extraction of an aqueous racemic amino acid derivative (3,5-dinitrobenzoyl-(R,S)-leucine) with a cinchona alkaloid chiral host in 1-octanol using a slug flow capillary microreactor (at an aqueous to organic flow ratio of 1:1). A good agreement between the model predictions and experimental results was obtained by taking the enhancement of the mass transfer rates due to the reactions in the aqueous and organic phases into account. An enantiomeric excess of the (S)-enantiomer higher than the equilibrium value was observed especially at shorter residence times due to kinetic effects. The observed phenomena could be explained by an instantaneous rate of the complexation of the (S)-enantiomer with the host and a finite rate of the complexation of the (R)-enantiomer. The developed model was used to determine guidelines for multi-stage operation in microreactors in order to increase yield and enantiopurity.

Surface molecularly imprinted amino-functionalized alginate microspheres for enantio-selective extraction of l-ascorbic acid

A surface molecular imprinting technique was utilized in the fabrication of an enantio-selective adsorbent based on amino-functionalized alginate microspheres for chiral resolution of ascorbic acid. Alginate microspheres were first strengthened via epichlorohydrin (ECH) covalent cross-linking then functionalized with amino groups through graft copolymerization of polyacrylamide (PAm) followed by Hofmann degradation. Surface molecular imprinting was then performed under mild conditions by ionic interaction between the surface incorporated amine groups and the template l-ascorbic acid enantiomers followed by cross-linking with glyoxal. l-Ascorbic acid enantio-selective adsorbent (LA-Alg) was finally obtained by removing the template molecules out of the cross-linked network formed on the surface of the modified alginate particles. The synthetic steps were monitored using elemental analysis and FTIR spectra. Also, the surface morphologies of the native unmodified alginate along with both imprinted and non-imprinted adsorbent particles were examined by SEM. Moreover, the crystalline profile and thermal properties of both native and modified samples were investigated using XRD spectra and thermogravimetric analysis (TGA), respectively. The effect of pH on the extraction process was studied and indicated that the maximum adsorption was obtained at pH 4. Also, adsorption isotherms over LA-Alg adsorbent displayed the best fit with Langmuir model with maximum adsorption capacity 116 ± 1 and 67 ± 1 mg/g with respect to both l- and d-ascorbic acid, respectively. Moreover, the chiral resolution experiment using batch technique indicated 72% enantiomeric excess.

Experiments and simulation on extraction of esmolol enantiomers from single stage to multistage

Abstract Enantioselective extraction of esmolol (ES) enantiomers was performed with tartaric acid derivatives and boric acid (BA) as chiral extractant. The single–stage extraction experiments were carried out to construct the extraction system for ES enantiomers through investigating type of tartaric acid derivatives, type of the organic solvent and temperature. The optimal conditions for extraction system were achieved, which involves 1,2–dichloroethane as organic solvent, iso–butyl–D–tartrate (DT) as chiral selector and 278 K for extraction temperature. A single–stage extraction model was established based on an interfacial reaction mechanism and proved to be reliable by verified experiments. Based on the single–stage extraction model and the law of mass conservation, a fractional extraction model was explored to simulate and optimize the fractional extraction process. The optimal operation conditions at temperature of 278 K were obtained including ES concentration of 0.01 mol/L, DT and BA concentrations of 0.1 mol/L, F/W of 0.25 and O/W of 1.0347, feeding in the middle stage at pH of 5.50. The eeeq of 0.98 and Yeq of 0.99 can be achieved by symmetric separation with the number of stages of 32 under the optimal conditions. As S–ES is the desired product, 10 stages are enough to obtain 0.98 of eeraffinate for S–ES by asymmetric separation under the conditions containing ES concentration of 0.01 mol/L, DT and BA concentrations of 0.1 mol/L, F/W of 0.25 and O/W of 1.64, feeding in the Stage 2 at pH of 5.50.

Separation of enantiomers of selected chiral sulfoxides with cellulose tris(4-chloro-3-methylphenylcarbamate)-based chiral columns in high-performance liquid chromatography with very high separation factor

The present study reports successful separations of enantiomers of selected chiral sulfoxides with very high separation factor in high-performance liquid chromatography by using chiral columns prepared with the chiral selector cellulose tris(4-chloro-3-methylphenylcarbamate). High separation factors were observed in polar organic, as well as in hydrocarbon-alcohol-type mobile phases. The key structural components of the solute for obtaining high chiral recognition are discussed as well as thermodynamic quantities of analyte adsorption on the chiral stationary phase were determined. Experiment aimed at the enantioselective extraction of racemates from solution are also described.

Modeling multiple chemical equilibrium in chiral extraction of metoprolol enantiomers from single-stage extraction to fractional extraction

Enantioselective extraction of metoprolol (MT) enantiomers with di-cyclohexyl (D)-tartrate (DT) and boric acid (BA) as chiral extractant was performed. The process involving multiple chemical equilibrium is very complicated and the process optimization is difficult. On the basis of an interfacial reaction mechanism, a single-stage extraction model was established. The operation conditions of pH and DT to BA ratio were obtained through simulation and optimization of the equilibrium of the two phase extraction system. Based on the single-stage extraction model and the law of mass conservation, a fractional extraction model was established to simulate and optimize the fractional extraction process. To pursue a high productivity and reduce the required stages, a high feed to aqueous phase ratio (F/W = 1) and an asymmetric separation mode were applied. By asymmetric separation where the optical purity of the product in extract phase and raffiniate phase is not equal, enantiomeric excess (ee) value for the eutomer of MT can reach up to 98.64% and yield can reach up to 64.68% with 20 extraction stages.