Chiral separation of terbutaline and non-steroidal anti-inflammatory drugs by using a new lysine–bridged hemispherodextrin in capillary electrophoresis (original) (raw)
Application of Sulfated Cyclodextrins to Chiral Separations by Capillary Zone Electrophoresis
Analytical Chemistry, 1996
Mixtures of randomly substituted sulfated cyclodextrins (degree of substitution, ∼7-10) were successfully used as chiral additives for the enantioseparation of 56 compounds of pharmaceutical interest, including anesthetics, antiarrhythmics, antidepressants, anticonvulsants, antihistamines, antihypertensives, antimalarials, relaxants, and bronchodilators. The separations were accomplished at pH 3.8, with the anode at the detector end of the column. Under these conditions, in which electroosmotic flow is directed toward the injection end of the column and the electrophoretic mobility of the negatively charged cyclodextrin is toward the detector, none of the analytes reached the detector in the absence of the sulfated cyclodextrin. Most (40) of the successfully resolved enantiomers contained basic functionality and a stereogenic carbon. However, the versatility of this sulfated cyclodextrin additive was also demonstrated by the fact that three atropisomers, 1,1′-binaphthyl-2,2′-diyl hydrogen phosphate, 1,1′-binaphthyl-2,2′-diol, and Troger's base, and several neutral analytes were also successfully enantioresolved under these conditions. The separation mechanism seems to involve inclusion complexation.
Journal of Chromatography A, 1995
Capillary zone electrophoresis was successfully applied to the enantiomeric resolution of racemic tramadol. Both uncoated and polyacrylamide-coated capillaries were tested for method optimization using either negatively charged or native cyclodextrins (CD) added to the background electrolyte (BGE). The resolution was strongly influenced by the CD type and concentration as well as by the pH and the concentration of the BGE. Among the CDs tested, carboxymethylated-P-cyclodextrin allowed the baseline separation of tramadol enantiomers. After the method was optimized, it was validated in a coated capillary for enantiomeric analysis of tramadol enantiomers in pharmaceutical formulation, including specificity and elution order, linearity, accuracy and precision, determination of limit of detection (LOD) and quantification (LOQ), enantiomeric purity linearity, freedom from interference, and stability of sample solutions. Precision at the target concentration was less than 2%, with an accuracy higher than 99%. Furthermore, the method was able to detect 0.3% and to quantify 1% of the minor enantiomer in the presence of the major one at the target value.
Journal of Chromatography A, 2002
A total of 26 different cyclodextrin (CD) derivatives with different functional groups and degrees of substitution were tested against 35 basic pharmaceutical compounds in an effort to investigate their effectiveness as chiral selectors for enantiomeric separation in capillary electrophoresis (CE). Testing was performed under the same conditions using a low pH buffer (25 mM phosphate buffer at pH|2.5). Five CD derivatives, namely, highly sulfated-b-CD, highly sulfated-a-CD, hydroxypropyl-b-CD (degree of substitution|1), heptakis-(2,6-O-dimethyl)-b-CD, and heptakis(2,3,6-O-trimethyl)-b-CD were identified to be most effective for enantiomeric separations and have a wide range of enantiomeric selectivity towards the model compounds. Over 90% of the model compounds were enantiomerically resolved with the five identified CD derivatives, at a minimum resolution of 0.5. An additional 20 compounds were also tested to demonstrate the validity of the identified CD derivatives. The five CD derivatives were recommended as the starting chiral selectors in developing enantiomeric separation methods by CE.
A persubstituted cationic beta-cyclodextrin for chiral separations
Analytical Chemistry
The applications of a novel polycationic derivative of beta-cyclodextrin (beta-CD), heptakis(6-hydroxyethylamino-6-deoxy-beta-cyclodextrin) (beta-CD-EA), as a chiral host--guest additive for the enantioseparation of various classes of chiral anionic analytes are presented. The cationic beta-CD described in this paper is persubstituted with seven ethanolamine side arms at the primary rim of each cyclodextrin (CD) molecule. It is found that the electrophoretic mobility of beta-CD-EA can be adjusted to influence the chiral selectivity by changing the pH of the background electrolyte. Most of the observed CD capillary zone electrophoresis (CZE) separations of anionic drugs and herbicides were accomplished in the pH range of 4.0-7.0 with a reverse polarity configuration. At pH 5.0, enantioseparation of a mixture of three structurally related antiinflammatory agents (fenoprofen, flurbiprofen, and ibuprofen) was possible in about 30 min. However, other chiral acids, such as a series of phe...
Chiral separation of basic drugs by capillary electrophoresis with carboxymethylcyclodextrins
Journal of Chromatography A, 2002
Capillary electrophoresis (CE) with carboxymethylated bor g-cyclodextrins was used to achieve the rapid enantiomeric separation of a set of basic drugs. The enantiomers of 12 chiral amino-containing pharmaceutical compounds belonging to various therapeutic categories were analyzed by CE using an uncoated 60 cm375 mm I.D. silica capillary. Several experimental parameters such as the nature, concentration and pH of the buffer, nature and concentration of the anionic cyclodextrin and temperature were studied in order to optimize the enantiomeric separation. The variation of the solute partition coefficient for the chiral selector, the enantioselectivity and resolution factors are used to assess the quality of the chiral separation. It is shown that the solute affinity for the chiral selector is not related to its enantioresolution factor. None of the two cyclodextrin selectors used was able to separate the whole set of basic drugs.
ELECTROPHORESIS, 2006
Five pure CD derivatives synthesized in our laboratory were used as chiral selectors in the presence of copper(II) ion. Three enantiomeric pairs of amino acids were submitted to separation experiments in CE, by exploiting the ligand exchange mechanism. The results obtained in the investigated systems, together with those of the analogous systems previously studied, clearly show the usefulness of this technique in chiral separations. By comparing the ligand exchange CE results with potentiometric results, either reported elsewhere or studied here for the first time (system Cu/CDampy/tyrosine), it has been possible to rationalise the separation results. The importance of the availability of pure selectors, and to characterise them both spectroscopically and thermodynamically is discussed.
Electrophoresis, 1997
Nine nonsteroidal anti-inflammatory drugs (NSAIDs) were enantioseparated by capillary electrophoresis using an anionic cyclodextrin derivative (sulfobutyl ether B-cyclodextrin or carboxymethyl-P-cyclodextrin) in combination with a neutral cyclodextrin as chiral additives to a pH 3 phosphoric acid-triethanolamine buffer. In the presence of a negatively charged cyclodextrin, the analytes were given an appropriate mobility but relatively low enantioselectivities were generally obtained when such a cyclodextrin was the only selector added to the buffer. The addition of an uncharged cyclodextrin, such as the native B-cyclodextrin or one of its derivatives (dimethyl-, trimethyl-and hydroxypropyl-fi-cyclodextrin), to this kind of buffer containing an anionic cyclodextrin, was found to give rise to considerable improvement in chiral resolution for all compounds studied. Resolution and analysis time were optimized by varying the nature and concentration of the two cyclodextrins. The best compromise was usually achieved by the simultaneous addition of sulfobutyl ether 0-cyclodextrin and trimethyl-0-cyclodextrin. Under optimum conditions, the enantiomers of all NSAIDs examined could be completely separated (most often with resolution values higher than 5) in short analysis times (generally lower than 15 min). Correspondence: Prof. J. Crommen, Laboratory of Drug Analysis, Institute of Pharmacy, University of Liege, rue Fusch, 5, B-4000 Liege, Belgium (Tel: +32-4-2322-962; Fax: +32-4-2322-937)
As part of a comprehensive screening program on the separation of chiral drugs by capillary zone electrophoresis, we have investigated the enantio-separation of 54 drug racemates with i-cyclodextrin as a chiral solvating agent (CSA), thus complementing previous studies on 34 drug racemates. Fourteen out of the 54 analytes investigated have been separated into the enantiomers, yielding an overall success rate of 24.4% for 86 drug racemates investigated in total.
ELECTROPHORESIS
The chiral separation ability of the full library of methylated--cyclodextrins towards pharmacologically significant racemic drugs including basic compounds was studied by chiral CE. The syntheses of all the methylated, single isomer -cyclodextrins were revised and optimized and the aqueous solubility of the derivatives was unambiguously established. The three most relevant commercially available methylated isomeric mixtures were also included in the screening, so a total of ten various methylated CDs were investigated. The effects of the selector concentration on the enantiorecognition properties at acidic pH were investigated. Among the dimethylated -cyclodextrins, the heptakis (2,6-di-Omethyl)--cyclodextrin isomer (2,6-DIMEB) resulted to be the most versatile chiral selector. Terbutaline was selected as a model compound for the in-depth investigation of host-guest enantiodiscrimination ability. The association constants between the two terbutaline enantiomers and 2,6-DIMEB were determined in order to support that the enantioseparation is driven by differences is host-guest binding. The migration order of the enantiomers was confirmed by performing spiking experiments with the pure enantiomers. 1D and 2D NMR spectroscopy was applied to the 2,3-, and 2,6-DIMEB/terbutaline systems to rationalize at molecular level the different enantioseparation ability of the dimethylated -cyclodextrin selectors.
New cyclodextrin derivatives as chiral selectors in capillary electrophoresis
Fresenius' Journal of Analytical Chemistry, 2001
The separation of three pairs of enantiomeric herbicides has been successfully achieved by capillary electrophoresis at two different pH values in the presence of cyclodextrin derivatives previously synthesized in our laboratory. Two of these derivatives constitute a new class of receptor, the hemispherodextrins, in which a trehalose capping moiety is bonded to β-cyclodextrin. Because of their peculiar structure hemispherodextrins have very promising characteristics and the low receptor concentration required to achieve separation deserves particular interest.
Chirality, 2003
This review focuses on the emerging role of sulfated cyclodextrins in the capillary electrophoretic (CE) separation of chiral analytes. Since being introduced as enantioselective agents for CE in 1995, these anionic additives have continued to demonstrate remarkable application universality. The broad spectrum of chiral compounds successfully separated using this approach includes acidic, basic, neutral, and zwitterionic species. This impressive array of analyte structures is derived from a growing diversity of compound classes including pharmaceuticals, plant extracts, biomarkers, herbicides, alkaloids, fungicides, and metal ions. Moreover, literature reports highlight the minimal optimization required to achieve a successful separation. Based on these findings, sulfated cyclodextrins appear to be well suited for the development of a more universal, comprehensive separation strategy for chiral compounds. This review explores this proposition by beginning with the structure and migration properties of sulfated cyclodextrins, using applications to highlight the separating power of this technique and ending with a pragmatic, comprehensive separation strategy. Chirality 15:709–723, 2003. © 2003 Wiley-Liss, Inc.
Hemispherodextrins, a new class of cyclodextrin derivatives, in capillary electrophoresis
Journal of Chromatography A, 2001
A capped cyclodextrin derivative (THCMH), called hemispherodextrin, was observed to behave as a very efficient chiral selector for a variety of phenoxyacid enantiomeric pairs, both at pH 6 and pH 9. The very low concentration necessary to obtain separation was particularly impressive. The behaviour of THCMH was compared with that of other hemispherodextrins and cyclodextrin derivatives and the conclusions are reported. Some interesting conclusions are drawn by comparing the behaviour of THCMH with that of other hemispherodextrins reported elsewhere.
Journal of Pharmaceutical and Biomedical Analysis, 1996
Three fl-cyclodextrin derivatives--carboxymethyl-, dimethyl-and hydroxypropyl-fl-cyclodextrin--were tested as chiral selectors for the enantioseparation of seven basic drugs in free solution capillary electrophoresis, using buffers made of 100 mM phosphoric acid adjusted to pH 3.0 with triethanolamine in fused silica capillaries thermostatted at 15°C. The best results with respect to chiral resolution were obtained with carboxymethyl-fl-cyclodextrin (CMCD): the enantiomers of all compounds examined were completely resolved with this fl-cyclodextrin derivative. The influence of the CMCD concentration on the migration times, the apparent electrophoretic mobility difference and the resolution of the drug enantiomers was investigated thoroughly. Particularly impressive resolution values, up to 23.7, were obtained for several compounds in these capillary electrophoretic systems, using CMCD in the 5-15 mM concentration range.
Single isomer cyclodextrins as chiral selectors in capillary electrophoresis
Journal of Chromatography A
Since decades, cyclodextrins are one of the most powerful selectors in chiral capillary electrophoresis for the enantioseparation of diverse organic compounds. This review concerns papers published over the last decade (from 2009 until nowadays), dealing with the capillary electrophoretic application of single isomer cyclodextrin derivatives in chiral separations. Following a brief overview of their synthetic approaches, the inventory of the neutral, negatively and positively charged (including both permanently ionic and pH-tunable ionizable substituents) and zwitterionic CD derivatives is presented, with insights to underlying structural aspects by NMR spectroscopy and molecular modeling. CE represents an ideal tool to study the weak, non-covalent supramolecular interactions. The published methods are reviewed in the light of enantioselectivity, enantiomer migration order and the fine-tuning of enantiodiscrimination by the substitution pattern of the single entity selector molecules, which is hardly possible for their randomly substituted counterparts. All the reviewed publications herein support that cyclodextrin-based chiral capillary electrophoresis seems to remain a popular choice in pharmaceutical and biomedical analysis.
Journal of Pharmaceutical and Biomedical Analysis, 1999
A simple, systematic method was developed for rapidly screening potential capillary electrophoresis (CE) separation conditions for small, amine-containing enantiomers. During method development, 39 pairs of enantiomers were investigated and partial or complete separation was achieved in every case. Baseline resolution was achieved by these initial screening conditions in over half of the cases. The screening strategy uses a bare fused silica capillary and a pH 2.5 amine-modified phosphate buffer containing one of the selected cyclodextrins (CD): dimethyl-b-CD, hydroxypropyl-b-CD, hydroxypropyl-a-CD, hydroxypropyl-g-CD and sulfated-b-CD. An additional set of compounds have been screened by this approach to demonstrate the validity of the method. The paper outlines the experimental work carried out to develop the screen and describes how one might implement it for a new compound.
A Persubstituted Cationic β-Cyclodextrin for Chiral Separations
Analytical Chemistry, 1997
The applications of a novel polycationic derivative of -cyclodextrin ( -CD), heptakis(6-hydroxyethylamino-6deoxy--cyclodextrin) ( -CD-EA), as a chiral host-guest additive for the enantioseparation of various classes of chiral anionic analytes are presented. The cationic -CD described in this paper is persubstituted with seven ethanolamine side arms at the primary rim of each cyclodextrin (CD) molecule. It is found that the electrophoretic mobility of -CD-EA can be adjusted to influence the chiral selectivity by changing the pH of the background electrolyte. Most of the observed CD capillary zone electrophoresis (CZE) separations of anionic drugs and herbicides were accomplished in the pH range of 4.0-7.0 with a reverse polarity configuration. At pH 5.0, enantioseparation of a mixture of three structurally related antiinflammatory agents (fenoprofen, flurbiprofen, and ibuprofen) was possible in about 30 min. However, other chiral acids, such as a series of phenoxypropionic acid herbicides and dansylated amino acids (glutamic acid and aspartic acids), were best separated at pH 6.0 or 7.0. An impressive separation of a mixture of six structurally related anionic herbicides [(()-2-phenoxypropionic acid, (()-2-(2-chlorophenoxy)propionic acid, (()-2-(3-chlorophenoxy)propionic acid, (()-2-(4-chlorophenoxy)propionic acid, (()-2-(2,4-dichlorophenoxy)propionic acid, and (()-2-(2,4,5-trichlorophenoxy)propionic acid] was achieved for the first time in about 15 min during a single run with 20 mM -CD-EA. The analytical applicability of this cationic CD molecule for chiral separations is discussed in detail.
Journal of Liquid Chromatography & Related Technologies, 2001
In this paper, we report the chiral separation of some drugs and their metabolites using sulfated β-cyclodextrin, a powerful chiral selector that has proven to be highly efficient for the separation of chiral drugs, alone or in combination, with other chiral additives. Praziquantel, its metabolite trans-4-hydroxypraziquantel, and albendazole sulfoxide are neutral compounds and could be separated at basic pH (8-10). The simultaneous chiral separation of praziquantel and its metabolite enantiomers was only possible by the addition of sodium deoxycholate to the running buffer. Fluoxetine, disopyramide, and mexiletine, as well as their metabolites are basic com-1115
Cyclodextrins as Dominant Chiral Selective Agents in the Capillary Separation Techniques
2021
This review paper shows the dominant role of the cyclodextrins in the chiral separations using capillary columns (GC, SFC, CE). The cyclodextrins (CDs) have extremely broad chiral selectivity spectra because they have several different chiral recognition sites in various arrangements and various interaction modes. Their chiral selectivity features can further improve with their various substitutions. Their selectivities are moderate therefore they need high efficiency separations (capillary columns) for good chiral resolutions. The shape selectivity of cyclodextrins is also shown with non-chiral isomers too. The utility of the cyclodextrins is demonstrated with several examples based on the personal observations of authors and critical review of literature. The theoretical backgrounds of their chiral recognitions (e.g. H-bond interaction, inclusion, induced fit) are discussed in depth. This paper is not application oriented but is dealing with mostly on the physical and chemical bac...