Anal. Chem.

2004, 76, 4635-4644

Chiral Separations
Timothy J. Ward* and Daisy-Malloy Hamburg

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

Review Contents metabolites in biological fluids by CE-mediated microanalysis were

Reviews 4635 summarized by Bonato (2), who observed an increase in the use
Capillary Electrophoresis (CE) 4635 of negatively charged β-CD derivatives as chiral selectors. The
High-Performance Liquid Chromatography 4635 use of combinations of different chiral selectors was also noted.
(HPLC) The direct chiral separation of short-chain organic acids by CE
Gas Chromatography (GC) 4636 was reviewed by Barbas and Saavedra (3), with existing methods
Thin-Layer Chromatography (TLC) 4636 using various techniques discussed. These techniques included
Capillary Electrochromatography (CEC) 4636
CE utilizing macrocyclic antibiotics, CDs, ion-pair method, transi-
Multiple Technique Reviews 4636
tion metal complexes, and exchange CE. Strategies to advance
Capillary Electrophoresis 4636
Cyclodextrins 4636 the chiral separations in these areas were also described. Altria
Antibiotics 4637 and Elder summarized the status and applications of CE to the
Micelles 4637 analysis of small molecules, with an application area devoted to
Microchip CE 4638 chiral separations (4).
Miscellaneous 4638 CE moved into microscale with microchip electrophoresis
Thin-Layer Chromatography 4638 (MCE) showing great promise for enantiomeric separations.
Supercritical Fluid Chromatography and Related 4638 Chiral MCE was reviewed by Belder and Ludwig (5) with an
Techniques
introduction given into the principles of chiral separation with
Gas Chromatography 4639
MCE regarding instrumentation and methodology. Emphasis in
Liquid Chromatography 4639
Cyclodextrin CSPs and Mobile-Phase Additives 4639 this review was on approaches to improve detection and resolution
Macrocyclic Antibiotic CSPs 4639 in chiral MCE.
Polysaccharide CSPs 4640 Several approaches used to couple CE and electrospray
Protein-Based CSPs 4640 ionization-mass spectrometry (ESI-MS) for the analysis of chiral
Micellaneous CSPs 4640 compounds were summarized by Shamsi (6). A short compilation
Capillary Electrochromatography 4641 of commercially available CE-MS instruments and interface
Miscellaneous Techniques 4642 design was given, followed by an extensive discussion on the
Literature Cited 4642 various modes of chiral CE-MS. These modes included chiral
capillary zone electrophoresis-mass spectrometry (CZE-MS)
This fundamental review article covers developments and
with neutral derivatized cyclodextrins, chiral electrokinetic chro-
applications in chiral separations from January 2002 to January
matography-mass spectrometry (EKC-MS) with a charged chiral
2004 and is restricted to the English language literature. With
selector, micellar electrokinetic chromatography-mass spectrom-
the tremendous number of publications in this field, a compre-
etry (MEKC-MS), and capillary electrochromatography-mass
hensive review of all published papers is not feasible; rather this
spectrometry (CEC-MS).
fundamental review focuses on major developments in the field
CE-MS was again discussed in regard to affinity CE and CD-
of chiral separations as well as representative applications. Several
EKC, with particular attention paid to method development in a
excellent general reviews covering chiral separations are pre-
review by Tanaka (7).
sented first, followed by a examination of the methods and
High-Performance Liquid Chromatography (HPLC). The
techniques utilized in each area.
HPLC methods for the enantiomeric separation of amphetamine
and related compounds were reviewed by Herraiz-Hernandez et
REVIEWS
Capillary Electrophoresis (CE). Capillary electrophoresis al. (8), with discussions of the direct enantioseparation of non-
remains a popular technique for the enantioseparation of biologi- derivatized amphetamines using β-cyclodextrin as the chiral
cally active compounds. A review discussing the determination selector, both immobilized on the stationary phase and added to
of the enantiomeric excess in enantiomerically pure drugs by the mobile phase. Other chiral stationary phases such as Pirkle
cyclodextrin (CD)-modified CE, compiled by Schmitt et al. (1), type, cellulose based, or protein based were also discussed. The
reviews strategies of method development, sensitivity of detection, use of immobilized proteins as chiral stationary phases (CSPs) in
and optimization of separation parameters. The recent develop- HPLC and in CE for the enantioseparation of drugs was sum-
ments in the determination of enantiomeric drugs and their marized by Millot (9), including the main procedures for protein
immobilization onto matrixes and factors affecting enantiosepa-
* Corresponding author: (phone) (601) 974-1405; (fax) (601) 974-1401; ration. Clarke and Hage reviewed the clinical application of affinity
(e-mail) wardtj@millsaps.edu. chromatography including chiral separations (10, 11).
10.1021/ac040093t CCC: $27.50 © 2004 American Chemical Society Analytical Chemistry, Vol. 76, No. 16, August 15, 2004 4635
Published on Web 06/19/2004
 Gas Chromatography (GC). The separation of enantiomers
by GC on CSPs was extensively reviewed by Schurig (12), with
discussion of the method development, applications, and ancillary
techniques of chiral separations using GC. CSPs with amino acid
derivatives, terpene-derived metal coordination compounds, and
modified cyclodextrins were included. Schurig also comprehen-
sively reviewed the practice and theory of enantioselective
complexation GC on optically active metal(II) bis[3-perfluoroacyl)-
(1R)-camphorate] selectors (13). Applications extend to chiral
analysis 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 of
stationary phases for TLC in the last 10 years was compiled by
Gocan (14), and included chiral separation and recent advances
in chiral stationary phases. The CSPs discussed included nonpolar
bonded stationary phases impregnated with transitional metal ions,
cellulose, modified cellulose, chitin, chitosan, and their derivatives.
Cyclodextrin and macrocyclic antibiotics were reported to have
very good results for enantioseparation by TLC, with molecular
imprinting polymers also finding use as CSPs in TLC.
Capillary Electrochromatography. The applications of CEC
were reviewed by Remcho et al. (15). Chiral separations with
cyclodextrins and their derivatives, biomolecules, molecularly
imprinted polymers, “brush”-type phases, ion exchangers, anti-
biotics, polysaccharide derivatives, and other CSPs were included
in this review. A summary of recent progress in open-tubular CEC
for chiral and achiral separations included stationary-phase
preparation (16), with the major developments, potential applica-
tions, technical difficulties, and advantages of each wall coating
discussed.
Multiple Technique Reviews. The use of cyclodextrins in
chiral chromatography was compiled by Juvancz and Szejtli (17).
The role of cyclodextrins in methods using capillary columns such
as GC, supercritical fluid chromatography (SFC), and CE was
detailed, as well as their use in other forms of chromatography
such as HPLC and TLC. The mechanism of chiral recognition
using cyclodextrins was also discussed. Williams and Wainer (18)
reviewed the role of chiral chromatography in therapeutic drug
monitoring and in clinical and forensic toxicology. Enantioselective
GC and HPLC were used as tools to unravel complex phenomena
associated with drug transport and metabolism.
CAPILLARY ELECTROPHORESIS
Cyclodextrins. Cyclodextrins and their derivatives remain one
of the most widely used chiral selectors for CE chiral separations.
Sulfated β-CDs and carboxymethyl-β-CD were used as chiral
selectors in the separation of 41 chiral sulfoxides and sulfinate
esters (19). The sulfated β-CDs were reported to separate a
greater number of compounds and had better separating capabili-
ties than carboxymethyl-β-CD. Hydroxypropylated, dimethylated,
and sulfated CDs were used as chiral additives in CE to evaluate
their effectiveness as chiral selectors (20). Eleven different CDs
including neutral and charged derivatives were used as chiral
selectors in the chiral CE separation of fluoxetine and four
analogues (21). Optimized separation conditions including type
of CDs, CD concentration, and pH of the background electrolyte
4636 Analytical Chemistry, Vol. 76, No. 16, August 15, 2004
were reported. Egger et al. demonstrated that sulfated β-CDs used
at low pH in the reversed polarity mode were found to give the
best separation of chiral dihydrofurocoumarin compounds in a
study comparing four different chiral methods using CE and
micellar CE (22). Sulfated β-CD was used as the chiral selector
in the simultaneous enantiomeric CE separation of citalopram and
its metabolite desmethylcitalopram (23).
A CE method for the chiral separation of racemic methotrexate
using hydroxypropyl-β-CD was developed and validated by Kuo
et al. (24). Various commercially available CDs were used in a
study concerning the CE separation of aminophosphonic acid
enantiomers, 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 of
propoxyphene, in which baseline resolution was achieved in ∼6
min (26). A dual CD system of polyanionic heptakis-6-sulfato-β-
CD with neutral heptakis(2,3,6-tri-O-methyl)-β-CD was utilized in
the CE enantioseparation of nonsteroidal antiinflammatory drugs
such as fenoprofen, flurbiprofen, ibuprofen, and ketoprofen (27).
Selectivity for the enantioseparation of these drugs was predicted
using mathematical models. Carboxymethylated β- or γ-CDs were
used in a CE method to achieve the rapid separation of a set of
12 basic amino-containing drugs (28), but neither of the two CDs
used was able to separate the entire set of drugs. A new CE
method was reported for the detection of enantiomeric purity of
imidazo(2,1-i)purin-5-ones and related tricyclic water-soluble purine
derivatives using native and modified β-CDs as chiral selectors
(29).
The distribution of enantiomers of methamphetamine, meth-
cathinone, ephedrine, and pseudoephedrine in clandestine tablets
and urine samples was analyzed by a β-CD-modified CE method
and described by Liau et al. (30). The chiral separation method
of 3,4-methylenedioxymethamphetamine and related compounds
by CE with β-CD and fluorescence spectroscopy was developed
and used to determine the distribution of isomers in clandestine
tablets and urine samples (31). Highly sulfated γ-CD was used in
the simultaneous chiral separation of nine amphetamine-type
stimulants by CE (32), and highly sulfated β-CD was the chiral
selector in the enantioseparation of warfarin (33).
A chiral CE method using heptakis(2,6-di-O-methyl)-β-CD was
reported for the resolution of the six enantiomers associated with
the metabolism of methadone (34). Native CDs and neutral and
charged CD derivatives were evaluated in the development of the
chiral separation of diastereomeric flavanone-7-O-glycosides in
citrus by CE (35). The chiral separation of deprenyl N-oxide
isomer using CE in the presence of various CD derivatives was
reported by Tabi et al. (36). Anionic and neutral compounds were
enantioseparated using a heptasubstituted cationic β-CD as chiral
selector in CE (37). Chiral separation was found to be highly
dependent on pH, with the resolution enhanced at higher pH. A
β-CD substituted by an imidazole-bound histamine was used to
separate underivatized tryptophan in CE in the presence of copper-
(II) ion in what is reported to be the first ligand-exchange chiral
separation by a CD derivative added to the background electrolyte
(38).
A chiral CE method using highly sulfated CDs in a low-pH
phosphate buffer and the short-end injection technique to enan-
tioseparate a basic, neutral, and acidic compound was evaluated
for robustness, and the statistical interpretation was presented by
Perrin et al. (39). The chiral separation of enantiomers of a plant
growth regulator, abscisic acid, by CE with CD additives was
reported (40), with dimethyl-β-CD, hydroxypropyl-β-CD, and γ-CD
giving satisfactory enantioselectivity. A novel assay method for
enantiomeric separation was developed using a combination of
CE and electrospray tandem MS connected with a homemade
interface (41). Nonaqueous CE using an ion-pairing reagent in
combination with an anionic CD derivative enantioresolved basic
pharmaceuticals, with the enantiomeric resolution lost or strongly
reduced in the absence of the ion-pairing reagent (42).
CE is often compared with or used in conjunction with HPLC
methods. A comparative study on the enantiomeric separation of
1,1′-binaphthyl-2,2′-diyl hydrogen phosphate and 1,1′-binaphthol
by HPLC and CE, using CDs and bile salts as single and dual
selectors, was reported by Bielejewska et al. (43). The chiral
separation of an M3 antagonist was investigated using CE with
various sulfated CDs and by reversed-phase HPLC with derivatized
cellulose, derivatized amylose, and two protein stationary phases
(44). Based on the comparison of techniques, a practical CE
method using sulfated γ-CD was selected and validated. The chiral
separation of bioactive cyclic Mannich ketones was performed
using HPLC with cellulose derivative CSPs or CD-CSPs, and in
CE, different CDs such as β-CD, γ-CD, carboxymethyl-β-CD, and
succinyl-β-CD were added to the background electrolyte as chiral
selectors (45). Two independent methods using HPLC on polysac-
charide-type CSP and CE with native and derivatized CDs were
developed for the chiral resolution of the vasodilator drug
isoxsuprine (46). The methods were compared for efficiency,
sensitivity, analysis time, and costs. The enantioseparation of
tetramisole by CE and HPLC was reported, and these techniques
were applied to the determination of the enantiomeric purity of a
veterinary drug formulation of L-levamisole (47). The CE methods
evaluated various CDs as chiral selectors, while the HPLC method
used a polysaccharide-type CSP. CE was determined to be the
preferred method.
CZE was used with sulfated β-CD for the simultaneous
determination of DOPA and carbidopa enantiomers (48). The
separation and migration behavior of 13 structurally related
phenothiazines in CD-modified CZE was reported by Chen et al.
(49), with β-CD and hydroxypropyl-β-CD evaluated. A method for
the 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)-dexchlorpheniramine
maleate was reported (51), using carboxymethyl-β-CD in an acidic
background electrolyte. The complete chiral separation of meth-
oxamine and lobeline was achieved by CZE on a ethylbenzene-
deactivated fused-silica capillary column, with dimethyl-β-CD and
hydroxypropyl-β-CD giving the best results (52). Carboxyethyl-
β-CD dissolved in the operating buffer in CZE was used for the
enantioseparation of dioxopromethazine in eye drops (53). Xu et
al. reported the chiral separation of 2,3-allenoic acid by CZE using
CD derivatives of hydroxypropyl-β-CD and hydroxypropyl-γ-CD
(54). Abscisic acid enantiomers were enantioseparated by CZE
using CDs and their derivatives (55), with γ-CD, hydroxypropyl-
β-CD, and dimethyl-β-CD forming strong complexes.
EKC with carboxymethylated γ-CD and β-CD was used to
monitor the stereoselectivity of biodegradation of chiral polychlo-
rinated biphenyls (56). A comparison of charged CD derivatives
for the enantioseparation of atropisomeric polychlorinated biphe-
nyls by CZE was reported by Garcia-Ruis (57), and the results
were compared with those obtained by the dual CD system
reported above. Cyclodextrin-based EKC was used with quenched
phosphorescence detection to monitor the stereoselective bio-
degradation of camphorquinone by yeast (58). CZE employing
vancomycin as a chiral selector was used in the chiral separations
of a nonsteroidal antiinflammatory drug candidate (59) and
racemic N-acetyl derivatized amino acids (60).
Antibiotics. The macrocyclic antibiotics were also used as
chiral selectors for CE enantioseparations during this review
period. A CE study including a theoretical approach was used to
determine the binding constant of acid herbicide enantiomers-
vancomycin complexes, and the dependence on salt concentration
was discussed (61). Several strategies for using vancomycin as a
chiral selector in CE were explored, including the dynamic coating
technique, the coelectroosmotic flow technique, and the partial
filling technique (62). The vancomycin analogue A82846B pro-
vided excellent selectivity for some acidic test solutes, with its
dimerization in solution proposed as the reason it showed
enhanced enantioseparations compared with vancomycin (63).
Micelles. Micellar methods continue to be used for chiral
separations in CE. A MEKC method was developed for the
detection of chiral amino acids in orange juice (64). This method
utilized β-CDs as chiral selectors and laser-induced fluorescence
for detection. A system using 1-S-octyl β-D-thioglucopyranoside,
SDS, and CD was used in the chiral separation of amino acids by
Tran and Kang (65), with the three-component system showing
better separations than 1-S-octyl β-D-thioglucopyranoside alone as
chiral selector. Another three-component system utilized 3-((3-
cholamidopropyl)dimethylammonio)-1-propanesulfonate with SDS
and 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 charged
CDs (67). A neutral CD derivative, hydroxypropyl-γ-CD, and an
ionic derivative, heptakis-6-sulfato-β-CD, were used as an additive
in CD-modified MEKC for the enantioseparation of triadimenol,
a component of systemic agricultural fungicide (68). Pemoline
enantiomers were separated with CD-modified MEKC, with the
chiral separation dependent on the type of CDs used as chiral
selectors (69).
Two amino acid-based alkenoxy micelle polymers were syn-
thesized and used as a pseudostationary phase in MEKC for the
simultaneous separation of eight chiral β-blockers (70), with the
polysodium N-undecenoxycarbonyl-L-leucinate polymer giving
overall better chiral resolution and a wider chiral window. A
synthetic chiral polymer was utilized as a pseudo stationary phase
in MEKC in aqueous buffers in methods showing high efficiencies
with the potential for rapid separations (71).
The separation of benzoporphyrin derivative mono- and diacid
enantiomers was achieved using 25 mM sodium cholate as the
chiral selector in a method using laser-induced fluorescence-
capillary electrophoresis (72). The chiral separation of 20 pairs
of amino acids derivatized with fluorescein-5-isothiocyanate was
studied with a mixture of β-CD and sodium taurocholate as chiral
Analytical Chemistry, Vol. 76, No. 16, August 15, 2004 4637
selectors (73), using CE and laser-induced fluorescence detection.
Resolution with the dual selectors was reported to be considerably
superior to that achieved with either selector alone.
Microchip CE. Microchip electrophoresis coupled with chemi-
luminescence detection was used with hydroxypropyl-β-CD as a
chiral selector for the enantioseparation of chiral dansyl amino
acids (74) and dansylphenylalanine (75). Sulfated CDs were used
in fast chiral separations of a variety of basic and acidic compounds
on a microchip electrophoresis instrument with linear imaging
UV detection (76). It was reported that a mixture of three chiral
drugs could be separated in less than 11 s. Chiral crown ether
was used as chiral selector in a CE and microchip CE method for
the enantioseparation of gemifloxacin in a sodium-containing
media (77).
Miscellaneous. Enantioseparations have also been carried out
using a number of miscellaneous chiral selectors, with a few
selected examples reported here. Nonaqueous ion-pair CE using
quinine and tert-butylcarbamoylquinine as chiral selectors was
used in the enantioseparation of N-protected amino acids (78, 79)
and peptides (80). Chiral separations in CE using cinchona
alkaloid 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 chiral
separations by CE was described by Wang et al. (82). A novel
chiral selector, N-benzoxycarbonylglycyl-L-proline, was introduced
by Hedeland et al. (83) for enantioseparation of pharmacologically
active amines in nonaqueous CE. The enantioseparation of
mepivacaine was achieved in 72 s using short-end injection with
an effective capillary length of 8.5 cm. Underivatized amino acids
were enantioseparated by ligand-exchange CE using L-lysine as
the ligand and copper(II) as the central ion (84). SDS was
necessary for simultaneous resolution of the amino acids but
caused precipitation at less than 32 mM at room temperature. It
was postulated that the precipitation might be caused by the
formation of a neutral substance from the SDS monomer and the
copper(II)-lysine complex.
THIN-LAYER CHROMATOGRAPHY
Thin-layer chromatography remains a reliable technique for
rapid screening of chiral separations. Some 2-arylpropionic acids
were enantioresolved using silica TLC plates impregnated with
optically pure L-(-)-serine, with the method applied to commercial
ampules of ketoprofen dosage formulation (85). Silica TLC plates
impregnated with L-(-)-serine and L-(-)-threonine and a mixture
of these chiral selectors were prepared for the enantioseparation
of more 2-arylpropionic drugs (86). Detection limits were reported
to 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 β-blockers, atenolol, metoprolol, and
propranolol, were enantioseparated using normal-phase TLC on
silica gel plates impregnated with L-aspartic acid with iodine
detection (87). Molecularly imprinted polymers of S-timolol were
prepared and used in the direct chiral separation of some
cardiovascular drugs, including propranolol, atenolol, timolol,
nadolol, nifedipine, and verapamil (88).
4638 Analytical Chemistry, Vol. 76, No. 16, August 15, 2004
SUPERCRITICAL FLUID CHROMATOGRAPHY AND
RELATED TECHNIQUES
A variety of CSPs have been used for chiral separations in SFC
during this review period. Phinney and Sander (89) studied the
polar additive concentration effects on CSPs containing either a
macrocyclic glycopeptide or a derivatized polysaccharide. The
polar additives were found to significantly decrease retention, and
many analytes failed to elute in the absence of the polar additives.
The commercially available column Chiralpak was used in the
enantioseparation of triadimenol and triadimefon in SFC (90), with
the separation occurring in 15 min. A Whelk-O1 column was used
in a SCF method to determine the enantiomerization energy
barrier for some 3-hydroxy-1,4-benzodiazepine drugs (91).
The enantioseparation of albendazole sulfoxide was achieved
on two columns, Chiralpak AD and Chiralcel OD, and the effects
of different modifiers were examined (92). This enantioseparation
was also achieved at the semipreparative scale (93), using an
adapted SFC chromatograph and a Chiralpak AD (250 mm × 10
mm) column. The effect of different injection volumes on purity
and throughput of the individual enantiomers was studied.
Three macrocyclic glycopeptide chiral selectors, teicoplanin
(Chirobiotic T), teicoplanin aglycon (Chirobiotic TAG), and
ristocetin (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,
β-blockers, sulfoxides, N-protected amino acids, and native amino
acids were separated on the three CSPs. Chirobiotic TAG and
Chirobiotic T were found to fully or partially resolve 92% of the
enantiomers in the compound set, while Chirobiotic R separated
only 60%. All separations were performed in less than 15 min, with
the 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 fluid
chromatography (95), with the Chirobiotic T CSP reported to
demonstrate the best enantioselectivity for 21 of the compounds.
Thermally unstable furan derivatives were enantioseparated by
SFC and HPLC with a derivatized cellulose or amylose CSP (96).
This report also included the separation of volatile furan ethers
using GC/MS.
Packed-column subcritical fluid chromatography was used in
the enantioseparation of a thiazolbenzenesulfonamide compound,
using a Chiralpak AD CSP (97). The effects of temperature and
alcohol modifier were also reported. A ristocetin CSP was
evaluated 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 on
the enantioseparations were presented.
SFC-MS was utilized in various applications during this review
period. A wide variety of pharmaceutical racemates were separated
and characterized using SFC coupled to a hybrid MS (Q-TOF)
equipped with an electrospray ion source (99). Three different
CSPs and different pressure/temperature working conditions were
used. A technique for rapid method development for chiral
separations in drug discovery using sample pooling and SCF-MS
was reported by Zhao et al. (100). Four CSPs and eight different
modifier concentrations were used in a fully automated process
lasting 15 h to attain optimal chiral separations for multiple
compounds.
GAS CHROMATOGRAPHY
Cyclodextrin-based GC columns were found to have wide-
spread use for the direct resolution of enantiomers during this
review period. Four derivatized CD-based CSPs, Chiraldex-G-TA,
G-PN, G-BP, and B-DM, were used in GC to enantioseparate 17
chiral sulfoxides and 8 chiral sulfinate esters (101), with the G-TA
and B-DM CSPs generally giving opposite elution orders for most
of the compounds. Alkylated β-CD and γ-CD CSPs were used in
the GC separation of enantiomers of seven N-TFA-O-alkylamino
acid derivatives (102). An evaluation of the nonpolar interactions
of the separations was also given.
The 2-O-methyl-3-O-acetyl and 2-O-acetyl-3-O-methyl derivatives
of 6-O-tert-hexyldimethylsilyl-γ-CD were synthesized as a GC CSP
and tested for chiral separation (103). Enantioseparations were
compared 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-β-CD CSP was reported by Ra-
mos et al. (104).
A chiral dual-column GC system was used in the chiral
separation of N-TFA-O-Me esters of six amino acids in a study to
vary the selectivity by adjusting the individual carrier gas flow
rates (105). Two columns, Chirasil-L-Val and Chirasil-D-Val, which
demonstrate opposite enantioselectivities, were coupled in series
for this study.
A method suitable for the enantioseparation of D-amino acids
in a wine sample was reported using a GC capillary column coated
with immobilized poly(dimethylsiloxane) anchored to (S)-(-)-tert-
Leu-(S)-(-)-1-R-naphthyl)ethylamide (106). The amino acids were
converted into N-pivaloyl methyl esters in two reaction steps.
LIQUID CHROMATOGRAPHY
Direct chiral separations using macrocyclic antiobiotics CSPs
in HPLC continue to be very common, with cyclodextrin- and
polysaccharide-based columns also finding much use.
Cyclodextrin CSPs and Mobile-Phase Additives. The
HPLC chiral analysis of alkoxy-substituted esters of phenylcar-
bamic acid was performed on β- and γ-CD CSPs (107). The
enantioselective separation of 28 racemic dihydrofurocoumarins
was studied using three native and six derivatized CD CSPs in
reversed-phase mode, polar organic mode, and normal-phase
mode (108), with the hydroxypropyl-β-CD reported as the most
effective CSP in the reversed-phase mode. Native and derivatized
CD CSPs were evaluated for the enantioseparation of aromatic
and aliphatic sulfoxides (109), and many sulfoxide enantiomers
were baseline resolved using the derivatized CD CSP in the
reversed-phase mode.
The enantioseparation of 42 derivatized amino acids and
biogenic amines was accomplished with an amino-β-CD CSP
(110). A novel urea-covalent-bonded methylated β-CD CSP was
used 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 β-CD and 2-hydroxypro-
pyl-β-CD as mobile-phase modifiers (112). Separations were
accomplished in less than 2 min using this method.
Macrocyclic Antibiotic CSPs. A set of 42 chiral sulfoxides
were enantioseparated by HPLC using 5 different macrocyclic
glycopeptide CSPs, ristocetin A, teicoplanin, teicoplanin aglycon,
vancomycin, and vancomycin aglycon, and 7 eluents, three normal
phase, two reversed phase, and two polar organic (113). The
teicoplanin and teicoplanin aglycon CSPs were reported to be the
most effective, with 35 and 33 of the 42 compounds studied
resolved, respectively. The enantiomers of 28 substituted dihy-
drofurocoumarins were separated by HPLC using CSPs containing
ristocetin A, teicoplanin, and teicoplanin aglycon (114), with the
teicoplanin CSP exhibiting the broadest enantioselectivity with 24
compounds baseline resolved.
A study of D,L-tryptophan enantiomer retention on a teicoplanin
CSP was reported, using the perturbation technique to determine
the solute distribution isotherms while varying the mobile-phase
sodium perchlorate concentration (115). Phenoxypropionic acid
herbicides were enantioseparated by teicoplanin CSP, and the
perturbation method was used to calculate the solute distribution
isotherms (116). The effects of both temperature and methanol
were described by a bi-Langmuir approach. A HPLC-MS assay
using a teicoplanin CSP for the determination of albuterol
enantiomers in human plasma was described (117). This method
allows adequate sensitivity and reproducibility for the application
of studies of inhaled albuterol.
The enantioseparation of secondary amino acids by HPLC was
studied using teicoplanin and ristocetin A as CSPs (118). An online
coupled 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 the
matrix (119). Teicoplanin and teicoplanin aglycon CSPs were used
in a study of the influence of carbohydrate moieties of teicoplanin
on the separation of some phenylcarbamic acid derivatives, with
the teicoplanin aglycon CSP achieving better separations (120).
An enantioselective HPLC method for the determination of
arotinolol in human plasma using teicoplanin CSP was validated
(121), and a method for the determination of baclofen in human
plasma using teicoplanin CSP was developed (122).
A semipreparative HPLC method for the enantioseparation of
two 2-arylpropionic acids on novel CSPs containing teicoplanin
A2-2 and A-40,926 was described by Alcaro et al. (123).
A vancomycin CSP used with a polar organic solvent in HPLC
was used in an investigation of the enantiorecognition process of
derivatives of substituted phenylcarbamic acid, with a discussion
of the interaction mechanism of the separation included (124). A
displacement study on a vancomycin CSP using N-acetyl-D-alanine
as a competing agent for the aglycon pocket was reported,
showing that dansyl amino acids bind to the active aglycon pocket
of the selector, with additional enantioselective sites at the
vancomycin surface also involved in chiral discrimination (125).
A vancomycin CSP was used in a method for the enantioseparation
of promethazine by HPLC (126), with vancomycin showing the
best resolution over teicoplanin and ristocetin A CSPs. The effects
of temperature and solute molecular size effects on the retention
and enantioselectivity of D,L-dansyl amino acids were studied using
a vancomycin CSP (127). Enantioseparation of fluoxetine (Prozac)
Analytical Chemistry, Vol. 76, No. 16, August 15, 2004 4639
in human plasma on a vancomycin CSP by HPLC-MS was
reported by Shen et al. (128). Vancomycin CSP was used in the
HPLC method for the enantiomeric separation of 1,4-dihydro-
pyridines (129), with the method suitable for semipreparative
separation.
A ristocetin A CSP was used in a HPLC study of the effects of
temperature on retention of tryptophan, 1,2,3,4-tetrahydroiso-
quinoline, and γ-butyrolactone analogues (130). Enantioselective
ion-exclusion chromatography on teicoplanin aglycon and (+)-
(18-crown-6)-2,3,11,12-tetracarboxylic acid CSPs was reported by
Steffeck and Zelechonok (131).
Polysaccharide CSPs. An amylose tris(3,5-dimethylphenyl)-
carbamate CSP was used in a study of the mechanistic aspects of
chiral discrimination (132). The direct chiral determination of
metyrapone and metabolites in plasma was accomplished using
a multidimensional achiral-chiral LC method (133). The CSP
used was amylose tris(3,5-dimethoxyphenylcarbamate). The un-
usual effect of column temperature on the enantioseparation of
dihydropyrimidinone acid and its methyl ester on Chiralpak AD
was summarized, with data suggesting that the CSP was under-
going a thermally induced irreversible conformational change that
altered the separation mechanism between the heating and cooling
cycles of the method used (134). This change was dependent on
the type of polar mobile-phase additive used. These thermal
changes 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 remove
bound additives was developed (135). The unusual equilibrium
behavior of the Troger’s base enantiomers on Chiralpak AD was
reported (136), with the finding that the adsorption of the more-
retained (-)-enantiomer was not competitive and the amount
adsorbed onto the CSP was independent of the concentration of
the (+)-enantiomer. However, the adsorption of the less retained
(+)-enantiomer was cooperative, with the amount adsorbed
increasing with increasing concentrations of the (-)-enantiomer.
The chiral HPLC separation of nucleoside analogues of d4T
and acyclovir was accomplished on the silica-based amylose CSPs
Chiralpak AD and Chiralpak AS, with the effect of structural
features studied in relation to retention, selectivity, resolution, and
elution order (137). The HPLC enantioseparation of hydroxy-
mebendazole in human plasma was achieved on a Chiralpak AD,
and a concurrent CE method using sulfated β-CD as chiral selector
was also developed (138). Both methods were validated. A
validated chiral HPLC normal-phase method for the enantiosepa-
ration of linezolid on Chiralpak AD was reported (139). The
resolution of the enantiomers of dialkylaminoalkylnaphthalenes
was achieved by a preparative HPLC method using Chiralpak AD
CSP (140). For the chiral resolution of flurbiprofen and its major
metabolites, four methods were developed using Chiral-AGP and
Chiralpak AD CSPs, one was developed using a reversed-phase
HPLC method using hydroxypropyl-β-CD as a chiral mobile-phase
additive, and another utilized a precolumn derivitization method
(141). Only the method utilizing the Chiralpak AD CSP showed
the separation and enantioresolution of all three analytes within
45 min. The enantioseparation of ibuprofen in human plasma was
performed using Chiralpak AD-RH in reversed-phase mode by
HPLC-MS, with the method reported to be suitable for single-
4640 Analytical Chemistry, Vol. 76, No. 16, August 15, 2004
dose pharmacokinetic studies (142). The enantiomers of 14
organophosphonate derivatives were directly separated on Chiral-
pak AD, with all of the selected compounds being baseline
separated (143).
A comparison of the enantioseparation of methylphenidate
(Ritalin) was achieved in normal-phase mode on three different
CSPs, Chiralpak AD, Chiralcel OD, and Chiralcel OB, and the
role of benzoic acid and phenol as mobile-phase additives was
also discussed (144).Two chiral methods for the separation of the
enantiomers 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 the
resolution obtained on the two columns found to be complemen-
tary. The enantiomeric resolution of o,p-DDT and o,p-DDD was
achieved on Chiralpak AD-R, Chiralcel OD-R, and Chiralcel OJ-R
(146). A comparison of the enantioseparation of several tetralone
derivatives was accomplished using Chiralcel OB, Chiralcel OD,
Chiralpak AD, Chiralpak AS, and Chiralcel OF, with most of the
compounds being completely separated (147).
Protein-Based CSPs. An enantioselective HPLC-MS method
was developed and validated for the simultaneous detection of
saliva concentrations of the enantiomers of methadone and its
metabolite EDDP using a CSP based on immobilized R 1-acid
glycoprotein (AGP). The method was deemed accurate and
precise and was used to successfully analyze saliva obtained from
patients enrolled in a methadone maintenance program. A Chiral-
AGP CSP was used in the investigation of the heterogeneous
adsorption behavior of selected enantiomers by Goetmar et al.
(148). Reboxetine and O-desethyl reboxetine enantiomers were
simultaneously resolved by three stereoselective chromatographic
methods, using Chiral-AGP, ChiraGrom 2, and Chiral-CBH,
respectively, in the reversed-phase mode (149). The chiral
resolution of mosapride enantiomers was achieved on Chiral AGP,
and temperature studies were performed to investigate the
thermodynamics of the reversal in retention order (150).
Amlodipine in human plasma was enantioseparated by a Chiral
AGP CSP in an HPLC-tandem MS method (151). The method
was validated, and the limit of quantitation was 0.1 ng/mL for
each amlodipine enantiomer. The enantiomers of ketamine and
norketamine in human plasma were determined using LC-MS
with a Chiral AGP CSP. The method was validated and applied to
samples from a clinical study of ketamine in pain management
(152).
CSPs obtained by immobilization of human serum albumin on
various 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 was
used in the study of the stereoselective binding of 2-(4-biphenylyl)-
3-substituted 3-hydroxypropionic acids (154). CSPs based on
human serum albumin and bovine serum albumin were utilized
to determine the species dependency in chiral drug recognition
(155).
Micellaneous CSPs. Novel CSPs based on cinchona alkaloids
were used in the chiral HPLC separation of 3,5-dinitrobenzoyl
amino acids (156), all-R- and all-S-enantiomers of oligoalanines
with 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 the
performance of the separation was investigated (160). This CSP
was also used in a micro-HPLC method for the separation of
peptide enantiomers (up to 6 amino acid residues) (161). Resolu-
tion of the enantiomers of diphosphines and of the corresponding
phosphine 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 mobile
phases, resolution factors ranged from 0.35 to 3.61 for the
Supelcosil CSPs and from 0.37 to 6.57 for the Chiralpak AD and
Whelk-O1 columns. The Whelk-O1 CSP was utilized in the HPLC
resolution of enantiomers of 2-methoxy-1-((4-methylpiperazino)-
methyl)ethyl esters of N-(2-,3-, and 4-alkoxyphenyl)carbamic acid
in the polar organic and reversed modes (163) and in a study of
the mechanism of enantioseparation. A method using HPLC-MS
with a Crownpak CR+ CSP was used for high-throughput
screening of enzymatic racemase activity (164). Antibody-based
CSPs were shown to be useful for routine enantiomeric separations
in HPLC in an immunoaffinity chromatography method (165).
CAPILLARY ELECTROCHROMATOGRAPHY
The popularity of capillary electrochromatography remained
high in this review period for the separation of chiral racemates,
with various separations performed using macrocyclic antibiotics
and other CSPs. The enantioseparations of 12 glycyl dipeptides
by CEC on a teicoplanin aglycon-packed capillary were compared
to results obtained using micro-HPLC with the same stationary
phase (166). Efficiency and resolution were generally found to
be higher in CEC than with micro-HPLC. Two different types of
fused-silica capillaries were evaluated for the enantioseparation
of several basic compounds by CEC (167). The first capillary was
a CSP containing teicoplanin mixed with silica microparticles,
while the second capillary contained only the teicoplain. Several
β-blockers were fully enantioseparated with both capillary types
in very short times. A capillary packed with teicoplanin aglycon
was used as a CSP in CE for the enantioresolution of diastereo-
meric di- and tripeptides (168). While all compounds studied could
be baseline resolved under optimized conditions, it was not
possible to find a uniform mobile phase showing optimal results
for all peptides.
A new CSP was prepared by Fanali et al. (169)by reacting MDL
63,246 (Hepta-Tyr), a glycopeptide antibiotic belonging to the
teicoplanin family, with silica particles. These particles were used
to pack a capillary column for only 6.6 cm. This short-end injection
capillary achieved separations in 1-3 min in CEC, but relatively
long retention times were observed for the same CSP capillary
using capillary liquid chromatography. Fanali et al. (170) also
reported the separation of hydroxy acid enantiomers using CEC
using the CSP reported above. Separation parameters such as
organic solvent type and concentration, buffer pH, and tempera-
ture on the enantioresolution factor, retention time, and retention
factor were studied. The silica-based packed capillary teicoplanin
derivative (Hepta-Tyr) CSP and a vancomycin CSP were employed
to enantioseparate some selected acidic nonsteroidal antiinflam-
matory drugs by CEC (171). A packed capillary with vancomycin
CSP 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 compounds
were enantioseparated using CEC with packed silica capillaries
derivatized with vancomycin with polar organic solvents as mobile
phases (173). It was reported that the enantiomeric resolution,
electroosmotic flow, and number of theoretical plates were
strongly influenced by the type and concentration of the organic
solvent.
Strong cation-exchange-type CSPs based on sulfodipeptide
chiral selectors were reported by Lindner et al. (174), and the
synthesized 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 for
the nonaqueous CEC enantioseparation of chiral bases including
β-blockers, β-sympathomimetics, and other basic drugs (175). A
CEC method for the determination of the enantiomeric excess of
D-ephedrine was developed using a novel low-molecular-weight
strong chiral cation exchanger based on penicillamine sulfonic
acid, which was immobilized on thiol-modified silica particles
(176). The high loadability of the CSP and good peak sensitivity
allowed the determination of less than 0.1% enantiomeric impurity
with good accuracy. Cation-exchange-type CSPs based on 3,5-
dichlorobenzoylamino acid and aminophosphonic acid derivatives
as chiral selectors and silica as the chromatographic support were
used in the enantioseparation of chiral bases by nonaqueous CEC
(177). A wide variety of chiral bases were reported resolved,
including β-blockers and other amino alcohols, local anesthetics
such as etidocaine, antimalarial agents such as mefloquine,
Troger’s base phenothiazines such as promethazine, and antihis-
taminics. A new chiral monomer derived from cinchona alkaloid
was used in an in situ preparation of an enantioselective monolithic
capillary column that was comparatively evaluated with previously
described analogues used as CSPs in CEC (178). The new CSP
showed enhanced enantioselectivities and faster separations than
the 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, the
Whelk-O1, and normal-phase solvents with small percentages of
water to separate a number of chiral analytes (179). The effects
of the different contributions of pressure and voltage were
reported. Another pressure-assisted CEC application was reported
by Honzatko et al. (180) in the enantioseparation of neutral amino
acids and amino alcohol derivatives. Two Pirkle-type columns were
used.
Chiral CEC-MS was used in the enantioseparation and
determination of warfarin enantiomers in human plasma (181),
using a Whelk-O1 CSP and electrospray ionization MS. A CSP of
avidin was prepared by physical adsorption to a monolithic silica
column and used for chiral separations in CEC and capillary HPLC
(182) for 12 chiral test compounds. An avidin CSP was used in
an evaluation of extended light path capillary and etched capillary
for use in open tubular CEC (183). A novel method to synthesize
a human serum albumin CSP was reported, and its use in CEC
and capillary HPLC was detailed (184). Affinity CEC with zonal
elution method was used to investigate the competitive binding
of enantiomers to a bovine serum albumin column (185).
A polyelectrolyte multilayer (PEM) coating was used to modify
fused-silica capillaries for open tubular CEC (186), with the PEM
coating constructed in situ with alternating rinses of positively
Analytical Chemistry, Vol. 76, No. 16, August 15, 2004 4641
and negatively charged polymers. Optimal conditions for the
coating procedure were reported, and the PEM-coated capillary
was used for the enantioseparation of 1,1′-binaphthyl-2,2′dihydro-
gen phosphate, 1,1′-bi-2-naphthol, secobarbital, pentobarbital, and
temazepam. The PEM-coated capillary was reported to show good
reproducibility and stability.
MISCELLANEOUS TECHNIQUES
Countercurrent chromatography (CCC) using cinchona deriva-
tives as chiral selectors achieved the enantioseparation of N-
derivatized amino acids and 2-aryloxypropionic acids, with the
results indicating the potential of CCC as a preparative enantiomer
separation technique (187). Simulated moving bed (SMB) chro-
matography was used in the preparative enantioseparation of
N-Cbz-tert-leucine on the cellulose-based phase Chiralcel OD, and
the enantioseparation of N)Boc-tert-leucinebenzyl ester on the
amylose-based phase Chiralpak AD (188). In both separations,
the enantiomers were obtained in high yield and high optical
purity. SMB chromatography was used in the enantioseparation
of 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) using
Chiralpak AD. An effective strategy for optimal design of batch
and simulated moving bed chromatographic separation processes
was reported by Jupke et al. (191), using a model system with
Chiralpak AD to separate a racemic mixture, EMD53986.
Affinity ultrafiltration uses a large stereospecific binding agent
to selectively bind and retain one of the enantiomers in a racemic
mixture. The effect of the solution, pH, and salt concentration on
the binding interactions of bovine serum albumin with D- and
L-tryptophan was studied by Ramero and Zydney (192). A
multistage affinity ultrafiltration process was shown to provide high
purification factors and yield for enantioseparations (193).
Optically active polyelectrolyte multilayers showed selectivity
in membrane separations of enantiomers such as L- and D-ascorbic
acid (194). The flux through the multilayers was reported to be
exceptionally high and could be controlled by the salt concentra-
tion in the permeating solutions. Microfluidics-based membrane
chromatography was utilized in the high-resolution chiral separa-
tion of racemic tryptophan and thiopental, using porous poly-
(vinylidene fluoride) membranes adsorbed with bovine serum
albumin (195).
The use of microfabricated cantilevers as bioaffinity sensors
was investigated using immunoglobulin G and bovine serum
albumin (196). The direct stereoselective detection of trace
amounts of R-amino acids was achieved based on immunome-
chanical responses involving nanoscale bending of the cantilever.
ACKNOWLEDGMENT
The authors thank Karen Ward for her generous assistance and
editing with this review. Her input and patience was much needed
and appreciated.
Timothy J. Ward, professor of chemistry and chair of the Chemistry
Department at Millsaps College (Jackson, MS), received his B.S. degree
from the University of Florida and his Ph.D. from Texas Tech University.
He joined Millsaps College in 1990, after working at Syntex in the
pharmaceutical process control division. His research interests include
chiral separations and the characterization of enantiomeric resolution,
the development of analytical LC and CE methods, and their application
to pharmaceutical and environmental separations.
4642 Analytical Chemistry, Vol. 76, No. 16, August 15, 2004
Daisy-Malloy Hamburg, currently a graduate student at the Uni-
versity of Cincinnati, received her B.S. degree from Millsaps College
(Jackson, MS).
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AC040093T