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In this study, perphenylcarbamated cyclodextrin clicked chiral stationary phase (CSP) was developed with high column efficiency. The characteristics of the column were evaluated in terms of linearity, limit of detection and limit of quantification. The enantioselectivity of the as-prepared clicked CSP was explored with 26 recemates including aryl alcohols, flavanoids and adrenergic drugs in reversed phase high-performance liquid chromatography. The effect of separation parameters including flow rate, column temperature, organic modifier and buffer on the enantioselectivity of the clicked CSP was investigated in detail. The correlation study of the analytes structure and their chiral resolution revealed the great influence of analytes' structure on the enantioseparations with cyclodextrin CSP. Methanol with 1% of triethylammonium acetate buffer (pH 4) was proved to be the best choice for the chiral separation of basic enantiomers.

The current article reviews the development and applications of novel cyclodextrin chiral stationary phases (CD-CSPs) in liquid chromatography (LC), capillary electrochromatography (CEC), gas chromatography (GC) and supercritical fluid chromatography (SFC) over the period of January 2007 to March 2012. The synthetic routes of CD-CSPs, as well as the presence of selective functional groups in effecting inclusion complexation and molecular interactions have been found to exert profound influence in the enantioseparation process. In this article, various synthetic and functional groups immobilization strategies of novel CD-CSPs, and their applications in chiral resolution using different chromatography techniques are discussed. After introducing the topic in Section 1, Section 2 describes novel CD-CSPs in LC applications, where the CSPs are classified according to its coating approaches (physical and chemical manners) for ease of readership. Section 3 discusses recent development of CD-CSPs in open tubular CEC (OT-CEC), packed-bed CEC (P-CEC), pseudostationary phase CEC (PSP-CEC) and monolithic CEC. The last part illustrates novel CD-CSPs in gas chromatography (GC) and supercritical fluid chromatography (SFC).

Fully or partially sub-2 μm porous silica materials have garnered strong interests as column packing materials in separation and analytical technologies due to the promise of rapid separation, enhanced efficiency and separation resolution. Silica support materials of different morphology and sub-2 μm size have been developed to improve separation performances in liquid chromatography (LC) and capillary electrochromatography (CEC). The current review highlights the recent development of sub-2 μm fully/partially porous silica materials and the demonstrations of their enhanced performance in achiral and chiral chromatography.

Mesoporous silica particles of relatively uniform sub-1-micron size (0.6–0.9 μm) were successfully prepared by a modified synthesis strategy and applied in chiral separation in an ultra-high pressure liquid chromatography system. These particles were prepared via a ternary surfactant system (Pluronic P123, F127 and hexadecyltrimethyl-ammonium bromide) and subsequently derivatized with perphenylcarbamoylated-β-cyclodextrin moieties. The mesoporous silica particles, despite their submicron size, enabled low back-pressure operation on an ultra-high pressure liquid chromatography system at a maximum flow rate of 2 ml/min. In addition, the particles possessed high surface area (480 m2/g) and thus afforded high cyclodextrin derivative loading (32 μmol/g), demonstrating rapid enantioseparation and good resolution of 6 basic and neutral racemates.

Two cyclodextrin-based chiral stationary phases have been prepared by immobilization of functionalized mono-6-azido-β-CD derivatives to alkynyl modified silica via “click” chemistry and applied to the HPLC enantioseparation of various chiral compounds. The perphenylcarbamated CD CSP (CCP-CSP) exhibited excellent chiral recognition of a wide range of analytes including racemic aryl alcohols, flavonoids, bendroflumethiazide, atropine and some β-blockers. Methanol proved to be a better organic modifier than acetonitrile for most of the analytes with the exception of bendroflumethiazide. The “click” chemistry immobilized permethylated CD CSP (CCM-CSP) afforded poor chiral recognition for most analytes, but could resolve non-aromatic ionone derivatives which were not separated on CCP-CSP. These results suggest that resolution with cyclodextrin derived CSPs depend on a complex interplay of ‘host’–‘guest’ inclusion, hydrogen bonding, π–π and hydrophobic interactions.

A novel positively charged single-isomer of β-cyclodextrin, mono-6-deoxy-6-(3R,4R-dihydroxypyrrolidine)-β-CD chloride (dhypy-CDCl), was synthesized and employed as a chiral selector for the first time in capillary electrophoresis (CE) for the enantioseparation of anionic and ampholytic acids. The effects of the running buffer pH, chiral selector concentration, analyte structure and organic modifier on the enantioseparation were studied in detail. The chiral selectivity and resolution for most of the studied analytes decreased as the buffer pH increased in the range of 6.0–9.0. Increasing selector concentration led to decreased effective mobility, increased chiral selectivity and resolution for most of the studied analytes. Moreover, the hydroxyl groups located on the dihydroxypyrrolidine substituent of the dhypy-CDCl could have influence on the chiral separation.

Four cationic beta-cyclodextrin derivatives, namely mono-6-(3-methylimidazolium)-6-deoxy-perphenylcarbamoyl-beta-cyclodextrin chloride (MPCCD), mono-6-(3-methylimidazolium)-6-deoxyper(3,5-dimethylphenylcarbamoyl)-beta-cyclodextrin chloride (MDPCCD), mono-6-(3-octylimidazolium)-6-deoxyperphenylcarbamoyl-beta-cyclodextrin chloride (OPCCD) and mono-6-(3-octylimidazolium)-6-deoxyper(3,5-dimethylphenylcarbamoyl)-beta-cyclodextrin chloride (ODPCCD), have been synthesized and physically coated onto porous spherical silica gel to obtain novel chiral stationary phases (CSPs). The performances of these CSPs are studied on high-performance liquid chromatography (HPLC) and supercritical fluid chromatography (SFC) using 18 racemic aryl alcohols as test analytes. Among these four CSPs, OPCCD shows the best separation results for all analytes on both HPLC and SFC analyses. Chromatographic studies reveal that the CSPs consisting of an n-octyl group on the imidazolium moiety and phenylcarbamoyl groups on the cyclodextrin ring provide enhancement of analyte-chiral substrate interactions over CSPs bearing the methyl group on the imidazolium moiety and 3,5-dimethylphenylcarbamoyl groups on the cyclodextrin ring.

The synthesis of mono-6-(3-methylimidazolium)-6-deoxyperphenylcarbamoyl-β-cyclodextrin chloride (MPCCD) and its application in chiral stationary phases (CSPs) for high-performance liquid chromatography (HPLC) and supercritical fluid chromatography (SFC) are being reported. This chiral selector is coated onto silica gel in different weight percentages (15, 20 and 35%, w/w) to obtain CSPs having different loading content. These new chiral stationary phases are tested using normal-phase HPLC for enantioseparation of racemic aromatic alcohols. Indeed, the enantiodiscrimination abilities of these CSPs are found to be influenced by the loading content of the chiral selector. Among the three columns (MPCCD-C15, MPCCD-C20 and MPCCD-C35), the best enantioseparation results are obtained using a column containing 20% (w/w) of MPCCD (MPCCD-C20). The resolution ( R s ) obtained for p -fluorophenylethanol, p -chlorophenylethanol, p -bromophenylethanol, p -iodophenylethanol and p -fluorophenyl-3-buten-1-ol using MPCCD-C20 ranges from 3.83 to 5.65. Good enantioseparation results are obtained for these analytes under SFC separation conditions using the MPCCD-C20 column.

Two novel chiral stationary phases (CSPs) were prepared based upon the regioselective immobilizations of beta-cyclodextrin (beta-CD) at its C2 position to the silica support. The mono-2A-azido-2A-deoxyperphenylcarbamoylated beta-cyclodextrin and mono-2A-azido-2A-deoxyperacetylated beta-cyclodextrin were synthesized by selective tosylation and azidolysis followed by perfunctionalisation. The derivatised cyclodextrins were then immobilized onto the aminised silica gel via the Staudinger reaction to provide new chiral stationary phases. Their application to high-performance liquid chromatography (HPLC) enantioseparation of racemic compounds was demonstrated using beta-adrenergic blockers, flavonone compounds, benzodiazepinones, antihistamines and weakly protolytic compounds, of which good separations were achieved for some racemic compounds, for instance, bendroflumethiazide (Rs 6.26), oxazepam (Rs 5.99), temazepam (Rs 2.85) and althiazide (Rs 1.13) when compared with the corresponding CSPs where the beta-CD molecule was regioselectively immobilized at the C6 position. The enantiodiscriminatory properties of these CSPs were found to be affected by the orientation of the CD cavity under reversed-phase conditions, and also by the derivitising groups of the CD. The HPLC results inferred that the mono-6A-azido-6A-deoxyperphenylcarbamoylated CD CSP (CD bonded at C6 position to silica) exhibited slightly better chiral recognition ability than mono-2A-azido-2A-deoxyperphenylcarbamoylated CD CSP under the normal-phase and reversed-phase modes on the separation of 31 different racemic compounds and drugs. On the contrary, higher chiral recognition abilities were observed on the mono-2(A)-azido-2A-deoxyperacetylated CD CSP compared to mono-6A-azido-6A-deoxyperacetylated CD CSP.

A facile synthetic approach for mono-6-amino-6-deoxy-beta-cyclodextrin (beta-CD-NH2) was proposed. Its hydroxy chloride salt, mono-6-ammonium-6-deoxy-beta-cyclodextrin chloride (beta-CD-NH3Cl) was further prepared and used for the enantioseparation of various anionic and ampholytic analytes by capillary electrophoresis (CE). The effect of background electrolyte (BGE) pH and selector concentration on the enantioseparation was studied. Results showed that beta-CD-NH3Cl displayed powerful chiral resolution ability towards anionic analytes. In addition, baseline separation of a standard mixture consisting of eight acids was achieved within 35 min.

A chiral selector, mono(6A-N-allylamino-6A-deoxy)permethylated β-cyclodextrin, was synthesized through a facile synthetic route and chemically immobilized onto porous silica gel via hydrosilylation to afford a cyclodextrin based chiral stationary phase MeCD-CSP. This chiral stationary phase exhibited good enantioselectivity under standard HPLC conditions. The optimal resolution of 1-(p-bromophenyl)ethanol and bromopheniramine was achieved under normal-phase conditions using a mobile phase comprising n-hexane (hexane) and 2-propanol (IPA). The enantioseparation of warfarin, suprofen and a series of flavanones under reversed-phase conditions were optimized and efficient enantioseparations for these analytes were obtained.

A novel methylated beta-cyclodextrin chiral stationary phase (CSP-ME), which was chemically immobilised onto porous silica via multiple urea-linkages was synthesised. The CSP-ME chiral stationary phase depicted good enantiomer separation abilities for some well-known flavour as well as fragrance compounds using high-performance liquid chromatography under reverse phase conditions. The optimum resolution for alpha-ionone, 3-methyl-alpha-ionone, flavanone, 5-methoxyflavanone, 6-methoxyflavanone, 7-methoxyflavanone, hesperetin, naringenin and taxifolin was achieved using a mobile phase composition consisting of 1 wt.% triethylammonium acetate buffer (pH 4.68)-methanol. The effects of pH of triethylammonium acetate buffer and the methanol-acetonitrile content of the mobile phase composition on their retention time and resolution were examined to optimise the separation conditions.

A novel chiral stationary phase (PPHCDN7) was prepared by immobilization of heptakis(6-azido-6-deoxy-2,3-di-O-phenylcarbamoylated)-beta-cyclodextrin (PPHCD) onto the surface of amino-functionalized silica gel via multiple urea linkages derived from an extended application of the Staudinger reaction. A wide range of structurally divergent racemic drugs and other compounds were successfully separated into their enantiomers under both normal and reversed-phase conditions. Beta-adrenergic blockers and racemic tertiary, secondary and primary amines were readily separated using a mixture of methanol and aqueous triethylammonium acetate buffer. The optimal pH value for the separation falls in the range of 4.65 to 6.30. With atropine and isoproterenol, good enantioseparations with separation factors of alpha>5 were easily attainable.

The continuous chromatographic separation of a racemic anthelmintic drug, praziquantel, was carried out using a simulated counter-current system. The system consists of four identical columns (445 mm × 12.5 mm I.D.) connected in series through solenoid valves. The chiral stationary phase used is microcrystalline cellulose triacetate and the eluent is methanol. Feed at 50 mg/ml was continuously introduced into the system at 0.3 ml/min and 429 mg/h of (+)-praziquantel and 404 mg/h of (−)-praziquantel were obtained from the extract and raffinate streams, respectively. The optical purity of the products was more than 90%. This method provides an extremely useful technique for preparative-scale enantioseparation. Compared with conventional batch preparative-scale processes, this system offers a higher solute to adsorbent mass ratio.