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Chiral Separation by Chromatographic and Electrophoretic Methods Applied in the Enantioseparation of Pharmaceuticals

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

Deadline for manuscript submissions: closed (1 January 2022) | Viewed by 36658

Special Issue Editor

Prof. Dr. Gabriel Hancu

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Guest Editor
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

Special Issue Information

Dear Colleagues,

Chirality is a property of asymmetry which governs life, as all molecules in nature function in the form of pure enantiomers. A large number synthetic substance exists and are used in different domains as racemic mixture, however in many cases the differences between the effects and profiles of their enantiomers are well known and documented. The development of new advanced analytical methods for the enantioseparation of chiral substances is a necessity but also remains one of the most challenging tasks in separation science.

The guidelines for the development of new drugs issued by regulating authorities (FDA, EMA) for the development of new pharmaceuticals call for effective enantiomeric purity control methods. During the last three decades, a wide range of approaches based on chromatographic techniques (high performance liquid chromatography (HPLC), gas chromatography (GC), supercritical fluid chromatography (SFC)) and electrophoretic (capillary electrophoresis (CE), capillary electrochromatography (CEC) have been developed for enantiomer separation on an analytical scale.

HPLC can be used to separate enantiomers either directly using chiral stationary phases or chiral mobile phase additives or indirectly with chiral derivatization reagents. The same methodologies apply also for CE separations, however most of the CE methods using a direct chiral separation method by simply adding a chiral selector in the background electrolyte.

This Special Issue covers all aspects of enantioseparation of chiral substances of pharmaceutical interest, emphasizing on the chiral determination of biologically active compounds in complex matrices, including biological ones. Additionally, research and review articles related to new aspects of chiral synthesis, analysis, pharmacokinetic and pharmacodynamic of molecules with pharmaceutical use will be included.

Dr. Gabriel Hancu
Guest Editor

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Keywords

  • chirality
  • enantiomers
  • chiral separation
  • high performance liquid chromatography
  • capillary electrophoresis
  • chiral selectors
  • chiral stationary phases
  • drug analysis

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Published Papers (8 papers)

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Research

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14 pages, 2345 KiB  
Article
Comparative Chiral Separation of Thalidomide Class of Drugs Using Polysaccharide-Type Stationary Phases with Emphasis on Elution Order and Hysteresis in Polar Organic Mode
by Mohammadhassan Foroughbakhshfasaei, Máté Dobó, Francisc Boda, Zoltán-István Szabó and Gergő Tóth
Molecules 2022, 27(1), 111; https://doi.org/10.3390/molecules27010111 - 24 Dec 2021
Cited by 16 | Viewed by 4985
Abstract
The enantioseparation of four phthalimide derivatives (thalidomide, pomalidomide, lenalidomide and apremilast) was investigated on five different polysaccharide-type stationary phases (Chiralpak AD, Chiralpak AS, Lux Amylose-2, Chiralcel OD and Chiralcel OJ-H) using neat methanol (MeOH), ethanol (EtOH), 1-propanol (PROP), 2-propanol (IPA) and acetonitrile (ACN) [...] Read more.
The enantioseparation of four phthalimide derivatives (thalidomide, pomalidomide, lenalidomide and apremilast) was investigated on five different polysaccharide-type stationary phases (Chiralpak AD, Chiralpak AS, Lux Amylose-2, Chiralcel OD and Chiralcel OJ-H) using neat methanol (MeOH), ethanol (EtOH), 1-propanol (PROP), 2-propanol (IPA) and acetonitrile (ACN) as polar organic mobile phases and also in combination. Along with the separation capacity of the applied systems, our study also focuses on the elution sequences, the effect of mobile phase mixtures and the hysteresis of retention and selectivity. Although on several cases extremely high resolutions (Rs > 10) were observed for certain compounds, among the tested conditions only Chiralcel OJ-H column with MeOH was successful for baseline-separation of all investigated drugs. Chiral selector- and mobile-phase-dependent reversals of elution order were observed. Reversal of elution order and hysteresis of retention and enantioselectivity were further investigated using different eluent mixtures on Chiralpak AD, Chiralcel OD and Lux Amylose-2 column. In an IPA/MeOH mixture, enantiomer elution-order reversal was observed depending on the eluent composition. Furthermore, in eluent mixtures, enantioselectivity depends on the direction from which the composition of the eluent is approached, regardless of the eluent pair used on amylose-based columns. Using a mixture of polar alcohols not only the selectivities but the enantiomer elution order can also be fine-tuned on Chiralpak AD column, which opens up the possibility of a new type of chiral screening strategy. Full article
(This article belongs to the Special Issue Chiral Separation by Chromatographic and Electrophoretic Methods Applied in the Enantioseparation of Pharmaceuticals)
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17 pages, 1391 KiB  
Article
Single Isomer N-Heterocyclic Cyclodextrin Derivatives as Chiral Selectors in Capillary Electrophoresis
by Ida Fejős, Eszter Kalydi, Edit Luca Kukk, Mimimorena Seggio, Milo Malanga and Szabolcs Béni
Molecules 2021, 26(17), 5271; https://doi.org/10.3390/molecules26175271 - 30 Aug 2021
Cited by 9 | Viewed by 2677
Abstract
In order to better understand the chiral recognition mechanisms of positively charged cyclodextrin (CD) derivatives, the synthesis, the pKa determination by 1H nuclear magnetic resonance (NMR)-pH titration and a comparative chiral capillary electrophoretic (CE) study were performed with two series [...] Read more.
In order to better understand the chiral recognition mechanisms of positively charged cyclodextrin (CD) derivatives, the synthesis, the pKa determination by 1H nuclear magnetic resonance (NMR)-pH titration and a comparative chiral capillary electrophoretic (CE) study were performed with two series of mono-substituted cationic single isomer CDs. The first series of selectors were mono-(6-N-pyrrolidine-6-deoxy)-β-CD (PYR-β-CD), mono-(6-N-piperidine-6-deoxy)-β-CD (PIP-β-CD), mono-(6-N-morpholine-6-deoxy)-β-CD (MO-β-CD) and mono-(6-N-piperazine-6-deoxy)-β-CD (PIPA-β-CD), carrying a pH-adjustable moiety at the narrower rim of the cavity, while the second set represented by their quaternarized, permanently cationic counterparts: mono-(6-N-(N-methyl-pyrrolidine)-6-deoxy)-β-CD (MePYR-β-CD), mono-(6-N-(N-methyl-piperidine)-6-deoxy)-β-CD (MePIP-β-CD), mono-(6-N-(N-methyl-morpholine)-6-deoxy)-β-CD (MeMO-β-CD) and mono-(6-N-(4,4-N,N-dimethyl-piperazine)-β-CD (diMePIPA-β-CD). Based on pH-dependent and selector concentration-dependent comparative studies of these single isomer N-heterocyclic CDs presented herein, it can be concluded that all CDs could successfully be applied as chiral selectors for the enantiodiscrimination of several negatively charged and zwitterionic model racemates. The substituent-dependent enantiomer migration order reversal of dansylated-valine using PIP-β-CD contrary to PYP-β-CD, MO-β-CD and PIPA-β-CD was also studied by 1H- and 2D ROESY NMR experiments. Full article
(This article belongs to the Special Issue Chiral Separation by Chromatographic and Electrophoretic Methods Applied in the Enantioseparation of Pharmaceuticals)
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Review

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51 pages, 7785 KiB  
Review
Capillary Electrophoresis Mass Spectrometry: Developments and Applications for Enantioselective Analysis from 2011–2020
by Shahab A. Shamsi and Ferdoushi Akter
Molecules 2022, 27(13), 4126; https://doi.org/10.3390/molecules27134126 - 27 Jun 2022
Cited by 15 | Viewed by 3754
Abstract
It is now more than 25 years since the first report of enantioselective analysis by capillary electrophoresis-mass spectrometry (CE-MS) appeared. This article reviews the power of chiral CE-MS in resolving issues on the use of chiral selector incompatibility with MS and poor detectability [...] Read more.
It is now more than 25 years since the first report of enantioselective analysis by capillary electrophoresis-mass spectrometry (CE-MS) appeared. This article reviews the power of chiral CE-MS in resolving issues on the use of chiral selector incompatibility with MS and poor detectability encountered for chiral compounds by UV detection. The review begins with the general principles, requirements, and critical aspects of chiral CE-MS instrumentation. Next, the review provides a survey of MS-compatible chiral selectors (CSs) reported during the past decade, and the key achievements encountered in the time period using these CSs. Within the context of the strategies used to combine CE and MS, special attention is paid to the approaches that feature partial filling technique, counter-migration techniques, and direct use of CS, such as molecular micelles. In particular, the development and application of moving and fixed CS for EKC-MS, MEKC-MS, and CEC-MS demonstrate how various chiral compounds analyses were solved in a simple and elegant way during the 2010–2020 review period. The most noteworthy applications in the determination of chiral compounds are critically examined. The operating analytical conditions are detailed in the Tables, and the authors provide commentary on future trends of chiral separations by CE-MS. Full article
(This article belongs to the Special Issue Chiral Separation by Chromatographic and Electrophoretic Methods Applied in the Enantioseparation of Pharmaceuticals)
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24 pages, 2621 KiB  
Review
The Use of Antibiotics as Chiral Selectors in Capillary Electrophoresis: A Review
by Gabriel Hancu, Lajos Attila Papp, Blanka Szekely-Szentmiklosi and Hajnal Kelemen
Molecules 2022, 27(11), 3601; https://doi.org/10.3390/molecules27113601 - 3 Jun 2022
Cited by 18 | Viewed by 2981
Abstract
Chirality is becoming an essential issue in modern pharmaceutical research as regulatory agencies emphasize the safety and efficiency of enantiomers in drug development. The development of efficient and reliable chiral separation methods became a necessity in the last 30 years, and capillary electrophoresis [...] Read more.
Chirality is becoming an essential issue in modern pharmaceutical research as regulatory agencies emphasize the safety and efficiency of enantiomers in drug development. The development of efficient and reliable chiral separation methods became a necessity in the last 30 years, and capillary electrophoresis (CE), due to its relatively low costs and “green” features, is attracting increased attention. Cyclodextrin (CD) and their derivatives are the most frequently used chiral selectors (CSs) in CE, however, the use of antibiotics as CSs represents an interesting alternative. Various classes of antibiotics (aminoglycosides, ansamycins, glycopeptides, lincosamides, macrolides, tetracyclines) have been used more or less successfully for the enantio-separation of pharmaceuticals. Antibiotics offer the possibility of a multitude of potential interactions (electrostatic, inclusion, hydrogen bonding, etc.) due to their chemical diversity, allowing the enantio-separation of analytes with a wide range of structural characteristics. This article aims to review the application of various classes of antibiotics in the CE enantio-separation of pharmaceuticals. Antibiotic physiochemical characteristics, variables impacting enantio-separation, advantages, and disadvantages when certain antibiotics are used as CSs in CE are also explored. Full article
(This article belongs to the Special Issue Chiral Separation by Chromatographic and Electrophoretic Methods Applied in the Enantioseparation of Pharmaceuticals)
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24 pages, 2542 KiB  
Review
Bile Salts in Chiral Micellar Electrokinetic Chromatography: 2000–2020
by Raymond B. Yu and Joselito P. Quirino
Molecules 2021, 26(18), 5531; https://doi.org/10.3390/molecules26185531 - 12 Sep 2021
Cited by 9 | Viewed by 2725
Abstract
Bile salts are naturally occurring chiral surfactants that are able to solubilize hydrophobic compounds. Because of this ability, bile salts were exploited as chiral selectors added to the background solution (BGS) in the chiral micellar electrokinetic chromatography (MEKC) of various small molecules. In [...] Read more.
Bile salts are naturally occurring chiral surfactants that are able to solubilize hydrophobic compounds. Because of this ability, bile salts were exploited as chiral selectors added to the background solution (BGS) in the chiral micellar electrokinetic chromatography (MEKC) of various small molecules. In this review, we aimed to examine the developments in research on chiral MEKC using bile salts as chiral selectors over the past 20 years. The review begins with a discussion of the aggregation of bile salts in chiral recognition and separation, followed by the use of single bile salts and bile salts with other chiral selectors (i.e., cyclodextrins, proteins and single-stranded DNA aptamers). Advanced techniques such as partial-filling MEKC, stacking and single-drop microextraction were considered. Potential applications to real samples, including enantiomeric impurity analysis, were also discussed. Full article
(This article belongs to the Special Issue Chiral Separation by Chromatographic and Electrophoretic Methods Applied in the Enantioseparation of Pharmaceuticals)
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23 pages, 1549 KiB  
Review
Enantioselectivity in Drug Pharmacokinetics and Toxicity: Pharmacological Relevance and Analytical Methods
by Maria Miguel Coelho, Carla Fernandes, Fernando Remião and Maria Elizabeth Tiritan
Molecules 2021, 26(11), 3113; https://doi.org/10.3390/molecules26113113 - 23 May 2021
Cited by 93 | Viewed by 8667
Abstract
Enzymes, receptors, and other binding molecules in biological processes can recognize enantiomers as different molecular entities, due to their different dissociation constants, leading to diverse responses in biological processes. Enantioselectivity can be observed in drugs pharmacodynamics and in pharmacokinetic (absorption, distribution, metabolism, and [...] Read more.
Enzymes, receptors, and other binding molecules in biological processes can recognize enantiomers as different molecular entities, due to their different dissociation constants, leading to diverse responses in biological processes. Enantioselectivity can be observed in drugs pharmacodynamics and in pharmacokinetic (absorption, distribution, metabolism, and excretion), especially in metabolic profile and in toxicity mechanisms. The stereoisomers of a drug can undergo to different metabolic pathways due to different enzyme systems, resulting in different types and/or number of metabolites. The configuration of enantiomers can cause unexpected effects, related to changes as unidirectional or bidirectional inversion that can occur during pharmacokinetic processes. The choice of models for pharmacokinetic studies as well as the subsequent data interpretation must also be aware of genetic factors (such as polymorphic metabolic enzymes), sex, patient age, hepatic diseases, and drug interactions. Therefore, the pharmacokinetics and toxicity of a racemate or an enantiomerically pure drug are not equal and need to be studied. Enantioselective analytical methods are crucial to monitor pharmacokinetic events and for acquisition of accurate data to better understand the role of the stereochemistry in pharmacokinetics and toxicity. The complexity of merging the best enantioseparation conditions with the selected sample matrix and the intended goal of the analysis is a challenge task. The data gathered in this review intend to reinforce the importance of the enantioselectivity in pharmacokinetic processes and reunite innovative enantioselective analytical methods applied in pharmacokinetic studies. An assorted variety of methods are herein briefly discussed. Full article
(This article belongs to the Special Issue Chiral Separation by Chromatographic and Electrophoretic Methods Applied in the Enantioseparation of Pharmaceuticals)
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31 pages, 3068 KiB  
Review
Chiral Capillary Electrokinetic Chromatography: Principle and Applications, Detection and Identification, Design of Experiment, and Exploration of Chiral Recognition Using Molecular Modeling
by Sami El Deeb, Camilla Fonseca Silva, Clebio Soares Nascimento Junior, Rasha Sayed Hanafi and Keyller Bastos Borges
Molecules 2021, 26(10), 2841; https://doi.org/10.3390/molecules26102841 - 11 May 2021
Cited by 34 | Viewed by 5765
Abstract
This work reviews the literature of chiral capillary electrokinetic chromatography from January 2016 to March 2021. This is done to explore the state-of-the-art approach and recent developments carried out in this field. The separation principle of the technique is described and supported with [...] Read more.
This work reviews the literature of chiral capillary electrokinetic chromatography from January 2016 to March 2021. This is done to explore the state-of-the-art approach and recent developments carried out in this field. The separation principle of the technique is described and supported with simple graphical illustrations, showing migration under normal and reversed polarity modes of the separation voltage. The most relevant applications of the technique for enantioseparation of drugs and other enantiomeric molecules in different fields using chiral selectors in single, dual, or multiple systems are highlighted. Measures to improve the detection sensitivity of chiral capillary electrokinetic chromatography with UV detector are discussed, and the alternative aspects are explored, besides special emphases to hyphenation compatibility to mass spectrometry. Partial filling and counter migration techniques are described. Indirect identification of the separated enantiomers and the determination of enantiomeric migration order are mentioned. The application of Quality by Design principles to facilitate method development, optimization, and validation is presented. The elucidation and explanation of chiral recognition in molecular bases are discussed with special focus on the role of molecular modeling. Full article
(This article belongs to the Special Issue Chiral Separation by Chromatographic and Electrophoretic Methods Applied in the Enantioseparation of Pharmaceuticals)
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18 pages, 882 KiB  
Review
The Use of Dual Cyclodextrin Chiral Selector Systems in the Enantioseparation of Pharmaceuticals by Capillary Electrophoresis: An Overview
by Gabriel Hancu, Lajos Attila Papp, Gergő Tóth and Hajnal Kelemen
Molecules 2021, 26(8), 2261; https://doi.org/10.3390/molecules26082261 - 14 Apr 2021
Cited by 31 | Viewed by 3374
Abstract
Cyclodextrin (CD) derivatives are the most efficient and frequently used chiral selectors (CSs) in capillary electrophoresis (CE). There are situations when the use of a single CD as CS is not enough to obtain efficient chiral discrimination of the enantiomers; in these cases, [...] Read more.
Cyclodextrin (CD) derivatives are the most efficient and frequently used chiral selectors (CSs) in capillary electrophoresis (CE). There are situations when the use of a single CD as CS is not enough to obtain efficient chiral discrimination of the enantiomers; in these cases, sometimes this problem can be resolved using a dual CD system. The use of dual CD systems can often dramatically enhance enantioseparation selectivity and can be applied for the separation of many analytes of pharmaceutical interest for which enantioseparation by CE with another CS systems can be problematic. Usually in a dual CD system an anionic CD is used together with a neutral one, but there are situations when the use of a cationic CD with a neutral one or the use of two neutral CDs or even two ionized CDs can be an efficient solution. In the current review we present general aspects of the use of dual CD systems in the analysis of pharmaceutical substances. Several examples of applications of the use of dual CD systems in the analysis of pharmaceuticals are selected and discussed. Theoretical aspects regarding the separation of enantiomers through simultaneous interaction with the two CSs are also explained. Finally, advantages, disadvantages, potential and new direction in this chiral analysis field are highlighted. Full article
(This article belongs to the Special Issue Chiral Separation by Chromatographic and Electrophoretic Methods Applied in the Enantioseparation of Pharmaceuticals)
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