Separation Of Enantiomers Research Articles

Four Pairs of Neuroprotective Aryldihydronapthalene-type Lignanamide Enantiomers from the Herbs ofSolanum lyratum.

Four pairs of aryldihydronapthalene-type lignanamide enantiomers were isolated from Solanum lyratum (Solanaceae). The enantiomeric separation was accomplished by chiral-phase HPLC, and five undescribed compounds were elucidated. Analysis by various spectroscopy and ECD calculations, the structures of undescribed compounds were illuminated. The neuroprotective effects of all compounds were evaluated using H2O2-induced human neuroblastoma SH-SY5Y cells and AchE inhibition activity. Among them, compound 4a exhibited remarkable neuroprotective effects at high concentrations of 25 and 50 μmol/L comparable to Trolox. Compound 1a showed the highest AchE inhibition with the IC50 value of 3.06 ± 2.40 μmol/L. Molecular docking of the three active compounds was performed and the linkage between the compounds and the active site of AchE was elucidated.

Magnetic Molecularly Imprinted Chitosan Combined with a Paper-Based Analytical Device for the Smartphone Discrimination of Tryptophan Enantiomers.

The separation of enantiomers plays a critical role in pharmaceutical development, ensuring therapeutic efficacy, safety, and patent protection. It enables the production of enantiopure drugs and enhances our understanding of the properties of chiral compounds. In this study, a straightforward and effective chiral detection strategy was developed for distinguishing between tryptophan (TRP) enantiomers. The approach involved the preparation of a magnetic molecularly imprinted chitosan (MMIC) for preparation of the sample, which was combined with a nitrocellulose membrane (a paper-based analytical device, PAD) integrated with D-TRP covalently grafted with polymethacrylic acid (PAD-PMA_D-TRP). Discriminating between the TRP enantiomers was achieved using AuNPs as a colorimetric probe. Indeed, the presence of D-TRP rapidly induced the aggregation of AuNPs due to its strong affinity to PAD-PMA_D-TRP, resulting in a noticeable change in the color of the AuNPs from red to purple. On the other hand, L-TRP did not induce any color changes. The chiral analysis could be easily performed with the naked eye and/or a smartphone. The developed method exhibited a detection limit of 3.3 µM, and it was successfully applied to detect TRP in serum samples, demonstrating good recovery rates. The proposed procedure is characterized by its simplicity, cost-effectiveness, rapidity, and ease of operation.

Cyclodextrin Incorporation into Covalent Organic Frameworks Enables Extensive Liquid and Gas Chromatographic Enantioseparations.

The separation of enantiomers using high-performance chromatography technologies represents great importance and interest. In this aspect, β-cyclodextrin (β-CD) and its derivatives have been extensively studied as chiral stationary phases (CSPs). Nevertheless, β-CD that was immobilized on a traditional matrix often exhibited low stabilities and limited operating ranges. Recently, covalent organic frameworks (COFs) with highly ordered nanopores are emerging as promising CSPs for enantioseparations, but their practical applications are still hampered by the difficulty of monomer and COF synthesis. Herein, two β-CD-driven COFs are synthesized via a fast and facile plasma-induced polymerization combined postsynthesis modification strategy. The precisely defined COF channels enhanced the accessibility of the accommodated β-CD to the analytes and acted as robust protective barriers to safeguard the β-CD from harsh environments. Therefore, the β-CD-modified COFs can be potentially general CSPs for extensive enantioseparation in both gas chromatography and high-performance liquid chromatography, and a wide range of racemates were separated. Compared to the commonly employed commercial chiral columns, these COF-based columns exhibited comparable resolution capability and superior application versatility. This work integrates the advantages and overcomes the defects of COFs and β-CD, thus advancing COFs as platforms for chiral selector modification and giving great promise for practical chromatographic enantioseparation.

Comparative studies of immobilized polysaccharide derivatives chiral stationary phases for enantioseparation of furanocoumarins and dihydroflavones and discussion on chiral recognition mechanism.

Enantiomeric separation of furanocoumarins and dihydroflavones compounds were systematically studied in the normal-phase mode using four different polysaccharide-type chiral stationary phases, namely, Chiralpak IA, Chiralpak IC, Chiralpak IG, and Chiralpak IK-3 by high-performance liquid chromatography. The effect of alcohol modifiers and alcohol content on enantiomeric separation was evaluated for the separation of furanocoumarins and dihydroflavones. All the eight compounds have achieved baseline separation with the resolutions ranging between 1.52 and 23.11. For a better insight into the enantiorecognition mechanisms, thermodynamic analysis was carried out. The mechanisms of chiral recognition have been discussed. Among four chiral columns, Chiralpak IG exhibited the most universal and the best enantioseparation ability toward furanocoumarins and dihydroflavones when used n-hexane-isopropanol and n-hexane-ethanol as mobile phase, respectively. The steric hindrance, hydrogen bonding, and π-π interaction played major roles in chiral recognition on Chiralpak IG. By comparing four chiral columns, this work systematically analyzed the separation methods of furanocoumarins and dihydroflavones for the first time and reported some active chiral ingredients of traditional Chinese medicine that have never been separated, which provided a further insight into the enantioseparation of furanocoumarins and dihydroflavones on chiral stationary phases.

Achiral nanoparticle trapping and chiral nanoparticle separating with quasi-BIC metasurface.

Dielectric metasurfaces based on quasi-bound states in the continuum (quasi-BICs) are a promising approach for manipulating light-matter interactions. In this study, we numerically demonstrate the potential of silicon elliptical tetramer dielectric metasurfaces for achirality nanoparticle trapping and chiral nanoparticle separation. We first analyze a symmetric tetramer metasurface, which exhibits dual resonances (P1 and P2) with high electromagnetic field intensity enhancement and a high-quality factor (Q-factor). This metasurface can trap achiral nanoparticles with a maximum optical trapping force of 35 pN for 20 nm particles at an input intensity of 100 mW. We then investigate an asymmetric tetramer metasurface, which can identify and separate enantiomers under the excitation of left-handed circularly polarized (LCP) light. Results show that the chiral optical force can push one enantiomer towards regions of the quasi-BIC system while removing the other. In addition, the proposed asymmetric tetramer metasurface can provide multiple Fano resonances (ranging from R1 to R5) and high trap potential wells of up to 33 kBT. Our results demonstrate that the proposed all-dielectric metasurface has high performance in nanoparticle detection, with potential applications in biology, life science, and applied physics.

Development of a liquid chromatographic method for enantioseparation of Eflornithine using (S)-α-ethyl benzylamine as a chiral derivatizing agent

ABSTRACT Eflornithine (2-fluoromethyl-DL-ornithine) is a potent and irreversible inhibitor that selectively targets ornithine decarboxylase, a key enzyme in the polyamine biosynthesis pathway. Due to the lack of chromophoric moiety in the eflornithine structure, its detection via UV detector is difficult. Thus, direct high-performance liquid chromatographic (HPLC) separation of enantiomers of Eflornithine is not feasible, and pre-column derivatization is required for its determination through chiral HPLC columns. We developed an indirect HPLC method using (S)-α-ethyl benzylamine as a chiral derivatizing agent for the enantioseparation of Eflornithine. The diastereomers thus produced were then separated via LiChrospher C18 column (5 μm particle size, L × I. D. 25 cm × 4.6 mm). The mobile phase used was a mixture of acetonitrile and 0.1% aq. TFA and varied in linear gradients of 30–70% of acetonitrile for 30 min run at a flow rate of 1.0 mL min−1 and UV detection at 320 nm. The separation parameters were optimized by altering the mobile phase composition and flow rate. The findings revealed that the chromatographic separation was accomplished within 15 min, with resolution values greater than 4.5 for Eflornithine enantiomers. The detection and quantitation limits were 9.26 ng mL− 1 and 18.52 ng mL− 1 for Eflornithine enantiomers.

The separation of the enantiomers of diquats by capillary electrophoresis using randomly sulfated cyclodextrins as chiral selectors.

Diquats, derivatives of the widely used herbicide diquat, represent a new class of functional organic molecules. A combination of their special electrochemical properties and axial chirality could potentially result in their important applications in supramolecular chemistry, chiral catalysis, and chiral analysis. However, prior to their practical applications, the diquats have to be prepared in enantiomerically pure forms and the enantiomeric purity of their P- and M-isomers has to be checked. Hence, a chiral capillary electrophoresis (CE) method has been developed and applied for separation of P- and M-enantiomers of 11 new diquats. Fast and better than baseline CE separations of enantiomers of all 11 diquats within a short time 5-7min were achieved using acidic buffer, 22mM NaOH, 35mM H3 PO4 , pH 2.5, as a background electrolyte, and 6mM randomly sulfated α-, β-, and γ-cyclodextrins as chiral selectors. The most successful selector was sulfated γ-cyclodextrin, which baseline separated the enantiomers of all 11 diquats, followed by sulfated β-cyclodextrin and sulfated α-cyclodextrin, which baseline separated enantiomers of 10 and nine diquats, respectively. Using this method, a high enantiopurity degree of the isolated P- and M-enantiomers of three diquats with a defined absolute configuration was confirmed and their migration order was identified.

Separation of left- and right-handed semiconducting single-walled carbon nanotube enantiomers using achiral amino acid surfactant

Synthesized single-walled carbon nanotubes (SWNTs) are racemic mixtures of various (n, m) species with different electronic types, which greatly impeded their practical applications and fundamental research. In this paper, achiral amino acid surfactant sodium N-cocoyl sarcosinate (N-CS) not only displayed selectivity toward s-SWNTs but also could further separate the sorted s-SWNTs by the chirality indices (n, m) and left- and right-handedness with the aid of density gradient ultracentrifugation (DGU). The specific molecular structure of N-CS offered the possibility of recognizing the left- and right-handedness of SWNTs. The enantiomer separation mechanism was illustrated by Molecular dynamics simulations.

Chiral organic-silica hybrid monolithic HPLC column with dynamic grafting BSA for the enantiomeric separation

BSA functionalized hybrid monolithic column prepared by in-situ dynamic grafting on traditional stainless steel column for enantiomeric separation. A hybrid silica monolithic column (HMC) was prepared using a single precursor (methytrimethoxysilane) in stainless steel HPLC column (50 mm × 4.6 mm) by sol–gel method. The chiral hybrid monolithic column (CHMC) was prepared by grafting 3-aminopropyl trimethoxysilane onto HMC, and then reacting bovine serum albumin (BSA) with Glutaraldehyde. The preparation conditions were optimized, and the maximum grafting amount of BSA was 48.6 mg g−1. The CHMC was characterized and its chromatographic performance was tested. The results showed that the CHMC has a homogeneous network skeleton structure, good stability and reproducibility. The CHMC was combined with HPLC, under optimized chromatographic conditions, the baseline separation of tryptophan and pidotimod enantiomers were successfully achieved.

Chiral LC-MS/MS method for the discrimination of triiodothyronine enantiomers on a crown ether-based chiral stationary phase.

Considering the greater pharmaceutical and clinical interest of triiodothyronine (T3 ) thyroid hormone, an effective D/L-T3 enantiomer separation was performed on a crown ether-based chiral stationary phase by LC-MS/MS. In optimal analytical condition and selected reaction monitoring mode, the two enantiomers of T3 were baseline separated within 10min. The limit of detection and limit of quantitation were found to be 0.05 and 0.10ng/μl; 0.20 and 0.50 ng/μl for D- and L-T3 , respectively. During validation, this method proved to be feasible, accurate as well as enantioselective and sensitive for the resolution of T3 enantiomers. For commercial D- and L-T3 chemicals, the enantiomeric impurities as the other enantiomer were 0.11% and 4.61%. On the other hand, the impurity as D-T3 for commercial pharmaceutical products (liothyronine sodium tablets, two suppliers) was 0.68% and 6.57%.

Separation and quantitative estimation of stereo-selective enantiomers of montelukast in pharmaceutical drug substance and tablets dosage forms by using stability-indicating normal phase-HPLC method.

Montelukast sodium (MLS) is a leukotriene receptor antagonist that relieves asthma, bronchospasm, allergic rhinitis, and urticaria. A simple, robust, and stability-indicating normal phase high-performance liquid chromatography method was developed to separate and quantitatively estimate the S-enantiomer of MLS. The chiral separation was achieved using USP L51 packing material along with a mobile phase consisting of a solvent mixture (n-hexane, ethanol, and propionic acid), a flow rate of 1.0mL/min, a detection wavelength of 284 nm, a column temperature of 30°C and an injection volume of 20 μL. The enantiomers peaks were well separated from the peaks of the placebo, diluting solvent, MLS, and its known impurities with a resolution of more than 2.2 and with no interference. Accuracy and linearity were studied in a range of 0.36-3.597 μg/mL (0.03%-0.30%), with good recoveries between 92.5% and 96.8% and a linear regression coefficient above 0.996. The suggested chiral chromatography method is being considered as an alternative and equivalent method to the United States Pharmacopeia and European Pharmacopeia monographs. The developed method was effectively employed for the study of release and stability samples of MLS. This HPLC method is also capable of separating and estimating the stereo-selective isomers (R- and S-enantiomers) of sulfoxide impurity of MLS in pharmaceutical medicine.

Chiral Analysis of Sertaconazole by HPLC Method on Polysaccharide Derivatives

Sertaconazole is a pharmaceutical product in the form of a cream, gel, powder, and solution for dermatological use and vaginal cream, tablets, and ovules for gynecological use. The active ingredient is 2% sertaconazole nitrate. Sertaconazole nitrate is an azole antifungal agent, with notable antifungal activity. The active principal structure of sertaconazole has an asymmetric carbon, which makes this molecule chiral and it is in the form of an enantiomeric mixture. Currently, the control of drugs is based on qualitative and quantitative analysis by the use of effective analytical methods for chiral active ingredients. The enantiomeric separation of an antifungal compound, Sertaconazole, using HPLC is described in this work. The columns employed were based on polysaccharide derivatives (Chiralpak IB, Chiralcel OD-H), and the results show that the separations obtained are better, in terms of high resolution and short analysis time. Chiral separation of Sertaconazole was explained by hydrogen bondings and π-π interactions, between the CSP and this antifungal agent.

Preparation and Enantiomeric Separation of l-Pro-l-Phe-l-Val-l-Leu Peptide Stationary Phases

Preparation and Enantiomeric Separation of l-Pro-l-Phe-l-Val-l-Leu Peptide Stationary Phases

Enantiomeric separation of ketoprofen using Frovatriptan as a chiral derivatizing reagent

AbstractWe established a validated high‐performance liquid chromatography method utilizing Frovatriptan as a chiral derivatizing agent to separate the enantiomers of ketoprofen from commercially available tablet formulations. The chiral derivatizing agent facilitated the synthesis of diastereomeric derivatives of ketoprofen, which were separated on a reversed‐phase C18 column using a mobile phase composed of acetonitrile and 0.1% trifluoroacetic acid under gradient elution from 30% to 70% of acetonitrile. The method demonstrated a limit of detection and quantitation of 2.52 and 8.31 ng/ml for the derivatives, respectively. Validation of the method was performed following the guidelines set by the International Council for Harmonisation to ensure accuracy, precision, and reliability, making it suitable for pharmaceutical industry applications. Notably, this study introduces the novel application of Frovatriptan as a chiral derivatizing agent in high‐performance liquid chromatography for the separation of ketoprofen enantiomers.

Dynamic in situ growth of bonded-phase silica nanospheres on silica capillary inner walls for open-tubular liquid chromatography

Silica nanospheres (SNS) were grown on the inner walls of silica capillaries through a dynamic in situ nucleation process to prepare a highly porous and large accessible surface area substrate. The SNS were then functionalized with octadecyl (C18), 3-aminopropyltriethoxysilane (APTES), beta-cyclodextrin (β-CD), and amino groups to develop robust and efficient chromatographic stationary phases. The modified silica capillaries were exploited for open-tubular liquid chromatography (OT-LC) and open-tubular capillary electrochromatography (OT-CEC) applications. The prepared stationary phases were compared to conventional capillaries in terms of separation performance. The synthesis process was optimized, and the bonded-phase stationary phases were characterized by the electron microscopy technique. The effects of different solvents, additives, and functional groups on the geometry and chromatographic resolving power of the SNS were envisaged. The capillaries modified with octadecyl groups were evaluated for the separation of non-steroidal anti-inflammatory drugs, phenones, alkenylbenzenes, and enantiomers of chlorophenoxy herbicides. As an application instance, an SNS-C18-coated capillary was utilized for the separation of alkenylbenzenes from clove extract and protein digest medium, through OT-LC and OT-CEC techniques, respectively. The β-CD functionalized capillary was applied for the OT-CEC separation of a dichlorprop racemic mixture.Graphical abstract

Preparation and application of a chiral Am7CD-modified COF composite membrane by interfacial polymerization

Membrane separation technology has infinite potential to produce optically pure drugs. However, there are still challenges regarding chiral membranes, such as the single separation object, poor mechanical properties, and constrained relationship between permeability and enantioselectivity. To improve the membrane properties, heptakis (6-amino-6-deoxy)-β-CD-modified carboxyl-functionalized COF (TpBD-Am7CD) was introduced as a chiral functional material for the preparation of a TpBD-Am7CD stainless steel I-Net cellulose acetate membrane (COF/SSCAM) via interfacial polymerization. Using tryptophan as the template molecule, the membrane preparation and filtration conditions were optimized to achieve maximum enantioselectivity. The optimized COF/SSCAM achieved a better enantiomeric excess percentage (e.e.% = 100.00%) and solute permeation flux (JS = 37 × 10−6 mol m−2 h−1) for racemic tryptophan than the support membrane, which was attributed to the enantioselectivity and hydrophilicity of TpBD-Am7CD. Moreover, COF/SSCAM achieved enantiomeric separation of racemates of propranolol, warfarin, atenolol, and metoprolol, and the e.e.% values were 39.51%, 5.60%, 16.04%, and 3.09%, respectively. In addition, the chiral recognition mechanism was investigated by molecular docking simulation.

Valbenazine isomers and enantiomer determination by chiral normal phase liquid chromatography.

A novel, simple, specific, rapid, enantioselective normal phase chiral high-performance liquid chromatographic method with amylose-based Chiral Pak IG-3(250 × 4.6 mM) 3.0 μM column was developed and validated for separation and quantification of isomers and enantiomer of Valbenazine. The mobile phase composed of n-Heptane, isopropyl alcohol, dichloromethane, ethanol, and diethylamine in the ratio of 70:10:15:5:0.1 (V/V/V/VV) with a gradient flow rate was applied. The injection volume was 10 μl, and detection was carried out using a photodiode array detector at 282 nM. The column compartment was set at 35°C. The resolution between the enantiomer and isomers was found to be more than 2.0. The method was linear over the concentration range of limit of quantitation to 250% for isomers and enantiomers. The method was found to be robust with column temperature. The proposed chiral method is applicable for the determination of isomers and enantiomer of Valibenazine and was successfully used in the quality control of bulk drug manufacturing and pharmaceuticals.

Bio‐Templated Chiral Zeolitic Imidazolate Framework for Enantioselective Chemoresistive Sensing

AbstractChiral metal–organic frameworks (MOFs) have gained rising attention as ordered nanoporous materials for enantiomer separations, chiral catalysis, and sensing. Among those, chiral MOFs are generally obtained through complex synthetic routes by using a limited choice of reactive chiral organic precursors as the primary linkers or auxiliary ligands. Here, we report a template‐controlled synthesis of chiral MOFs from achiral precursors grown on chiral nematic cellulose‐derived nanostructured bio‐templates. We demonstrate that chiral MOFs, specifically, zeolitic imidazolate framework (ZIF), unc‐[Zn(2‐MeIm)2, 2‐MeIm=2‐methylimidazole], can be grown from regular precursors within nanoporous organized chiral nematic nanocelluloses via directed assembly on twisted bundles of cellulose nanocrystals. The template‐grown chiral ZIF possesses tetragonal crystal structure with chiral space group of P41, which is different from traditional cubic crystal structure of I‐43 m for freely grown conventional ZIF‐8. The uniaxially compressed dimensions of the unit cell of templated ZIF and crystalline dimensions are signatures of this structure. We observe that the templated chiral ZIF can facilitate the enantiotropic sensing. It shows enantioselective recognition and chiral sensing abilities with a low limit of detection of 39 μM and the corresponding limit of chiral detection of 300 μM for representative chiral amino acid, D‐ and L‐ alanine.

Bio-Templated Chiral Zeolitic Imidazolate Framework-8 for Enantioselective Chemoresistive Sensing.

Chiral metal-organic frameworks (MOFs) have gained rising attention as ordered nanoporous materials for enantiomer separations, chiral catalysis, and sensing. Among those, chiral MOFs are generally obtained through complex synthetic routes by using a limited choice of reactive chiral organic precursors as the primary linkers or auxiliary ligands. Here, we report a template-controlled synthesis of chiral MOFs from achiral precursors grown on chiral nematic cellulose-derived nanostructured bio-templates. We demonstrate that chiral MOFs, specifically, zeolitic imidazolate framework-8 (ZIF-8), can be grown from regular precursors within nanoporous organized chiral nematic nanocelluloses via directed assembly on twisted bundles of cellulose nanocrystals. The template-grown chiral ZIF-8 possesses tetragonal crystal structure with chiral space group of P41, which is different from traditional cubic crystal structure of I-43m for freely grown conventional ZIF-8. The uniaxially compressed dimensions of the unit cell of templated ZIF-8 and crystalline dimensions are signatures of this structure. We observe that the templated chiral ZIF-8 can facilitate the enantiotropic sensing. It shows enantioselective recognition and chiral sensing abilities with a low limit of detection of 39 µM and the corresponding limit of chiral detection of 300 µM for representative chiral amino acid, D- and L- alanine.

Chiral separation and molecular modeling study of decursinol and its derivatives using polysaccharide-based chiral stationary phases

Plant-based bioactive substances have long been used to treat inflammatory ailments, owing to their low toxicity and cost-effectiveness. To enhance plant treatment by eliminating undesirable isomers, optimizing the chiral separation techniques in pharmaceutical and clinical studies is important. This study reported a simple and effective method for chiral separation of decursinol and its derivatives, which are pyranocoumarin compounds with anti-cancer and anti-inflammatory properties. Baseline separation (Rs >1.5) was achieved using five different polysaccharide-based chiral stationary phases (CSPs) that differed in chiral origin, chiral selector chemistry, and preparation technique. To separate all six enantiomers simultaneously, n-hexane and three alcohol modifiers (ethanol, isopropanol, and n-butanol) were used as mobile phases in the normal-phase mode. The chiral separation ability of each column with various mobile phase compositions was compared and discussed. As a result, amylose-based CSPs with linear alcohol modifiers demonstrated superior resolution. Three cases of elution order reversal caused by modifications of CSPs and alcohol modifiers were observed and thoroughly analyzed. To elucidate the chiral recognition mechanism and enantiomeric elution order (EEO) reversal phenomenon, detailed molecular docking simulations were conducted. The R- and S-enantiomers of decursinol, epoxide, and CGK012 exhibited binding energies of –6.6, –6.3, –6.2, –6.3, –7.3, and –7.5 kcal/mol, respectively. The magnitude of the difference in binding energies was consistent with the elution order and enantioselectivity (α) of the analytes. The molecular simulation results demonstrated that hydrogen bonds, π–π interactions, and hydrophobic interactions have a significant impact on chiral recognition mechanisms. Overall, this study presented a novel and logical approach of optimizing chiral separation techniques in the pharmaceutical and clinical industries. Our findings could be further applied for screening and optimizing enantiomeric separation.