chiral separations

Chiral SeparationsTimothy J. Ward* and Daisy-Malloy Hamburg

Department of Chemistry, Millsaps College, 1701 North State Street, Box 150306, Jackson, Mississippi 39210

Review Contents

Reviews 4635Capillary Electrophoresis (CE) 4635High-Performance Liquid Chromatography(HPLC)

4635

Gas Chromatography (GC) 4636Thin-Layer Chromatography (TLC) 4636Capillary Electrochromatography (CEC) 4636Multiple Technique Reviews 4636

Capillary Electrophoresis 4636Cyclodextrins 4636Antibiotics 4637Micelles 4637Microchip CE 4638Miscellaneous 4638

Thin-Layer Chromatography 4638Supercritical Fluid Chromatography and RelatedTechniques

4638

Gas Chromatography 4639Liquid Chromatography 4639

Cyclodextrin CSPs and Mobile-Phase Additives 4639Macrocyclic Antibiotic CSPs 4639Polysaccharide CSPs 4640Protein-Based CSPs 4640Micellaneous CSPs 4640

Capillary Electrochromatography 4641Miscellaneous Techniques 4642Literature Cited 4642

This fundamental review article covers developments andapplications in chiral separations from January 2002 to January2004 and is restricted to the English language literature. Withthe tremendous number of publications in this field, a compre-hensive review of all published papers is not feasible; rather thisfundamental review focuses on major developments in the fieldof chiral separations as well as representative applications. Severalexcellent general reviews covering chiral separations are pre-sented first, followed by a examination of the methods andtechniques utilized in each area.

REVIEWSCapillary Electrophoresis (CE). Capillary electrophoresis

remains a popular technique for the enantioseparation of biologi-cally active compounds. A review discussing the determinationof the enantiomeric excess in enantiomerically pure drugs bycyclodextrin (CD)-modified CE, compiled by Schmitt et al. (1),reviews strategies of method development, sensitivity of detection,and optimization of separation parameters. The recent develop-ments in the determination of enantiomeric drugs and their

metabolites in biological fluids by CE-mediated microanalysis weresummarized by Bonato (2), who observed an increase in the useof negatively charged â-CD derivatives as chiral selectors. Theuse of combinations of different chiral selectors was also noted.The direct chiral separation of short-chain organic acids by CEwas reviewed by Barbas and Saavedra (3), with existing methodsusing various techniques discussed. These techniques includedCE utilizing macrocyclic antibiotics, CDs, ion-pair method, transi-tion metal complexes, and exchange CE. Strategies to advancethe chiral separations in these areas were also described. Altriaand Elder summarized the status and applications of CE to theanalysis of small molecules, with an application area devoted tochiral separations (4).

CE moved into microscale with microchip electrophoresis(MCE) showing great promise for enantiomeric separations.Chiral MCE was reviewed by Belder and Ludwig (5) with anintroduction given into the principles of chiral separation withMCE regarding instrumentation and methodology. Emphasis inthis review was on approaches to improve detection and resolutionin chiral MCE.

Several approaches used to couple CE and electrosprayionization-mass spectrometry (ESI-MS) for the analysis of chiralcompounds were summarized by Shamsi (6). A short compilationof commercially available CE-MS instruments and interfacedesign was given, followed by an extensive discussion on thevarious modes of chiral CE-MS. These modes included chiralcapillary zone electrophoresis-mass spectrometry (CZE-MS)with neutral derivatized cyclodextrins, chiral electrokinetic chro-matography-mass spectrometry (EKC-MS) with a charged chiralselector, micellar electrokinetic chromatography-mass spectrom-etry (MEKC-MS), and capillary electrochromatography-massspectrometry (CEC-MS).

CE-MS was again discussed in regard to affinity CE and CD-EKC, with particular attention paid to method development in areview by Tanaka (7).

High-Performance Liquid Chromatography (HPLC). TheHPLC methods for the enantiomeric separation of amphetamineand related compounds were reviewed by Herraiz-Hernandez etal. (8), with discussions of the direct enantioseparation of non-derivatized amphetamines using â-cyclodextrin as the chiralselector, both immobilized on the stationary phase and added tothe mobile phase. Other chiral stationary phases such as Pirkletype, cellulose based, or protein based were also discussed. Theuse of immobilized proteins as chiral stationary phases (CSPs) inHPLC and in CE for the enantioseparation of drugs was sum-marized by Millot (9), including the main procedures for proteinimmobilization onto matrixes and factors affecting enantiosepa-ration. Clarke and Hage reviewed the clinical application of affinitychromatography including chiral separations (10, 11).

* Corresponding author: (phone) (601) 974-1405; (fax) (601) 974-1401;(e-mail) [email protected].

Anal. Chem. 2004, 76, 4635-4644

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Gas Chromatography (GC). The separation of enantiomersby GC on CSPs was extensively reviewed by Schurig (12), withdiscussion of the method development, applications, and ancillarytechniques of chiral separations using GC. CSPs with amino acidderivatives, terpene-derived metal coordination compounds, andmodified cyclodextrins were included. Schurig also comprehen-sively reviewed the practice and theory of enantioselectivecomplexation GC on optically active metal(II) bis[3-perfluoroacyl)-(1R)-camphorate] selectors (13). Applications extend to chiralanalysis in asymmetric synthesis, enzymic reactions, pheromone,and flavor chemistry. The elucidation of thermodynamic param-eters of enantioselectivity and the investigation of the enantiomer-ization of configurationally labile enantiomers was also discussed.

Thin-Layer Chromatography (TLC). The development ofstationary phases for TLC in the last 10 years was compiled byGocan (14), and included chiral separation and recent advancesin chiral stationary phases. The CSPs discussed included nonpolarbonded stationary phases impregnated with transitional metal ions,cellulose, modified cellulose, chitin, chitosan, and their derivatives.Cyclodextrin and macrocyclic antibiotics were reported to havevery good results for enantioseparation by TLC, with molecularimprinting polymers also finding use as CSPs in TLC.

Capillary Electrochromatography. The applications of CECwere reviewed by Remcho et al. (15). Chiral separations withcyclodextrins and their derivatives, biomolecules, molecularlyimprinted polymers, “brush”-type phases, ion exchangers, anti-biotics, polysaccharide derivatives, and other CSPs were includedin this review. A summary of recent progress in open-tubular CECfor chiral and achiral separations included stationary-phasepreparation (16), with the major developments, potential applica-tions, technical difficulties, and advantages of each wall coatingdiscussed.

Multiple Technique Reviews. The use of cyclodextrins inchiral chromatography was compiled by Juvancz and Szejtli (17).The role of cyclodextrins in methods using capillary columns suchas GC, supercritical fluid chromatography (SFC), and CE wasdetailed, as well as their use in other forms of chromatographysuch as HPLC and TLC. The mechanism of chiral recognitionusing cyclodextrins was also discussed. Williams and Wainer (18)reviewed the role of chiral chromatography in therapeutic drugmonitoring and in clinical and forensic toxicology. EnantioselectiveGC and HPLC were used as tools to unravel complex phenomenaassociated with drug transport and metabolism.

CAPILLARY ELECTROPHORESISCyclodextrins. Cyclodextrins and their derivatives remain one

of the most widely used chiral selectors for CE chiral separations.Sulfated â-CDs and carboxymethyl-â-CD were used as chiralselectors in the separation of 41 chiral sulfoxides and sulfinateesters (19). The sulfated â-CDs were reported to separate agreater number of compounds and had better separating capabili-ties than carboxymethyl-â-CD. Hydroxypropylated, dimethylated,and sulfated CDs were used as chiral additives in CE to evaluatetheir effectiveness as chiral selectors (20). Eleven different CDsincluding neutral and charged derivatives were used as chiralselectors in the chiral CE separation of fluoxetine and fouranalogues (21). Optimized separation conditions including typeof CDs, CD concentration, and pH of the background electrolyte

were reported. Egger et al. demonstrated that sulfated â-CDs usedat low pH in the reversed polarity mode were found to give thebest separation of chiral dihydrofurocoumarin compounds in astudy comparing four different chiral methods using CE andmicellar CE (22). Sulfated â-CD was used as the chiral selectorin the simultaneous enantiomeric CE separation of citalopram andits metabolite desmethylcitalopram (23).

A CE method for the chiral separation of racemic methotrexateusing hydroxypropyl-â-CD was developed and validated by Kuoet al. (24). Various commercially available CDs were used in astudy concerning the CE separation of aminophosphonic acidenantiomers, with variation of pH of background electrolyte,concentration of CD, and type of CD used as the chiral selector(25). Neutral CDs were used in the CE enantioseparation ofpropoxyphene, in which baseline resolution was achieved in ∼6min (26). A dual CD system of polyanionic heptakis-6-sulfato-â-CD with neutral heptakis(2,3,6-tri-O-methyl)-â-CD was utilized inthe CE enantioseparation of nonsteroidal antiinflammatory drugssuch as fenoprofen, flurbiprofen, ibuprofen, and ketoprofen (27).Selectivity for the enantioseparation of these drugs was predictedusing mathematical models. Carboxymethylated â- or γ-CDs wereused in a CE method to achieve the rapid separation of a set of12 basic amino-containing drugs (28), but neither of the two CDsused was able to separate the entire set of drugs. A new CEmethod was reported for the detection of enantiomeric purity ofimidazo(2,1-i)purin-5-ones and related tricyclic water-soluble purinederivatives using native and modified â-CDs as chiral selectors(29).

The distribution of enantiomers of methamphetamine, meth-cathinone, ephedrine, and pseudoephedrine in clandestine tabletsand urine samples was analyzed by a â-CD-modified CE methodand described by Liau et al. (30). The chiral separation methodof 3,4-methylenedioxymethamphetamine and related compoundsby CE with â-CD and fluorescence spectroscopy was developedand used to determine the distribution of isomers in clandestinetablets and urine samples (31). Highly sulfated γ-CD was used inthe simultaneous chiral separation of nine amphetamine-typestimulants by CE (32), and highly sulfated â-CD was the chiralselector in the enantioseparation of warfarin (33).

A chiral CE method using heptakis(2,6-di-O-methyl)-â-CD wasreported for the resolution of the six enantiomers associated withthe metabolism of methadone (34). Native CDs and neutral andcharged CD derivatives were evaluated in the development of thechiral separation of diastereomeric flavanone-7-O-glycosides incitrus by CE (35). The chiral separation of deprenyl N-oxideisomer using CE in the presence of various CD derivatives wasreported by Tabi et al. (36). Anionic and neutral compounds wereenantioseparated using a heptasubstituted cationic â-CD as chiralselector in CE (37). Chiral separation was found to be highlydependent on pH, with the resolution enhanced at higher pH. Aâ-CD substituted by an imidazole-bound histamine was used toseparate underivatized tryptophan in CE in the presence of copper-(II) ion in what is reported to be the first ligand-exchange chiralseparation by a CD derivative added to the background electrolyte(38).

A chiral CE method using highly sulfated CDs in a low-pHphosphate buffer and the short-end injection technique to enan-tioseparate a basic, neutral, and acidic compound was evaluated

4636 Analytical Chemistry, Vol. 76, No. 16, August 15, 2004

for robustness, and the statistical interpretation was presented byPerrin et al. (39). The chiral separation of enantiomers of a plantgrowth regulator, abscisic acid, by CE with CD additives wasreported (40), with dimethyl-â-CD, hydroxypropyl-â-CD, and γ-CDgiving satisfactory enantioselectivity. A novel assay method forenantiomeric separation was developed using a combination ofCE and electrospray tandem MS connected with a homemadeinterface (41). Nonaqueous CE using an ion-pairing reagent incombination with an anionic CD derivative enantioresolved basicpharmaceuticals, with the enantiomeric resolution lost or stronglyreduced in the absence of the ion-pairing reagent (42).

CE is often compared with or used in conjunction with HPLCmethods. A comparative study on the enantiomeric separation of1,1′-binaphthyl-2,2′-diyl hydrogen phosphate and 1,1′-binaphtholby HPLC and CE, using CDs and bile salts as single and dualselectors, was reported by Bielejewska et al. (43). The chiralseparation of an M3 antagonist was investigated using CE withvarious sulfated CDs and by reversed-phase HPLC with derivatizedcellulose, derivatized amylose, and two protein stationary phases(44). Based on the comparison of techniques, a practical CEmethod using sulfated γ-CD was selected and validated. The chiralseparation of bioactive cyclic Mannich ketones was performedusing HPLC with cellulose derivative CSPs or CD-CSPs, and inCE, different CDs such as â-CD, γ-CD, carboxymethyl-â-CD, andsuccinyl-â-CD were added to the background electrolyte as chiralselectors (45). Two independent methods using HPLC on polysac-charide-type CSP and CE with native and derivatized CDs weredeveloped for the chiral resolution of the vasodilator drugisoxsuprine (46). The methods were compared for efficiency,sensitivity, analysis time, and costs. The enantioseparation oftetramisole by CE and HPLC was reported, and these techniqueswere applied to the determination of the enantiomeric purity of aveterinary drug formulation of L-levamisole (47). The CE methodsevaluated various CDs as chiral selectors, while the HPLC methodused a polysaccharide-type CSP. CE was determined to be thepreferred method.

CZE was used with sulfated â-CD for the simultaneousdetermination of DOPA and carbidopa enantiomers (48). Theseparation and migration behavior of 13 structurally relatedphenothiazines in CD-modified CZE was reported by Chen et al.(49), with â-CD and hydroxypropyl-â-CD evaluated. A method forthe enantiseparation of synthetic tetrahydronaphthalenic deriva-tives using anionic CDs as chiral selectors and CZE was developed(50). A CZE method for the detection of 0.1% of (R)-levochlor-pheniramine maleate in samples of (S)-dexchlorpheniraminemaleate was reported (51), using carboxymethyl-â-CD in an acidicbackground electrolyte. The complete chiral separation of meth-oxamine and lobeline was achieved by CZE on a ethylbenzene-deactivated fused-silica capillary column, with dimethyl-â-CD andhydroxypropyl-â-CD giving the best results (52). Carboxyethyl-â-CD dissolved in the operating buffer in CZE was used for theenantioseparation of dioxopromethazine in eye drops (53). Xu etal. reported the chiral separation of 2,3-allenoic acid by CZE usingCD derivatives of hydroxypropyl-â-CD and hydroxypropyl-γ-CD(54). Abscisic acid enantiomers were enantioseparated by CZEusing CDs and their derivatives (55), with γ-CD, hydroxypropyl-â-CD, and dimethyl-â-CD forming strong complexes.

EKC with carboxymethylated γ-CD and â-CD was used tomonitor the stereoselectivity of biodegradation of chiral polychlo-rinated biphenyls (56). A comparison of charged CD derivativesfor the enantioseparation of atropisomeric polychlorinated biphe-nyls by CZE was reported by Garcia-Ruis (57), and the resultswere compared with those obtained by the dual CD systemreported above. Cyclodextrin-based EKC was used with quenchedphosphorescence detection to monitor the stereoselective bio-degradation of camphorquinone by yeast (58). CZE employingvancomycin as a chiral selector was used in the chiral separationsof a nonsteroidal antiinflammatory drug candidate (59) andracemic N-acetyl derivatized amino acids (60).

Antibiotics. The macrocyclic antibiotics were also used aschiral selectors for CE enantioseparations during this reviewperiod. A CE study including a theoretical approach was used todetermine the binding constant of acid herbicide enantiomers-vancomycin complexes, and the dependence on salt concentrationwas discussed (61). Several strategies for using vancomycin as achiral selector in CE were explored, including the dynamic coatingtechnique, the coelectroosmotic flow technique, and the partialfilling technique (62). The vancomycin analogue A82846B pro-vided excellent selectivity for some acidic test solutes, with itsdimerization in solution proposed as the reason it showedenhanced enantioseparations compared with vancomycin (63).

Micelles. Micellar methods continue to be used for chiralseparations in CE. A MEKC method was developed for thedetection of chiral amino acids in orange juice (64). This methodutilized â-CDs as chiral selectors and laser-induced fluorescencefor detection. A system using 1-S-octyl â-D-thioglucopyranoside,SDS, and CD was used in the chiral separation of amino acids byTran and Kang (65), with the three-component system showingbetter separations than 1-S-octyl â-D-thioglucopyranoside alone aschiral selector. Another three-component system utilized 3-((3-cholamidopropyl)dimethylammonio)-1-propanesulfonate with SDSand CD for the separation of dansyl amino acids (66). Organo-phosphorus pesticides were enantioseparated in a capillary mixed-mode EKC method using surfactants and neutral and chargedCDs (67). A neutral CD derivative, hydroxypropyl-γ-CD, and anionic derivative, heptakis-6-sulfato-â-CD, were used as an additivein CD-modified MEKC for the enantioseparation of triadimenol,a component of systemic agricultural fungicide (68). Pemolineenantiomers were separated with CD-modified MEKC, with thechiral separation dependent on the type of CDs used as chiralselectors (69).

Two amino acid-based alkenoxy micelle polymers were syn-thesized and used as a pseudostationary phase in MEKC for thesimultaneous separation of eight chiral â-blockers (70), with thepolysodium N-undecenoxycarbonyl-L-leucinate polymer givingoverall better chiral resolution and a wider chiral window. Asynthetic chiral polymer was utilized as a pseudo stationary phasein MEKC in aqueous buffers in methods showing high efficiencieswith the potential for rapid separations (71).

The separation of benzoporphyrin derivative mono- and diacidenantiomers was achieved using 25 mM sodium cholate as thechiral selector in a method using laser-induced fluorescence-capillary electrophoresis (72). The chiral separation of 20 pairsof amino acids derivatized with fluorescein-5-isothiocyanate wasstudied with a mixture of â-CD and sodium taurocholate as chiral

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selectors (73), using CE and laser-induced fluorescence detection.Resolution with the dual selectors was reported to be considerablysuperior to that achieved with either selector alone.

Microchip CE. Microchip electrophoresis coupled with chemi-luminescence detection was used with hydroxypropyl-â-CD as achiral selector for the enantioseparation of chiral dansyl aminoacids (74) and dansylphenylalanine (75). Sulfated CDs were usedin fast chiral separations of a variety of basic and acidic compoundson a microchip electrophoresis instrument with linear imagingUV detection (76). It was reported that a mixture of three chiraldrugs could be separated in less than 11 s. Chiral crown etherwas used as chiral selector in a CE and microchip CE method forthe enantioseparation of gemifloxacin in a sodium-containingmedia (77).

Miscellaneous. Enantioseparations have also been carried outusing a number of miscellaneous chiral selectors, with a fewselected examples reported here. Nonaqueous ion-pair CE usingquinine and tert-butylcarbamoylquinine as chiral selectors wasused in the enantioseparation of N-protected amino acids (78, 79)and peptides (80). Chiral separations in CE using cinchonaalkaloid derivatives as chiral selectors were reviewed by Lam-merhofer and Lindner (81). A new chiral receptor containing 1,7-diaza-12-crown-4 was synthesized, and its application in chiralseparations by CE was described by Wang et al. (82). A novelchiral selector, N-benzoxycarbonylglycyl-L-proline, was introducedby Hedeland et al. (83) for enantioseparation of pharmacologicallyactive amines in nonaqueous CE. The enantioseparation ofmepivacaine was achieved in 72 s using short-end injection withan effective capillary length of 8.5 cm. Underivatized amino acidswere enantioseparated by ligand-exchange CE using L-lysine asthe ligand and copper(II) as the central ion (84). SDS wasnecessary for simultaneous resolution of the amino acids butcaused precipitation at less than 32 mM at room temperature. Itwas postulated that the precipitation might be caused by theformation of a neutral substance from the SDS monomer and thecopper(II)-lysine complex.

THIN-LAYER CHROMATOGRAPHYThin-layer chromatography remains a reliable technique for

rapid screening of chiral separations. Some 2-arylpropionic acidswere enantioresolved using silica TLC plates impregnated withoptically pure L-(-)-serine, with the method applied to commercialampules of ketoprofen dosage formulation (85). Silica TLC platesimpregnated with L-(-)-serine and L-(-)-threonine and a mixtureof these chiral selectors were prepared for the enantioseparationof more 2-arylpropionic drugs (86). Detection limits were reportedto range between 0.25 and 0.5 µg/mL, and the effect of temper-ature, pH, and chiral selector concentration was studied.

Three commonly used â-blockers, atenolol, metoprolol, andpropranolol, were enantioseparated using normal-phase TLC onsilica gel plates impregnated with L-aspartic acid with iodinedetection (87). Molecularly imprinted polymers of S-timolol wereprepared and used in the direct chiral separation of somecardiovascular drugs, including propranolol, atenolol, timolol,nadolol, nifedipine, and verapamil (88).

SUPERCRITICAL FLUID CHROMATOGRAPHY ANDRELATED TECHNIQUES

A variety of CSPs have been used for chiral separations in SFCduring this review period. Phinney and Sander (89) studied thepolar additive concentration effects on CSPs containing either amacrocyclic glycopeptide or a derivatized polysaccharide. Thepolar additives were found to significantly decrease retention, andmany analytes failed to elute in the absence of the polar additives.The commercially available column Chiralpak was used in theenantioseparation of triadimenol and triadimefon in SFC (90), withthe separation occurring in 15 min. A Whelk-O1 column was usedin a SCF method to determine the enantiomerization energybarrier for some 3-hydroxy-1,4-benzodiazepine drugs (91).

The enantioseparation of albendazole sulfoxide was achievedon two columns, Chiralpak AD and Chiralcel OD, and the effectsof different modifiers were examined (92). This enantioseparationwas also achieved at the semipreparative scale (93), using anadapted SFC chromatograph and a Chiralpak AD (250 mm × 10mm) column. The effect of different injection volumes on purityand throughput of the individual enantiomers was studied.

Three macrocyclic glycopeptide chiral selectors, teicoplanin(Chirobiotic T), teicoplanin aglycon (Chirobiotic TAG), andristocetin (Chirobiotic R), were exhaustively evaluated for enan-tioseparations with supercritical and subcritical fluid chromatog-raphy by Armstrong et al. (94). A set of 111 chiral compounds,including hetercycles, nonsteroidal antiinflammatory compounds,â-blockers, sulfoxides, N-protected amino acids, and native aminoacids were separated on the three CSPs. Chirobiotic TAG andChirobiotic T were found to fully or partially resolve 92% of theenantiomers in the compound set, while Chirobiotic R separatedonly 60%. All separations were performed in less than 15 min, withthe majority of compounds separating in less than 4 min.

Twenty-four chiral dihydrofurocoumarin derivatives and struc-turally related compounds were enantioseparated on three mac-rocyclic glycopeptide CSPs using supercritical and subcritical fluidchromatography (95), with the Chirobiotic T CSP reported todemonstrate the best enantioselectivity for 21 of the compounds.Thermally unstable furan derivatives were enantioseparated bySFC and HPLC with a derivatized cellulose or amylose CSP (96).This report also included the separation of volatile furan ethersusing GC/MS.

Packed-column subcritical fluid chromatography was used inthe enantioseparation of a thiazolbenzenesulfonamide compound,using a Chiralpak AD CSP (97). The effects of temperature andalcohol modifier were also reported. A ristocetin CSP wasevaluated for chiral separations in subcritical fluid chromatogra-phy, with solutes of differing structures and pKa values tested (98).The effects of modifiers, additives, temperature, and flow rate onthe enantioseparations were presented.

SFC-MS was utilized in various applications during this reviewperiod. A wide variety of pharmaceutical racemates were separatedand characterized using SFC coupled to a hybrid MS (Q-TOF)equipped with an electrospray ion source (99). Three differentCSPs and different pressure/temperature working conditions wereused. A technique for rapid method development for chiralseparations in drug discovery using sample pooling and SCF-MSwas reported by Zhao et al. (100). Four CSPs and eight differentmodifier concentrations were used in a fully automated process


lasting 15 h to attain optimal chiral separations for multiplecompounds.

GAS CHROMATOGRAPHYCyclodextrin-based GC columns were found to have wide-

spread use for the direct resolution of enantiomers during thisreview period. Four derivatized CD-based CSPs, Chiraldex-G-TA,G-PN, G-BP, and B-DM, were used in GC to enantioseparate 17chiral sulfoxides and 8 chiral sulfinate esters (101), with the G-TAand B-DM CSPs generally giving opposite elution orders for mostof the compounds. Alkylated â-CD and γ-CD CSPs were used inthe GC separation of enantiomers of seven N-TFA-O-alkylaminoacid derivatives (102). An evaluation of the nonpolar interactionsof the separations was also given.

The 2-O-methyl-3-O-acetyl and 2-O-acetyl-3-O-methyl derivativesof 6-O-tert-hexyldimethylsilyl-γ-CD were synthesized as a GC CSPand tested for chiral separation (103). Enantioseparations werecompared with those of 2,3-di-O-methyl- and 2,3-di-O-acetyl-6-tert-hexyldimethylsilyl-γ-CD CSPs, with the 2-O-methyl-3-O-acetyl-6-O-tert-hexyldimethylsilyl-γ-CD exhibiting the highest enantio-selectivity. The chiral GC separation of 2-alkyl-2-keto-γ-butyrolac-tone derivatives and their alcohol analogues using a 2,3-di-O-methyl-6-O-tert-butyldimethylsilyl-â-CD CSP was reported by Ra-mos et al. (104).

A chiral dual-column GC system was used in the chiralseparation of N-TFA-O-Me esters of six amino acids in a study tovary the selectivity by adjusting the individual carrier gas flowrates (105). Two columns, Chirasil-L-Val and Chirasil-D-Val, whichdemonstrate opposite enantioselectivities, were coupled in seriesfor this study.

A method suitable for the enantioseparation of D-amino acidsin a wine sample was reported using a GC capillary column coatedwith immobilized poly(dimethylsiloxane) anchored to (S)-(-)-tert-Leu-(S)-(-)-1-R-naphthyl)ethylamide (106). The amino acids wereconverted into N-pivaloyl methyl esters in two reaction steps.

LIQUID CHROMATOGRAPHYDirect chiral separations using macrocyclic antiobiotics CSPs

in HPLC continue to be very common, with cyclodextrin- andpolysaccharide-based columns also finding much use.

Cyclodextrin CSPs and Mobile-Phase Additives. TheHPLC chiral analysis of alkoxy-substituted esters of phenylcar-bamic acid was performed on â- and γ-CD CSPs (107). Theenantioselective separation of 28 racemic dihydrofurocoumarinswas studied using three native and six derivatized CD CSPs inreversed-phase mode, polar organic mode, and normal-phasemode (108), with the hydroxypropyl-â-CD reported as the mosteffective CSP in the reversed-phase mode. Native and derivatizedCD CSPs were evaluated for the enantioseparation of aromaticand aliphatic sulfoxides (109), and many sulfoxide enantiomerswere baseline resolved using the derivatized CD CSP in thereversed-phase mode.

The enantioseparation of 42 derivatized amino acids andbiogenic amines was accomplished with an amino-â-CD CSP(110). A novel urea-covalent-bonded methylated â-CD CSP wasused in the chiral resolution of flavor and fragrance compounds(111). Ultrahigh-pressure liquid chromatography was demon-strated for fast and efficient chiral separations of pharmaceuticals

on silica packed capillary columns using â-CD and 2-hydroxypro-pyl-â-CD as mobile-phase modifiers (112). Separations wereaccomplished in less than 2 min using this method.

Macrocyclic Antibiotic CSPs. A set of 42 chiral sulfoxideswere enantioseparated by HPLC using 5 different macrocyclicglycopeptide CSPs, ristocetin A, teicoplanin, teicoplanin aglycon,vancomycin, and vancomycin aglycon, and 7 eluents, three normalphase, two reversed phase, and two polar organic (113). Theteicoplanin and teicoplanin aglycon CSPs were reported to be themost effective, with 35 and 33 of the 42 compounds studiedresolved, respectively. The enantiomers of 28 substituted dihy-drofurocoumarins were separated by HPLC using CSPs containingristocetin A, teicoplanin, and teicoplanin aglycon (114), with theteicoplanin CSP exhibiting the broadest enantioselectivity with 24compounds baseline resolved.

A study of D,L-tryptophan enantiomer retention on a teicoplaninCSP was reported, using the perturbation technique to determinethe solute distribution isotherms while varying the mobile-phasesodium perchlorate concentration (115). Phenoxypropionic acidherbicides were enantioseparated by teicoplanin CSP, and theperturbation method was used to calculate the solute distributionisotherms (116). The effects of both temperature and methanolwere described by a bi-Langmuir approach. A HPLC-MS assayusing a teicoplanin CSP for the determination of albuterolenantiomers in human plasma was described (117). This methodallows adequate sensitivity and reproducibility for the applicationof studies of inhaled albuterol.

The enantioseparation of secondary amino acids by HPLC wasstudied using teicoplanin and ristocetin A as CSPs (118). An onlinecoupled HPLC method for the determination of diperodon enan-tiomers in blood serum used a teicoplanin CSP for enantiosepa-ration after the reversed-phase separation of diperodon from thematrix (119). Teicoplanin and teicoplanin aglycon CSPs were usedin a study of the influence of carbohydrate moieties of teicoplaninon the separation of some phenylcarbamic acid derivatives, withthe teicoplanin aglycon CSP achieving better separations (120).An enantioselective HPLC method for the determination ofarotinolol in human plasma using teicoplanin CSP was validated(121), and a method for the determination of baclofen in humanplasma using teicoplanin CSP was developed (122).

A semipreparative HPLC method for the enantioseparation oftwo 2-arylpropionic acids on novel CSPs containing teicoplaninA2-2 and A-40,926 was described by Alcaro et al. (123).

A vancomycin CSP used with a polar organic solvent in HPLCwas used in an investigation of the enantiorecognition process ofderivatives of substituted phenylcarbamic acid, with a discussionof the interaction mechanism of the separation included (124). Adisplacement study on a vancomycin CSP using N-acetyl-D-alanineas a competing agent for the aglycon pocket was reported,showing that dansyl amino acids bind to the active aglycon pocketof the selector, with additional enantioselective sites at thevancomycin surface also involved in chiral discrimination (125).A vancomycin CSP was used in a method for the enantioseparationof promethazine by HPLC (126), with vancomycin showing thebest resolution over teicoplanin and ristocetin A CSPs. The effectsof temperature and solute molecular size effects on the retentionand enantioselectivity of D,L-dansyl amino acids were studied usinga vancomycin CSP (127). Enantioseparation of fluoxetine (Prozac)


in human plasma on a vancomycin CSP by HPLC-MS wasreported by Shen et al. (128). Vancomycin CSP was used in theHPLC method for the enantiomeric separation of 1,4-dihydro-pyridines (129), with the method suitable for semipreparativeseparation.

A ristocetin A CSP was used in a HPLC study of the effects oftemperature on retention of tryptophan, 1,2,3,4-tetrahydroiso-quinoline, and γ-butyrolactone analogues (130). Enantioselectiveion-exclusion chromatography on teicoplanin aglycon and (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid CSPs was reported bySteffeck and Zelechonok (131).

Polysaccharide CSPs. An amylose tris(3,5-dimethylphenyl)-carbamate CSP was used in a study of the mechanistic aspects ofchiral discrimination (132). The direct chiral determination ofmetyrapone and metabolites in plasma was accomplished usinga multidimensional achiral-chiral LC method (133). The CSPused was amylose tris(3,5-dimethoxyphenylcarbamate). The un-usual effect of column temperature on the enantioseparation ofdihydropyrimidinone acid and its methyl ester on Chiralpak ADwas summarized, with data suggesting that the CSP was under-going a thermally induced irreversible conformational change thataltered the separation mechanism between the heating and coolingcycles of the method used (134). This change was dependent onthe type of polar mobile-phase additive used. These thermalchanges were not observed when the cellulose-based CSP Chiral-cel OD was used.

The memory effect of mobile-phase additives in chiral separa-tions on Chiralpak AD was studied, and a procedure to removebound additives was developed (135). The unusual equilibriumbehavior of the Troger’s base enantiomers on Chiralpak AD wasreported (136), with the finding that the adsorption of the more-retained (-)-enantiomer was not competitive and the amountadsorbed onto the CSP was independent of the concentration ofthe (+)-enantiomer. However, the adsorption of the less retained(+)-enantiomer was cooperative, with the amount adsorbedincreasing with increasing concentrations of the (-)-enantiomer.

The chiral HPLC separation of nucleoside analogues of d4Tand acyclovir was accomplished on the silica-based amylose CSPsChiralpak AD and Chiralpak AS, with the effect of structuralfeatures studied in relation to retention, selectivity, resolution, andelution order (137). The HPLC enantioseparation of hydroxy-mebendazole in human plasma was achieved on a Chiralpak AD,and a concurrent CE method using sulfated â-CD as chiral selectorwas also developed (138). Both methods were validated. Avalidated chiral HPLC normal-phase method for the enantiosepa-ration of linezolid on Chiralpak AD was reported (139). Theresolution of the enantiomers of dialkylaminoalkylnaphthaleneswas achieved by a preparative HPLC method using Chiralpak ADCSP (140). For the chiral resolution of flurbiprofen and its majormetabolites, four methods were developed using Chiral-AGP andChiralpak AD CSPs, one was developed using a reversed-phaseHPLC method using hydroxypropyl-â-CD as a chiral mobile-phaseadditive, and another utilized a precolumn derivitization method(141). Only the method utilizing the Chiralpak AD CSP showedthe separation and enantioresolution of all three analytes within45 min. The enantioseparation of ibuprofen in human plasma wasperformed using Chiralpak AD-RH in reversed-phase mode byHPLC-MS, with the method reported to be suitable for single-

dose pharmacokinetic studies (142). The enantiomers of 14organophosphonate derivatives were directly separated on Chiral-pak AD, with all of the selected compounds being baselineseparated (143).

A comparison of the enantioseparation of methylphenidate(Ritalin) was achieved in normal-phase mode on three differentCSPs, Chiralpak AD, Chiralcel OD, and Chiralcel OB, and therole of benzoic acid and phenol as mobile-phase additives wasalso discussed (144).Two chiral methods for the separation of theenantiomers of 25 racemic 4-aryl-7,7-dimethyl- and 1,7,7-trimethyl-1,2,3,4,5,6,7,8-octahydroquinazoline-2,5-diones were developed us-ing a Chiralpak AD and a Chiralcel OD CSP (145), with theresolution obtained on the two columns found to be complemen-tary. The enantiomeric resolution of o,p-DDT and o,p-DDD wasachieved on Chiralpak AD-R, Chiralcel OD-R, and Chiralcel OJ-R(146). A comparison of the enantioseparation of several tetralonederivatives was accomplished using Chiralcel OB, Chiralcel OD,Chiralpak AD, Chiralpak AS, and Chiralcel OF, with most of thecompounds being completely separated (147).

Protein-Based CSPs. An enantioselective HPLC-MS methodwas developed and validated for the simultaneous detection ofsaliva concentrations of the enantiomers of methadone and itsmetabolite EDDP using a CSP based on immobilized R 1-acidglycoprotein (AGP). The method was deemed accurate andprecise and was used to successfully analyze saliva obtained frompatients enrolled in a methadone maintenance program. A Chiral-AGP CSP was used in the investigation of the heterogeneousadsorption behavior of selected enantiomers by Goetmar et al.(148). Reboxetine and O-desethyl reboxetine enantiomers weresimultaneously resolved by three stereoselective chromatographicmethods, using Chiral-AGP, ChiraGrom 2, and Chiral-CBH,respectively, in the reversed-phase mode (149). The chiralresolution of mosapride enantiomers was achieved on Chiral AGP,and temperature studies were performed to investigate thethermodynamics of the reversal in retention order (150).

Amlodipine in human plasma was enantioseparated by a ChiralAGP CSP in an HPLC-tandem MS method (151). The methodwas validated, and the limit of quantitation was 0.1 ng/mL foreach amlodipine enantiomer. The enantiomers of ketamine andnorketamine in human plasma were determined using LC-MSwith a Chiral AGP CSP. The method was validated and applied tosamples from a clinical study of ketamine in pain management(152).

CSPs obtained by immobilization of human serum albumin onvarious polymer-coated silicas were investigated for the enantio-separation of racemic mixtures of tryptophan, oxazepam, warfarin,and NBP (153). An immobilized human serum albumin CSP wasused in the study of the stereoselective binding of 2-(4-biphenylyl)-3-substituted 3-hydroxypropionic acids (154). CSPs based onhuman serum albumin and bovine serum albumin were utilizedto determine the species dependency in chiral drug recognition(155).

Micellaneous CSPs. Novel CSPs based on cinchona alkaloidswere used in the chiral HPLC separation of 3,5-dinitrobenzoylamino acids (156), all-R- and all-S-enantiomers of oligoalanineswith N-terminal protection groups (157), N-acylated amino acids(158), and N-protected peptides (159). Enantiomeric discrimina-tion for these CSPs was exceptionally high. A quinine-based chiral


anion-exchange CSP achieved the enantioseparation of 23 N-acylated amino acids, and the effect of temperature on theperformance of the separation was investigated (160). This CSPwas also used in a micro-HPLC method for the separation ofpeptide enantiomers (up to 6 amino acid residues) (161). Resolu-tion of the enantiomers of diphosphines and of the correspondingphosphine oxides was accomplished using four different CSPs,Supelcosil LC-(S)-naphthylurea and LC-(R)-phenylurea, Chiral-pak AD, and Whelk-O1 (162). After optimization of the mobilephases, resolution factors ranged from 0.35 to 3.61 for theSupelcosil CSPs and from 0.37 to 6.57 for the Chiralpak AD andWhelk-O1 columns. The Whelk-O1 CSP was utilized in the HPLCresolution of enantiomers of 2-methoxy-1-((4-methylpiperazino)-methyl)ethyl esters of N-(2-,3-, and 4-alkoxyphenyl)carbamic acidin the polar organic and reversed modes (163) and in a study ofthe mechanism of enantioseparation. A method using HPLC-MSwith a Crownpak CR+ CSP was used for high-throughputscreening of enzymatic racemase activity (164). Antibody-basedCSPs were shown to be useful for routine enantiomeric separationsin HPLC in an immunoaffinity chromatography method (165).

CAPILLARY ELECTROCHROMATOGRAPHYThe popularity of capillary electrochromatography remained

high in this review period for the separation of chiral racemates,with various separations performed using macrocyclic antibioticsand other CSPs. The enantioseparations of 12 glycyl dipeptidesby CEC on a teicoplanin aglycon-packed capillary were comparedto results obtained using micro-HPLC with the same stationaryphase (166). Efficiency and resolution were generally found tobe higher in CEC than with micro-HPLC. Two different types offused-silica capillaries were evaluated for the enantioseparationof several basic compounds by CEC (167). The first capillary wasa CSP containing teicoplanin mixed with silica microparticles,while the second capillary contained only the teicoplain. Severalâ-blockers were fully enantioseparated with both capillary typesin very short times. A capillary packed with teicoplanin aglyconwas used as a CSP in CE for the enantioresolution of diastereo-meric di- and tripeptides (168). While all compounds studied couldbe baseline resolved under optimized conditions, it was notpossible to find a uniform mobile phase showing optimal resultsfor all peptides.

A new CSP was prepared by Fanali et al. (169)by reacting MDL63,246 (Hepta-Tyr), a glycopeptide antibiotic belonging to theteicoplanin family, with silica particles. These particles were usedto pack a capillary column for only 6.6 cm. This short-end injectioncapillary achieved separations in 1-3 min in CEC, but relativelylong retention times were observed for the same CSP capillaryusing capillary liquid chromatography. Fanali et al. (170) alsoreported the separation of hydroxy acid enantiomers using CECusing the CSP reported above. Separation parameters such asorganic solvent type and concentration, buffer pH, and tempera-ture on the enantioresolution factor, retention time, and retentionfactor were studied. The silica-based packed capillary teicoplaninderivative (Hepta-Tyr) CSP and a vancomycin CSP were employedto enantioseparate some selected acidic nonsteroidal antiinflam-matory drugs by CEC (171). A packed capillary with vancomycinCSP was used to achieve the enantioseparation of the antidepres-sant drug fluoxetine and its main metabolite norfluoxetine by CEC

using a high-sensitivity UV detection cell (172). Basic compoundswere enantioseparated using CEC with packed silica capillariesderivatized with vancomycin with polar organic solvents as mobilephases (173). It was reported that the enantiomeric resolution,electroosmotic flow, and number of theoretical plates werestrongly influenced by the type and concentration of the organicsolvent.

Strong cation-exchange-type CSPs based on sulfodipeptidechiral selectors were reported by Lindner et al. (174), and thesynthesized CSPs were used to separate chiral bases by nonaque-ous CEC. New CSPs derived from enantiomerically pure deriva-tives of cysteine carrying sulfonic acid groups were evaluated forthe nonaqueous CEC enantioseparation of chiral bases includingâ-blockers, â-sympathomimetics, and other basic drugs (175). ACEC method for the determination of the enantiomeric excess ofD-ephedrine was developed using a novel low-molecular-weightstrong chiral cation exchanger based on penicillamine sulfonicacid, which was immobilized on thiol-modified silica particles(176). The high loadability of the CSP and good peak sensitivityallowed the determination of less than 0.1% enantiomeric impuritywith good accuracy. Cation-exchange-type CSPs based on 3,5-dichlorobenzoylamino acid and aminophosphonic acid derivativesas chiral selectors and silica as the chromatographic support wereused in the enantioseparation of chiral bases by nonaqueous CEC(177). A wide variety of chiral bases were reported resolved,including â-blockers and other amino alcohols, local anestheticssuch as etidocaine, antimalarial agents such as mefloquine,Troger’s base phenothiazines such as promethazine, and antihis-taminics. A new chiral monomer derived from cinchona alkaloidwas used in an in situ preparation of an enantioselective monolithiccapillary column that was comparatively evaluated with previouslydescribed analogues used as CSPs in CEC (178). The new CSPshowed enhanced enantioselectivities and faster separations thanthe analogues, with derivatized amino acids being enantiosepa-rated with resolution values between 2 and 4.

Pressure-assisted CEC was used with a Pirkle-type CSP, theWhelk-O1, and normal-phase solvents with small percentages ofwater to separate a number of chiral analytes (179). The effectsof the different contributions of pressure and voltage werereported. Another pressure-assisted CEC application was reportedby Honzatko et al. (180) in the enantioseparation of neutral aminoacids and amino alcohol derivatives. Two Pirkle-type columns wereused.

Chiral CEC-MS was used in the enantioseparation anddetermination of warfarin enantiomers in human plasma (181),using a Whelk-O1 CSP and electrospray ionization MS. A CSP ofavidin was prepared by physical adsorption to a monolithic silicacolumn and used for chiral separations in CEC and capillary HPLC(182) for 12 chiral test compounds. An avidin CSP was used inan evaluation of extended light path capillary and etched capillaryfor use in open tubular CEC (183). A novel method to synthesizea human serum albumin CSP was reported, and its use in CECand capillary HPLC was detailed (184). Affinity CEC with zonalelution method was used to investigate the competitive bindingof enantiomers to a bovine serum albumin column (185).

A polyelectrolyte multilayer (PEM) coating was used to modifyfused-silica capillaries for open tubular CEC (186), with the PEMcoating constructed in situ with alternating rinses of positively


and negatively charged polymers. Optimal conditions for thecoating procedure were reported, and the PEM-coated capillarywas used for the enantioseparation of 1,1′-binaphthyl-2,2′dihydro-gen phosphate, 1,1′-bi-2-naphthol, secobarbital, pentobarbital, andtemazepam. The PEM-coated capillary was reported to show goodreproducibility and stability.

MISCELLANEOUS TECHNIQUESCountercurrent chromatography (CCC) using cinchona deriva-

tives as chiral selectors achieved the enantioseparation of N-derivatized amino acids and 2-aryloxypropionic acids, with theresults indicating the potential of CCC as a preparative enantiomerseparation technique (187). Simulated moving bed (SMB) chro-matography was used in the preparative enantioseparation ofN-Cbz-tert-leucine on the cellulose-based phase Chiralcel OD, andthe enantioseparation of N)Boc-tert-leucinebenzyl ester on theamylose-based phase Chiralpak AD (188). In both separations,the enantiomers were obtained in high yield and high opticalpurity. SMB chromatography was used in the enantioseparationof a pharmaceutical racemate, with the initial method development,batch resolution, and different approaches discussed (189).Another SMB process was developed for the resolution of FTC-ester enantiomers, a potential anti-HIV drug precursor, (190) usingChiralpak AD. An effective strategy for optimal design of batchand simulated moving bed chromatographic separation processeswas reported by Jupke et al. (191), using a model system withChiralpak AD to separate a racemic mixture, EMD53986.

Affinity ultrafiltration uses a large stereospecific binding agentto selectively bind and retain one of the enantiomers in a racemicmixture. The effect of the solution, pH, and salt concentration onthe binding interactions of bovine serum albumin with D- andL-tryptophan was studied by Ramero and Zydney (192). Amultistage affinity ultrafiltration process was shown to provide highpurification factors and yield for enantioseparations (193).

Optically active polyelectrolyte multilayers showed selectivityin membrane separations of enantiomers such as L- and D-ascorbicacid (194). The flux through the multilayers was reported to beexceptionally high and could be controlled by the salt concentra-tion in the permeating solutions. Microfluidics-based membranechromatography was utilized in the high-resolution chiral separa-tion of racemic tryptophan and thiopental, using porous poly-(vinylidene fluoride) membranes adsorbed with bovine serumalbumin (195).

The use of microfabricated cantilevers as bioaffinity sensorswas investigated using immunoglobulin G and bovine serumalbumin (196). The direct stereoselective detection of traceamounts of R-amino acids was achieved based on immunome-chanical responses involving nanoscale bending of the cantilever.

ACKNOWLEDGMENTThe authors thank Karen Ward for her generous assistance and

editing with this review. Her input and patience was much neededand appreciated.

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Daisy-Malloy Hamburg, currently a graduate student at the Uni-versity of Cincinnati, received her B.S. degree from Millsaps College(Jackson, MS).

Timothy J. Ward, professor of chemistry and chair of the ChemistryDepartment at Millsaps College (Jackson, MS), received his B.S. degreefrom the University of Florida and his Ph.D. from Texas Tech University.He joined Millsaps College in 1990, after working at Syntex in thepharmaceutical process control division. His research interests includechiral separations and the characterization of enantiomeric resolution,the development of analytical LC and CE methods, and their applicationto pharmaceutical and environmental separations.


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AC040093T


chiral separations

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