A new example of reversal of the order of migration of enantiomers, as a function of cyclodextrin concentration and pH, by cyclodextrin-modified capillary zone electrophoresis: enantioseparation of 6,6′-dibromo-1,1′-binaphthyl-2,2′-diol

Enantioseparation of 6,6′-dibromo-1,1′-binaphthyl-2,2′-diol (DBBD) by cyclodextrin-modified capillary zone electrophoresis (CD-CZE) was studied using the three native α, β, and γ cyclodextrins, the three hydroxypropylated cyclodextrins (2-hydroxypropyl-α, β, and γ), heptakis-2,6-di-O-methyl-β-CD (DM-β-CD), and heptakis-2,3,6-tri-O-methyl-β-cyclodextrin (TM-β-CD). First, the acidity constants of DBBD were determined using capillary electrophoresis, before performing enantioseparation. The influence of the concentrations of the studied cyclodextrins on the enantioseparation was explored and the experimental optimal concentrations were determined and compared to the theoretical optimal concentrations. Moreover, the apparent complexation constants between each studied cyclodextrin and the two DBBD enantiomers were evaluated using a non-linear curve fitting method and three linear plotting methods (x-reciprocal, y-reciprocal and double reciprocal). For TM-β-CD, the order of migration of the enantiomers of DBBD reversed as a function of TM-β-CD concentration. The influence of the nature of methylated cyclodextrin derivatives (methyl-β-CD (M-β-CD) and DM-β-CD) was then studied. Inversion of the order of migration of the enantiomers of DBBD was observed for DM-β-CD, whereas the S enantiomer of DBBD always migrated first for M-β-CD.     

Comparison of different heptakis(6-O-alkyldimethylsilyl-2-3-di-O-ethyl)-β-cyclodextrins as chiral stationary phases in capillary GC

Three new β-cyclodextrin derivatives, heptakis(6-O-isopropyldi-methylsilyl-2,3-di-O-ethyl)-β-cyclodextrin, heptakis(6-O-thexyldi-methylsilyl-2,3-di-O-ethyl)-β-cyclodextrin, and heptakis(6-O-cy-clohexyldimethyl-2,3-di-O-ethyl)-β-cyclodextrin (IPDE-β-CD, TXDE-β-CD, and CHDE-β-CD), were synthesized and the enan-tioselectivities of these three CD derivatives and heptakis(6-O-tert-butyldimethylsilyl-2,3-di-O-ethyl)-β-cyclodextrin (TBDE-β-CD) were compared for GC separation of a range of chiral test com-pounds. In particular TXDE-β-CD showed much higher enentio-selectivity than TBDE-β-CD. Enentioselectivities of IPDE-β-CD and CHDE-β-CD are somewhat lower than that of TXDE-β-CD and CHDE-β-Cd are somewhat lower than that of TXDE-β-CD. These observations are indicative of significant effects of subtle changes in the structure of the 6-O-substituent on the enantioselec-tivity of the β-CD derivatives. The difference in enantioselectivities of the 6-O-substituted CD derivatives were explained in terms of relative contributions of the effects of hydrophobicity and steric hindrance of the substituent to the inclusion process. CHDE-β-CD showed the lowest enantioselectivity among the threederivatives. It is likely that the unfavorable steric hindrance of the bulky cyclo-hexyl group plays a greater role than the favorable hydrophobicity effect of the cyclohexyl group in the inclusion process in CHDE-β-CD. IPDE-β-CD showed lower selectivity than TXDE-β-CD and TBDE-β-CD. In the case of these CD derivatives having acyclic substituents the relative hydrophobicity of the substituent seems to be a dominant factor affecting the inclusion process. Isopropyl groups factor affecting the inclusion process. Isopropyl groups are less hydrophobic than thexyl and tert-butyl groups.     

The role of β-cyclodextrin and hydroxypropyl β-cyclodextrin in the secondary chemical equilibria associated to the separation of β-carbolines by HPLC

The use of cyclodextrins (CDs) in HPLC as mobile phase additives provides a flexible alternative for the separation of chemically related compounds because these separations can be performed on conventional columns and are economically advantageous over the use of chiral stationary phases. The present paper describes the influence of the presence of β-cyclodextrin (β-CD) and 2-hydroxypropyl-β-cyclodextrin (HPβ-CD) on the separation of the β-carboline alkaloids norharmane, harmane and harmine. The nature of the stationary phase (reverse phases C₁ and C₁₈) affects the chromatographic separations and also the stability of the inclusion complexes that are developed. The changes in the proportion of the organic solvents at constant concentration of CDs (3 mM for β-CD and 15 mM for HPβ-CD) modify the retention factors (k′) for all alkaloids studied. The nature of the organic solvent in the mobile phase also changes the chromatographic parameters. The logarithm of the capacity factor (k′) is linearly increased with the proportion of water in the hydro-organic mobile phase (ethanolic or methanolic) but the slopes obtained vary depending on the CD added to the mobile phase. The role of competitive equilibria, i.e., chromatographic distribution and inclusion complexes formation is discussed. This paper was presented at XIIIth International Cyclodextrin Symposium. Torino, Italy, May, 14–17, 2006     

Complexation behavior of antiestrogen drug tamoxifen citrate with natural and modified β-cyclodextrins

Inclusion complexes of the poorly-soluble antiestrogen drug tamoxifen citrate (TMX) were prepared with β-cyclodextrin (β-CD) and 2,3-di-O-hexanoyl-β-cyclodextrin (β-CDC6) being natural and amphiphilic cyclodextrins, respectively using the co-lyophilization technique. Complexation occurred in aqueous medium for natural cyclodextrin β-CD and a medium of water:ethanol mixture for the amphiphilic cyclodextrin β-CDC6. The complexes were characterized using analytical techniques including Differential Scanning Calorimetry (DSC), Fourier Transform Infrared spectroscopy (FTIR) and proton Nuclear Magnetic Resonance Spectrometry (¹H NMR). Anticancer efficacies of the complexes were determined against MCF-7 human breast carcinoma cell line with MTT assay. It was found that tamoxifen citrate can be incorporated in the cavity for β-CD and both in the cavity and the aliphatic chains for β-CDC6. The latter having two hydrophobic sites for inclusion of water-insoluble drug exhibited significantly higher anticancer efficacy accordingly.     

Spectrofluorimetric Study of an Inclusion Complex of 2-Hydroxypropyl-β-Cyclodextrin with the Antitumour 11-Methyl Benzophenothiazine. Analytical Application to Urine

The electronic absorption and fluorescence spectral properties of 11-methyl-12H-benzo[a]phenothiazine (11-MeBPHT) were investigated in various media (water, ethanol, β-cyclodextrin (β-CD) and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) aqueous solutions). Fluorescence quantum yields were respectively about 20 and 2 times larger in HP-β-CD and β-CD than in water. The formation of a 1:1 stoichiometry inclusion complex between 11-MeBPHT and HP-β-CD (association constant K _f=118±3 M⁻¹ at 20 °C) was studied in aqueous medium by fluorescence spectroscopy. Analytical figures of merit were satisfactory for 11-MeBPHT with linear dynamic ranges over at least two orders of magnitude and limits of detection (LODs) between 0.2 and 1 ng/ml according to the medium. An analytical application to the determination of 11-MeBPHT in human urine samples by the standard addition procedure led to satisfactory recovery percentages (91–108%).     

Binary Systems of Nifedipine And Various Cyclodextrins in The Solid State. Thermal,FTIR, XRD studies

Nifedipine complexes with β-cyclodextrin (β-CD), γ-cyclodextrin (γ-CD), 2-hydroxypropyl-β-cyclodextrin (2HP-β-CD), randomly methylated-β-cyclodextrin (RM-β-CD) and heptakis(2,6-O-dimethyl)-β-cyclodextrin (DM-β-CD) have been prepared by both kneading and heating methods and their behaviour studied by differential scanning calorimetry (DSC), diffuse reflectance mid-infrared spectroscopy (FTIR) and X-ray diffractometry (XRD). DSC revealed the nifedipine melting endotherm with onset at approximately 171°C for the kneaded mixtures with β-CD, γ-CD and 2HP-β-CD, thus confirming the presence of nifedipine in the crystalline state, while some decrease in crystallinity was observed in the DM-β-CD kneaded mixture. With RM-β-CD, however, broadening and shifting of the nifedipine endotherm and reduction in its intensity suggested that the kneading could have produced an amorphous inclusion complex. These differing extents of interaction of nifedipine with the cyclodextrins were confirmed by FTIR and XRD studies. This revised version was published online in August 2006 with corrections to the Cover Date.     

Determination of Enthalpic Interaction Coefficients by ITC Measurements. 2-Hydroxypropyl-β-cyclodextrin in aqueous solution of NaCl

Aqueous solutions of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD)at different concentrations of NaCl (0–1.90 mol) were studied by isothermal titration calorimetry (ITC) at 298.15 K. The thermal effects obtained were analysed according to the thermodynamic approach developed by McMillan and Mayer. The calculated enthalpic pair coefficients of HP-β-CD in water and in aqueous solutions of NaCl were analysed taking into consideration electrostatic and structural changes caused by the presence of NaCl in solution. This revised version was published online in July 2006 with corrections to the Cover Date.     

Inclusion complexes of modified cyclodextrins with some flavonols

The inclusion complexes of four flavonols with modified cyclodextrins (CDs) have been investigated. The effect of heptakis (2,6-di-O-methyl) β-cyclodextrin (DM-β-CD) and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) on the aqueous solubility of flavonols, namely, galangin, kaempferol, quercetin, and myricetin was investigated, respectively. The increased solubility of all flavonols in the presence of CD was evidenced. The NMR experiment and molecular modeling studies showed that flavonols interact with each modified CD through different binding modes. Flavonols can complex with CDs largely by two binding modes. The first one is that B-ring of flavonols is oriented toward secondary rim of CD. The second one is that A-ring of flavonols is oriented toward secondary rim of CD. Whereas only the first mode was observed in DM-β-CD complexes, both the first and the second mode were observed in HP-β-CD complexes in this study.     

Inclusion complexation of Itraconazole with β-and 2-hydroxypropyl-β-cyclodextrins in aqueous solutions

The inclusion behavior of Itraconazole (Itra) with β-cyclodextrin (β-CD) and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) was investigated by using phase solubility and molecular mechanics techniques. The effects of pH and temperature on complex stabilit were also explored. The aqueous solubility of Itra was significantly enhanced as CD concentration increased. Itra tends to form 1: 3 complexes with β-and HP-β-CD at pH ≥ 4 and 1: 2 at pH 2. Thermodynamic parameters for Itra/HP-β-CD show that the 1: 1 complex is driven by enthalpy but retarded by entropy changes. In contrast, the formation of 1: 2 and 1: 3 complexes is largely favored by entropy due to higher desolvation induced by total enclosure of Itra with two (or three) favorably interacting CD molecules. The inclusion mode of Itra/β-CD complexes was proved by molecular mechanics technique, which provided a powerful means for understanding inclusion interactions and processes. Published in Russian in Zhurnal Fizicheskoi Khimii, 2006, Vol. 80, No. 7, pp. 1200–1205. The text was submitted by the authors in English.     

Inclusion complexation of diclofenac with natural and modified cyclodextrins explored through phase solubility, 1H-NMR and molecular modeling studies

Guest–host interactions were examined for neutral diclofenac (Diclo) and Diclofenac sodium (Diclo sodium) with each of the cyclodextrin (CD) derivatives: α-CD, β-CD, γ-CD and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), all in 0.05 M aqueous phosphate buffer solution adjusted to 0.2 M ionic strength with NaCl at 20 °C, and with β-CD at different pHs and temperatures. The pH solubility profiles were measured to obtain the acid–base ionization constants (pK _as) for Diclo in the presence and absence of β-CD. Phase solubility diagrams (PSDs) were also measured and analyzed through rigorous procedures to obtain estimates of the complex formation constants for Diclo/CD and Diclo sodium/CD complexation in aqueous solutions. The results indicate that both Diclo and Diclo sodium form soluble 1:1 complexes with α-, β-, and HP-β-CD. In contrast, Diclo forms soluble 1:1 Diclo/γ-CD complexes, while Diclo sodium forms 1:1 and 2:1 Diclo/γ-CD, but the 1:1 complex saturates at 5.8 mM γ-CD with a solubility product constant (pK _sp = 5.5). Therefore, though overall complex stabilities were found to follow the decreasing order: γ-CD > HP-β-CD > β-CD > α-CD, some complex precipitation problems may be faced with aqueous formulations of Diclo sodium with γ-CD, where the overall concentration of the latter exceeds 5.8 mM γ-CD. Both ¹H-NMR spectroscopic and molecular mechanical modeling (MM⁺) studies of Diclo/β-CD indicate the possible formation of soluble isomeric 1:1 complexes in water.     

Enantiomeric composition of the chiral constituents in essential oils. Part 1: Monoterpene hydrocarbons

Using a dual column gas chromatograph equipped with two capillary columns coated with heptakis(6-O-methyl-2,3-di-O-pentyl)-β-cyclodextrin (6-me-2,3-pe-β-CD) and octakis(6-O-methyl-2,3-di-O-pentyl)-γ-cyclodextrin (6-me-2,3-pe-γ-CD), respectively, all important olefinic monoterpene hydrocarbons occurring in essential oils, including α-thujene, α- and β-pinene, camphene, sabinene, α- and β-phellandrene, Δ-3-carene and limonene can be resolved into enantiomers. With the chromatographic system described the characteristic enantiomeric composition of these monoterpene hydrocarbons in essential oils can be determined.     

Enantiomeric separation of racemic sulphoxides on chiral stationary phases by gas and liquid chromatography

Summary The enantiomeric resolution of seven racemic sulphoxides on chiral stationary phases has been investigated by gas and liquid chromatography. In gas chromatography the separations were performed on octakis-(2,6-di-O-pentyl-3-O-butyryl)-γ-cyclodextrin (FS Lipodex-E) and heptakis-(2,6-di-O-methyl-3-O-pentyl)-β-cyclodextrin (DMP-β-CD). Both stationary phases were suitable for separation of the enantiomers of the sulphoxides. With one exception for each series all racemetes could be resolved on both stationary phases; FS Lipodex-E was more enantioselective than DMP-β-CD, whereas the latter seemed more generally applicable. Liquid chromatographic separations with Chiralcel-OB as stationary phase were significantly improved by optimization of mobile phase composition and temperature. Resolution factors up to R_s=6 were achieved indicating that the improved separations could now be easily used for preparative purposes.     

Enhancement of aqueous solubility of tricyclic acyclovir derivatives by their complexation with hydroxypropyl-β-cyclodextrin

Solubilities of tricyclic acyclovir derivatives in buffered aqueous solutions of hydroxypropyl-β-cyclodextrin (HP-β-CD) at pH 5.5 and 7.0 were determined at 25 and 37 °C. Complexation of these compounds with HP-β-CD resulted in a noticeable increase of their solubility; nevertheless it was limited to tricyclic derivatives of acyclovir carrying an aryl substituent. Combination of ¹H NMR and DSC techniques demonstrated the existence of inclusion complexes between acyclovir derivatives and HP-β-CD. The stability constants, estimated using the Higuchi–Connors method, were found in the range of 10–100 M⁻¹. Additionally, the pK _a values at 25 °C and molar extinction coefficients in aqueous buffered solutions were also determined for all studied compounds.     

Cyclodextrin carbamates as novel chiral stationary phases for capillary gas chromatography

The following carbamate derivatives of cyclodextrins (CDs) were prepared as novel chiral stationary phases for capillary gas chromatography: hexakis(2,6-di-O-pentyl)-α-cyclodextrin hexa(3-n-propyl, 3-isopropyl, and 3-phenylcarbamate), heptakis-(2,6-di-O-pentyl)-β-cyclodextrin hepta(3-n-propyl, 3-isopropyl, and 3-phenylcarbamate), and octakis(2,6-di-O-pentyl)-γ-cyclodextrin octa(3-n-propyl, 3-isopropyl, and 3-isopropyl, and 3-phenylcarbamate). Metal capillary columns coated with these stationary phases resolved many kinds of racemic mixture. In general, they were especially effective towards polar compounds such as free alcohols, amines, and epoxides. The types of sample which were effectively resolved depended on the cavity size of the CD: α-CD derivatives were specifically effective toward compounds having linear alkyl chains, and β-CD derivatives toward compounds with phenyl groups. The results indicate that chiral separation with the cyclodextrin carbamates depends on the formation of inclusion complexes and also on the hydrogen-bonding interactions between the samples and the CD carbamates.     

Enhancement of cyclosporine aqueous solubility using α- and hydroxypropyl β-cyclodextrin mixtures

Cyclodextrins (CDs) are cyclic oligosaccharides that form inclusion complexes with lipophilic molecules through their hydrophobic central cavity. In this study, the effect of α-CD, hydroxylpropyl-β-CD (HP-β-CD) and mixtures of these two CDs on the aqueous solubility of cyclosporine A (CyA) was investigated. Infrared spectroscopy and thermal analysis were used to confirm CyA-CD complex formation. CyA aqueous solubility was increased by 10 and 80 fold in the presence of α-CD and HP β-CD, respectively. The phase-solubility profile for HP-β-CD was linear while that for α-CD had positive deviation from linearity. In the presence of constant concentration of α-CD (15% w/v), aqueous solubility of CyA was further increased upon addition of HP-β-CD up to a concentration of 20% w/v. At higher HP-β-CD concentrations, aqueous solubility of CyA was observed to decrease. Addition of sodium acetate (up to 5% w/v) to aqueous solutions containing 20% w/v HP-β-CD and increasing concentrations of α-CD resulted in a significant reduction in CyA solubility. Complex formation between CyA and both α-CD and HP-β-CD was confirmed by differential scanning calorimetry (DSC). No significant changes were observed in the IR spectra of either CyA or CD following complex formation suggesting chemical interaction between CyA and the CD was unlikely. Phase-solubility studies showed that α-CD had a much greater effect on the solubility of CyA than HP-β-CD. Addition of HP-β-CD to aqueous solutions of α-CD affected the solubility of CyA in these systems. A mixture of 15% w/v α-CD and 20% w/v HP-β-CD was optimal for increasing aqueous solubility of CyA.     

Separation of terbutaline enantiomers in capillary electrophoresis with neutral cyclodextrin-type chiral selectors and investigation of the structure of selector-selectand complexes using nuclear magnetic resonance spectroscopy

The major goal of this study was to determine the affinity pattern of the terbutaline (TB) enantiomers toward α-, β-, γ-, and heptakis(2,3-di-O-acetyl)-β-cyclodextrins and using NMR spectroscopy for the understanding of the fine mechanisms of interaction between the cyclodextrins (CD) and TB enantiomers. It was shown once again that CE in combination with NMR spectroscopy represents a sensitive tool to study the affinity patterns and structure of CD complexes with chiral guests. Opposite affinity patterns of TB enantiomers toward native α- and β-CDs were associated with significant differences between the structure of the related complexes in solution. In particular, the complex between TB enantiomers and α-CD was of the external type, whereas an inclusion complex was formed between TB enantiomers and β-CD. One of the possible structures of the complex between TB and heptakis(2,3-di-O-acetyl)-β-CD (HDA-β-CD) was quite similar to that of TB and β-CD, although the chiral recognition pattern and enantioselectivity of TB complexation with these two CDs were very different.     

Application of combined thermoanalytical techniques in the investigation of cyclodextrin inclusion complexes

Citronellol and citronellyl acetate have been entrapped with α-, β- and γ-cyclodextrin (CD). Evolved gas detection and TG-MS coupling was applied to prove the actual inclusion complex formation between monoterpens and CDs. The terpene content was determined by UV-VIS specrophotometry and RP-HPLC and the effect of storage time on the terpene content was also investigated. The α- and γ-cyclodextrin inclusion complexes showed higher thermal stabilities vs. dynamic heating compared to the β-CD complexes. On the contray, the retention of guest using β-cyclodextrin even after 10 years of storage was much more pronounced. Experimental data other than 1:1 complex compositions are assumed. Molecular modeling experiments also suggested multiple complex compositions.     

Separation of the enantiomers of four chiral drugs by neutral cyclodextrin-mediated capillary zone electrophoresis

Summary Neutral cyclodextrin (CD)-modified capillary zone electrophoresis (CZE) has been applied to the chiral separation of four basic drugs— clorprenaline, benzhexol, esmolol and terazosin. Selector screening and concentration optimization experiments were performed. The resolution was 3.9 for clorprenaline, 2.3 for benzhexol, 3.1 for esmolol and 1.2 for terazosin when the running electrolyte was 60 mM hydroxypropyl-β-CD, 15 mM heptakis (2,3,6-Tri-O-methyl)-β-CD, 60 mM γ-CD and 60 mM heptakis (2,6-di-O-methyl)-β-CD, respectively, in 50 mM, pH 2.5 sodium phosphate buffer.     

Cyclodextrin derivatives for GC separation of racemic mixtures of volatile compounds. Part VIII: 2,6-di-O-methyl-3-O-pentyl-γ-cyclodextrin and 2,6-di-O-methyl-3-O-(4-oxo-pentyl)- and 2,6-di-O-pentyl-3-O-(4-oxo-pentyl)-β-and -γ-cyclodextrins

In pre vious papers, 2,6-di-O-methyl-3-O-pentyl-β-cyclodextrin (CD) was demonstrated to be successful in separating volatile compounds, while avoiding the drawbacks of 2,3,6-tri-O-methyl-O-methyl-β-CD in terms of column stability and operating temperature. Since a CD chiral selector of universal use has not yet been found, and at least two (or more) columns coated with different CD derivatives are therefore necessary for routine work, the performance of 2,6-di-O-methyl-3-O-pentyl-γ-CD, 2,6-di-O-methyl-3-O-(4-oxopentyl)-γ-CD, 2,6-di-O-pentyl-3-O-(4-oxo-pentyl)-β-CD, and 2,6-di-O-pentyl-3-O-(-4-oxo-pentyl)-γ-CD diluted in polysiloxanes for the separation of volatile compounds in aromas and essential oils will be illustrated; each column coated with each of the newly synthesized CD derivatives was evaluated by analyzing more than 150 different recemates with different structures.     

Usefulness of cyclodextrin media for the determination of α-cypermethrin by photochemically induced fluorescence: analytical applications to natural waters

The photochemically induced fluorescence (PIF) spectral properties of α-cypermethrin in organic solvents (hexane, dichloromethane, acetonitrile, ethanol) and in cyclodextrin aqueous solutions (β-CD and 2-hydroxypropyl-β-CD, 2-HP-β-CD) were investigated. The photolysis kinetics of α-cypermethrin were evaluated in the various media. The PIF signal was found to be significantly enhanced in the CD media relative to the organic solvents. The stoichiometry and the formation constants of the α-cypermethrin inclusion complexes formed with the CDs were determined. The analytical performances of the PIF method were improved in the presence of HP-β-CD relative to the other media, and a CD-enhanced PIF analytical method was developed. The limits of detection and limits of quantification ranged, respectively, between 6 and 98 ng/mL and between 24 and 343 ng/mL, depending on the medium. Application to the analysis of tap water and Senegal natural water samples collected close to agricultural areas and spiked with α-cypermethrin yielded satisfactory recoveries going from about 77% to 98%. An interference study of foreign species, including pesticides and inorganic ions likely to be present in natural waters, was also carried out. Figure Photolysis reaction of α-cypermethrin in presence of HP-β-CD