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Advances in Chiral Analysis

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Analytical Chemistry".

Deadline for manuscript submissions: 31 March 2024 | Viewed by 13234

Special Issue Editors

Department of Pharmaceutical Chemistry, Semmelweis University, Hőgyes E. Str. 9, H-1085 Budapest, Hungary
Interests: analytical chemistry; chirality; drug analysis; separation techniques; capillary electrophoresis; high performance liquid chromatography
Special Issues, Collections and Topics in MDPI journals
Pharmaceutical and Therapeutical Chemistry Department, Faculty of Pharmacy, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, 38 Gheorghe Marinescu Street, 540142 Targu Mureș, Romania
Interests: drug analysis; chirality; chiral separation; separation techniques; capillary electrophoresis; high performance liquid chromatography
Special Issues, Collections and Topics in MDPI journals
Department of Pharmaceutical Industry and Management, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, Gh. Marinescu 38, RO-540139 Targu Mures, Romania
Interests: chiral separations; cyclodextrins; capillary electrophoresis; liquid chromatography; experimental design; nanofibers; electrospinning
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Chirality is a property of asymmetry that impacts all aspects of our lives. Many synthetic substances exist and are used in different domains, such as racemic mixtures; however, in several cases, there are well-documented differences in the effects, pharmacokinetic profiles, toxicities, or environmental fates of individual enantiomers. This is no surprise, as one of the key features of life on Earth is the homochirality of biomolecules. Thus, the development of new and advanced analytical methods for the enantioseparation of chiral substances is a necessity, but also remains one of the most challenging tasks in separation science.

Many fields, such as chemistry, biomedicine, the pharmaceutical industry, agriculture, and food science, involve chiral analysis. The separation, identification, and quantification of enantiomers assures that pharmaceutical drug ingredients and drug products are safe and effective. Enantiomeric separation is also required for several food ingredients and substances used in agriculture.

During the last three decades, a wide range of approaches were reported based on chromatographic techniques (high-performance liquid chromatography (HPLC), gas chromatography (GC), supercritical fluid chromatography (SFC), and thin-layer chromatography (TLC)) and electrophoretic techniques (capillary electrophoresis (CE) and capillary electrochromatography (CEC)) for enantiomeric separations.

HPLC can be used to separate enantiomers either directly, by using chiral stationary phases or chiral mobile-phase additives, or indirectly, by employing chiral derivatization reagents. The same methodologies can also be applied for CE separations; however, most of the CE methods use the direct approach by simply dissolving one or more chiral selectors in the background electrolyte. Although a myriad of chiral selectors is already available on the market and several technical advancements have been made, chiral recognition mechanisms are still not fully understood.

This Special Issue covers all aspects related to enantioseparations, emphasizing the enantiospecific determination of bioactive molecules in complex matrices, including biological matrices, as well as mechanistic studies regarding enantioseparations. Additionally, research and review articles related to new aspects of chiral synthesis, analysis, and the pharmacokinetic and pharmacodynamic aspects of drugs and agrochemicals are also welcome.

Dr. Gergo Toth
Dr. Gabriel Hancu
Dr. Zoltán István Szabó
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • chirality
  • HPLC
  • capillary electrophoresis
  • enantiomers
  • enantioseparation
  • chiral separation
  • chiral selectors
  • chiral stationary phases
  • chiral pesticides

Published Papers (9 papers)

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Research

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9 pages, 808 KiB  
Article
A Chiral-LC-MS Method for the Simultaneous Quantification of Short-Chain Fatty Acids and D/L-Lactate in the Ruminal Fluid of Dairy Cows
by Zhiqian Liu, S. Richard O. Williams, Joe L. Jacobs, Aodan S. O. Neachtain and Simone Rochfort
Molecules 2024, 29(6), 1398; https://doi.org/10.3390/molecules29061398 - 21 Mar 2024
Viewed by 332
Abstract
Short-chain fatty acids (SCFA) and lactate in ruminal fluid are products resulting from the microbial fermentation of substrates and can be used to reflect the composition and activity of the ruminal microbiome. Determination of SCFA and D-/L-lactate in ruminal fluid currently requires two [...] Read more.
Short-chain fatty acids (SCFA) and lactate in ruminal fluid are products resulting from the microbial fermentation of substrates and can be used to reflect the composition and activity of the ruminal microbiome. Determination of SCFA and D-/L-lactate in ruminal fluid currently requires two separate protocols, which is time-consuming and costly. In this study, we have optimised and validated a simple and unified 3-nitrophenylhydrazine (3-NPH) derivatisation protocol and a 20 min chiral-LC-MS method for the simultaneous quantification of all SCFA and D- and L-lactate in ruminal fluid. This method, which requires no sample pretreatment or purification shows adequate sensitivity (limit of detection (LOD): 0.01 µg/mL), satisfactory accuracy (recovery: 88–103%), and excellent reproducibility (relative standard deviation (RSD) for repeated analyses < 3% for most analytes). The application of this method to a cohort of 24 animals allowed us to reveal a large inter-cow variation in ruminal SCFA and lactate level, the concentration range for each species, the widespread correlation between different SCFA, and the strong correlation between D- and L-lactate. Full article
(This article belongs to the Special Issue Advances in Chiral Analysis)
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20 pages, 2761 KiB  
Article
Cyclodextrin-Enabled Enantioselective Complexation Study of Cathinone Analogs
by András Dohárszky, Eszter Kalydi, Gergely Völgyi, Szabolcs Béni and Ida Fejős
Molecules 2024, 29(4), 876; https://doi.org/10.3390/molecules29040876 - 16 Feb 2024
Viewed by 745
Abstract
The characteristic alkaloid component of the leaves of the catnip shrub (Catha edulis) is cathinone, and its synthetic analogs form a major group of recreational drugs. Cathinone derivatives are chiral compounds. In the literature, several chiral methods using cyclodextrins (CDs) have [...] Read more.
The characteristic alkaloid component of the leaves of the catnip shrub (Catha edulis) is cathinone, and its synthetic analogs form a major group of recreational drugs. Cathinone derivatives are chiral compounds. In the literature, several chiral methods using cyclodextrins (CDs) have been achieved so far for diverse sets of analogs; however, a comprehensive investigation of the stability of their CD complexes has not been performed yet. To characterize the enantioselective complex formation, a systematic experimental design was developed in which a total number of 40 neutral, positively, and negatively charged CD derivatives were screened by affinity capillary electrophoresis and compared according to their cavity size, substituent type, and location. The functional groups responsible for the favorable interactions were identified in the case of para-substituted cathinone analog mephedrone, flephedrone, and 4-methylethcathinone (4-MEC) and in the case of 3,4-methylendioxy derivative butylone and methylenedioxypyrovalerone (MDPV). The succinylated-β-CD and subetadex exhibited the highest complex stabilities among the studied drugs. The complex stoichiometry was determined using the Job’s plot method, and the complex structures were further studied using ROESY NMR measurements. The results of our enantioselective complex formation study can facilitate chiral method development and may lead to evaluate potential CD-based antidotes for cathinone analogs. Full article
(This article belongs to the Special Issue Advances in Chiral Analysis)
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24 pages, 5935 KiB  
Article
Development of an HPLC-MS/MS Method for Chiral Separation and Quantitation of (R)- and (S)-Salbutamol and Their Sulfoconjugated Metabolites in Urine to Investigate Stereoselective Sulfonation
by Lukas Corbinian Harps, Annika Lisa Jendretzki, Clemens Alexander Wolf, Ulrich Girreser, Gerhard Wolber and Maria Kristina Parr
Molecules 2023, 28(20), 7206; https://doi.org/10.3390/molecules28207206 - 21 Oct 2023
Viewed by 840
Abstract
The aim of this study was to develop and optimize a chiral HPLC-MS/MS method for quantitative analysis of (R)-/(S)-salbutamol and (R)-/(S)-salbutamol-4′-O-sulfate in human urine to allow for bioanalytical quantitation of the targeted analytes [...] Read more.
The aim of this study was to develop and optimize a chiral HPLC-MS/MS method for quantitative analysis of (R)-/(S)-salbutamol and (R)-/(S)-salbutamol-4′-O-sulfate in human urine to allow for bioanalytical quantitation of the targeted analytes and investigations of stereoselectivity in the sulfonation pathway of human phase Ⅱ metabolism. For analytical method development, a systematic screening of columns and mobile phases to develop a separation via enantiomerically selective high performance liquid chromatography was performed. Electrospray ionization settings were optimized via multiple-step screening and a full factorial design-of-experiment. Both approaches were performed matrix-assisted and the predicted values were compared. The full factorial design was superior in terms of prediction power and knowledge generation. Performing a longitudinal excretion study in one healthy volunteer allowed for the calculation of excretion rates for all four targeted analytes. For this proof-of-concept, either racemic salbutamol or enantiopure levosalbutamol was administered perorally or via inhalation, respectively. A strong preference for sulfonation of (R)-salbutamol for inhalation and peroral application was found in in vivo experiments. In previous studies phenol sulfotransferase 1A3 was described to be mainly responsible for salbutamol sulfonation in humans. Thus, in vitro and in silico investigations of the stereoselectivity of sulfotransferase 1A3 complemented the study and confirmed these findings. Full article
(This article belongs to the Special Issue Advances in Chiral Analysis)
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16 pages, 3034 KiB  
Article
Lipase as a Chiral Selector Immobilised on Carboxylated Single-Walled Carbon Nanotubes and Encapsulated in the Organic Polymer Monolithic Capillary for Nano-High Performance Liquid Chromatography Enantioseparation of Racemic Pharmaceuticals
by Ali Fouad, Frady G. Adly, Moustafa K. Soltan and Ashraf Ghanem
Molecules 2023, 28(18), 6663; https://doi.org/10.3390/molecules28186663 - 16 Sep 2023
Viewed by 765
Abstract
Herein, we report the preparation of lipase immobilised on single-walled carbon nanotubes (SWCNTs) as an enantioselector for capillary monolithic columns and their application in the chiral separation of racemic pharmaceuticals. The columns were prepared through the encapsulation of functionalised SWCNTs (c-SWCNTs) within an [...] Read more.
Herein, we report the preparation of lipase immobilised on single-walled carbon nanotubes (SWCNTs) as an enantioselector for capillary monolithic columns and their application in the chiral separation of racemic pharmaceuticals. The columns were prepared through the encapsulation of functionalised SWCNTs (c-SWCNTs) within an organic monolithic polymer, followed by the immobilisation of lipase over the obtained monolith, over a three-day (L1) and five-day (L2) period. The prepared columns were tested for the enantioselective nano-HPLC separation of 50 racemic drugs. A suitable resolution was achieved for 25 drugs using nano-RP-HPLC conditions for both the L1 and L2 capillaries, while no specific resolution was detected under normal-phase HPLC conditions. The developed c-SWCNT-lipase-based polymeric monolithic capillaries are a promising expansion for separating pharmaceutical enantiomers’ using nano-HPLC. Full article
(This article belongs to the Special Issue Advances in Chiral Analysis)
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19 pages, 6123 KiB  
Article
Stereochemistry of Chiral 2-Substituted Chromanes: Twist of the Dihydropyran Ring and Specific Optical Rotation
by Bei-Bei Yang, Fan Gao, Ya-Dong Yang, Ru Wang, Xin Li and Li Li
Molecules 2023, 28(1), 439; https://doi.org/10.3390/molecules28010439 - 03 Jan 2023
Viewed by 1408
Abstract
Chiral 2-substituted chromanes are important substructures in organic synthesis and appear in numerous natural products. Herein, the correlation between specific optical rotations (SORs) and the stereochemistry at C2 of chiral 2-substituted chromanes was investigated through data mining, quantum-chemical calculations using density functional theory [...] Read more.
Chiral 2-substituted chromanes are important substructures in organic synthesis and appear in numerous natural products. Herein, the correlation between specific optical rotations (SORs) and the stereochemistry at C2 of chiral 2-substituted chromanes was investigated through data mining, quantum-chemical calculations using density functional theory (DFT), and mechanistic analyses. For 2-aliphatic (including acyloxy and alkenyl) chromanes, the P-helicity of the dihydropyran ring usually corresponds to a positive SOR; however, 2-aryl chromanes with P-helicity tend to exhibit negative SORs. 2-Carboxyl (including alkoxycarbonyl and carbonyl) chromanes often display small experimental SORs, and theoretical calculations for them are prone to error because of the fluctuating conformational distribution with computational parameters. Several typical compounds were discussed, including detailed descriptions of the asymmetric synthesis, absolute configuration (AC) assignment methods, and systematic conformational analysis. We hope this work will enrich the knowledge of the stereochemistry of chiral 2-substituted chromanes. Full article
(This article belongs to the Special Issue Advances in Chiral Analysis)
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21 pages, 5707 KiB  
Article
UHPLC Enantiomer Resolution for the ɑ/β-Adrenoceptor Antagonist R/S-Carvedilol and Its Major Active Metabolites on Chiralpak IB N-5
by Liza Samir, Rasha Hanafi, Sami El Deeb and Hilde Spahn-Langguth
Molecules 2022, 27(15), 4998; https://doi.org/10.3390/molecules27154998 - 05 Aug 2022
Cited by 2 | Viewed by 1542
Abstract
Carvedilol (CAR), a racemic lipophilic aryloxy propanolamine, acts as a selective α1-adrenoreceptor antagonist and a nonselective β-adrenoreceptor antagonist. CAR metabolism mainly produces three active metabolites: desmethyl carvedilol (DMC), 4′-hydroxy carvedilol (4′OHC) and 5′-hydroxy carvedilol (5′OHC). The oxidative S-(-)-metabolites contribute to [...] Read more.
Carvedilol (CAR), a racemic lipophilic aryloxy propanolamine, acts as a selective α1-adrenoreceptor antagonist and a nonselective β-adrenoreceptor antagonist. CAR metabolism mainly produces three active metabolites: desmethyl carvedilol (DMC), 4′-hydroxy carvedilol (4′OHC) and 5′-hydroxy carvedilol (5′OHC). The oxidative S-(-)-metabolites contribute to the β-antagonistic effect, yet not to the α-antagonistic effect to be observed after drug dosage. Therefore, the three β-adrenoceptor blocking metabolites, which are structurally closely related to the parent CAR, are included into the development of a bioanalytical quantitative method for all major active species relevant with respect to adrenoceptor-blockade. Because of the given pharmacological profile, resolution of the enantiomers of carvedilol, of 4′- and 5′-hydroxy carvedilol as well as of DMC, is mandatory. The current study aims to determine the response surface for the enantiomer separation of the parent CAR as well as the major metabolites on a suitable chiral stationary phase. Design of experiment approach (DoE) was utilized in an initial screening phase followed by central-composite design for delimitation of the response surface for resolution of the four enantiomeric pairs in least run time. The impact of chromatographic variables (composition and percentage of organic modifier(s), buffer type, buffer pH, flow rate) on critical peaks resolution and adjusted retention time was evaluated, in order to select the most significant critical quality attributes. On this basis, a robust UHPLC-UV method was developed and optimized for the simultaneous, enantioselective determination of CAR along with its major active metabolites (4′OHC, 5′OHC, and DMC) on Chiralpak IBN-5. The optimized UHPLC-UV method (which includes metoprolol as the internal standard) was validated according to the ICH M10 guidelines for bioanalytical methods and proven to be linear, precise, accurate, and robust. The validated assay was applied to plasma samples from cardiovascular patients treated with rac-CAR (blood randomly drawn at different times after oral CAR intake). In order to provide more insight into the mechanism of the enantiomer separation of CAR and its metabolites on the CSP, docking experiments were performed. Molecular simulation studies suggest the chiral recognition to be mainly due to different binding poses of enantiomers of the same compound. Full article
(This article belongs to the Special Issue Advances in Chiral Analysis)
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13 pages, 3983 KiB  
Article
Determination of Chiral Impurity of Naproxen in Different Pharmaceutical Formulations Using Polysaccharide-Based Stationary Phases in Reversed-Phased Mode
by Lajos-Attila Papp, Sarolta Krizbai, Máté Dobó, Gabriel Hancu, Zoltán-István Szabó and Gergő Tóth
Molecules 2022, 27(9), 2986; https://doi.org/10.3390/molecules27092986 - 06 May 2022
Cited by 10 | Viewed by 2472
Abstract
A novel, validated, reversed-phase (RP), chiral high performance liquid chromatography (HPLC) method was developed for the enantiopurity control analysis of naproxen, a frequently used non-steroidal anti-inflammatory agent using polysaccharide-type chiral stationary phase (CSP). In the screening phase of method development, seven columns were [...] Read more.
A novel, validated, reversed-phase (RP), chiral high performance liquid chromatography (HPLC) method was developed for the enantiopurity control analysis of naproxen, a frequently used non-steroidal anti-inflammatory agent using polysaccharide-type chiral stationary phase (CSP). In the screening phase of method development, seven columns were tested in polar organic (PO) mode using mobile phases consisting of 0.1% acetic acid in methanol, ethanol, 2-propanol, and acetonitrile. Enantiorecognition was observed only in five cases. The best enantioseparation was observed on a Lux Amylose-1 column with 0.1% (v/v) acetic acid in ethanol with a resolution (Rs) of 1.24. The enantiomer elution order was unfavorable, as the distomer eluted after the eutomer. When the ethanolic mobile phase was supplemented with water, enantiomer elution order reversal was observed, indicating a difference in the enantiorecognition mechanism upon switching from PO to RP mode. Furthermore, by changing ethanol to methanol, not only lower backpressure, but also higher resolution was obtained. Subsequent method optimization was performed using a face-centered central composite design (FCCD) to achieve higher chiral resolution in a shorter analysis time. Optimized parameters offering baseline separation were as follows: Lux Amylose-1 stationary phase, thermostated at 40 °C, and a mobile phase consisting of methanol:water:acetic acid 85:15:0.1 (v/v/v), delivered with 0.65 mL/min flow rate. Using these optimized parameters, a Rs = 3.21 ± 0.03 was achieved within seven minutes. The optimized method was validated according to the ICH guidelines and successfully applied for the analysis of different pharmaceutical preparations, such as film-coated tablets and gel, as well as fixed-dose combination tablets, containing both naproxen and esomeprazole. Full article
(This article belongs to the Special Issue Advances in Chiral Analysis)
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Review

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29 pages, 9603 KiB  
Review
Molecular Dynamics Simulations of Amylose- and Cellulose-Based Selectors and Related Enantioseparations in Liquid Phase Chromatography
by Roberto Dallocchio, Alessandro Dessì, Barbara Sechi and Paola Peluso
Molecules 2023, 28(21), 7419; https://doi.org/10.3390/molecules28217419 - 03 Nov 2023
Cited by 2 | Viewed by 826
Abstract
In the last few decades, theoretical and technical advancements in computer facilities and computational techniques have made molecular modeling a useful tool in liquid-phase enantioseparation science for exploring enantioselective recognition mechanisms underlying enantioseparations and for identifying selector–analyte noncovalent interactions that contribute to binding [...] Read more.
In the last few decades, theoretical and technical advancements in computer facilities and computational techniques have made molecular modeling a useful tool in liquid-phase enantioseparation science for exploring enantioselective recognition mechanisms underlying enantioseparations and for identifying selector–analyte noncovalent interactions that contribute to binding and recognition. Because of the dynamic nature of the chromatographic process, molecular dynamics (MD) simulations are particularly versatile in the visualization of the three-dimensional structure of analytes and selectors and in the unravelling of mechanisms at molecular levels. In this context, MD was also used to explore enantioseparation processes promoted by amylose and cellulose-based selectors, the most popular chiral selectors for liquid-phase enantioselective chromatography. This review presents a systematic analysis of the literature published in this field, with the aim of providing the reader with a comprehensive picture about the state of the art and what is still missing for modeling cellulose benzoates and the phenylcarbamates of amylose and cellulose and related enantioseparations with MD. Furthermore, advancements and outlooks, as well as drawbacks and pitfalls still affecting the applicability of MD in this field, are also discussed. The importance of integrating theoretical and experimental approaches is highlighted as an essential strategy for profiling mechanisms and noncovalent interaction patterns. Full article
(This article belongs to the Special Issue Advances in Chiral Analysis)
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28 pages, 2893 KiB  
Review
New Trends in the Quality Control of Enantiomeric Drugs: Quality by Design-Compliant Development of Chiral Capillary Electrophoresis Methods
by Serena Orlandini, Gabriel Hancu, Zoltán-István Szabó, Adriana Modroiu, Lajos-Attila Papp, Roberto Gotti and Sandra Furlanetto
Molecules 2022, 27(20), 7058; https://doi.org/10.3390/molecules27207058 - 19 Oct 2022
Cited by 17 | Viewed by 2920
Abstract
Capillary electrophoresis (CE) is a potent method for analyzing chiral substances and is commonly used in the enantioseparation and chiral purity control of pharmaceuticals from different matrices. The adoption of Quality by Design (QbD) concepts in analytical method development, optimization and validation is [...] Read more.
Capillary electrophoresis (CE) is a potent method for analyzing chiral substances and is commonly used in the enantioseparation and chiral purity control of pharmaceuticals from different matrices. The adoption of Quality by Design (QbD) concepts in analytical method development, optimization and validation is a widespread trend observed in various analytical approaches including chiral CE. The application of Analytical QbD (AQbD) leads to the development of analytical methods based on sound science combined with risk management, and to a well understood process clarifying the influence of method parameters on the analytical output. The Design of Experiments (DoE) method employing chemometric tools is an essential part of QbD-based method development, allowing for the simultaneous evaluation of experimental parameters as well as their interaction. In 2022 the International Council for Harmonization (ICH) released two draft guidelines (ICH Q14 and ICH Q2(R2)) that are intended to encourage more robust analytical procedures. The ICH Q14 guideline intends to harmonize the scientific approaches for analytical procedures’ development, while the Q2(R2) document covers the validation principles for the use of analytical procedures including the recent applications that require multivariate statistical analyses. The aim of this review is to provide an overview of the new prospects for chiral CE method development applied for the enantiomeric purity control of pharmaceuticals using AQbD principles. The review also provides an overview of recent research (2012–2022) on the applicability of CE methods in chiral drug impurity profiling. Full article
(This article belongs to the Special Issue Advances in Chiral Analysis)
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