Crystalline β-cyclodextrin hydrate is non-stoichiometric with 10.5–12 waters per cyclodextrin molecule

Abstract

Solid-state ¹³C NMR spectroscopy was used to follow the dehydration of β-cyclodextrin hydrate from 12 to 10.5 waters per cyclodextrin. The process takes place without loss of crystalline order, or the presence of a phase transition. The water molecules involved can best be described as space-filling guests enclathrated in the cyclodextrin cavity. Hence the hydrate is non-stoichiometric within the limits of 10.5–12 waters per cyclodextrin molecule. On the other hand, dehydration of crystalline α-cyclodextrin hexahydrate involves a phase transition.     

Fluorescence Suppression of 7-Methoxycoumarin upon Inclusion into Cyclodextrins

The fluorescence intensity of 7-methoxycoumarin (7MC) in aqueoussolution is found to significantly decrease upon addition of variouscyclodextrins. This observed phenomenon is described asfluorescence suppression, to distinguish it from fluorescencereduction via bimolecular quenching. The decrease in fluorescenceof 7MC is proposed to be the result of the formation of ahost–guest inclusion complex with cyclodextrin. Since 7MC isa polarity-sensitive fluorophore, which is less fluorescent ina nonpolar environment, its fluorescence decreases uponinclusion into the relatively nonpolar internal cavity of thecyclodextrin. The same equation used for extracting the associationconstant in the case of 1 : 1 host–guest inclusion-induced fluorescenceenhancement is shown to be applicable to the case of fluorescencesuppression. In the case of β-cyclodextrin, the degree of fluorescencesuppression, as well as the value of the binding constant for formationof the inclusion complex, are found to be unaffected by modificationof the cyclodextrin rims, suggesting that the molecule iscompletely included within the β-cyclodextrin cavity. In the case ofγ-cyclodextrin, the degree of fluorescence suppression, butnot the value of the binding constant, is found to be significantlyaffected by modification of the cyclodextrin rims, suggesting thatthe molecule is experiencing a less polar environment in the modifiedγ-cyclodextrin cavity. The binding constant is three timeslarger in β- as compared to γ-cyclodextrin, indicatinga much better size match in the smaller β-cyclodextrin cavity.     

Spectrofluorimetric determination of beryllium based on the inclusion complex of 1-amino-4-hydroxyanthraquinone with β-cyclodextrin as ligand

The use of the inclusion complex of 1-amino-4-hydroxyanthraquinone (AHA) in the internal cavity of β-cyclodextrin is compared with AHA alone as a ligand for the spectrofluorimetric determination of beryllium. The organizing ability of the cyclodextrin medium and the protection of the ligand from the micro-environment confers increased sensitivity, selectivity and detection limit, and allows the determination of 10–70 ng ml^?1 beryllium, compared to 60–500 ng ml^?1 in the absence of the cyclodextrin.     

Application of flow injection analysis—photo-induced fluorescence (FIA-PIF) for the determination of α-cypermethrin pesticide residues in natural waters

Flow injection analysis combined with photo-induced fluorescence (FIA-PIF) has been applied for the determination of α-cypermethrin pesticide residues in Senegalese natural waters, using organic solutions and cyclodextrin (β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin) aqueous media. The α-cypermethrin insecticide has a very weak natural fluorescence, but it is converted into strongly fluorescent photoproduct(s) by UV irradiation. Cyclodextrins were found to enhance the PIF signal. FIA parameters, including mobile phase flow rate, injected volume, and reactor length, were optimized. Analytical performances of the FIA-PIF method for the determination of α-cypermethrin were satisfactory, with concentration linear dynamic ranges over one to two orders of magnitude and with rather low limits of detection and limits of quantification, in the ng mL⁻¹ range, and relative standard deviations comprised between 1.2% and 3.8%. Application of FIA-PIF for the analysis of fortified natural water samples collected from Senegal yielded good recovery values (84–112%). Because of its high sampling rate, the FIA-PIF method constitutes a rapid analytical tool, useful for quantification of α-cypermethrin residues in natural waters.     

Spectrofluorimetric study and determination of desipramine in the presence of β-cyclodextrin

The native fluorescence intensity of desipramine was enhanced in the presence of β-cyclodextrin in aqueous solution. The inclusion complex formation between these compounds was studied by spectrofluorimetry. A stable complex with a 2: 1 stoichiometry of β-cyclodextrin to desipramine was formed (logβ₂ = 9.29 ± 0.01). In the presence of an optimum concentration of β-cyclodextrin, the fluorescence intensity was linearly proportional to desipramine concentration in the range of 0.1–100 μg/mL (7.2 × 10^?7?1.0 × 10^?4 M) with a limit of detection of 7 × 10^?8 M. The method was successfully applied to the detection of desipramine in its tablets.     

β-Cyclodextrin Derivatives as Fluorescence Enhancers of the Drug,Hesperidin

Abstract

The fluorescence behavior of the drug hesperidin in several cyclodextrins(CDS):β-cyclodextrin(β-CD), hydroxypropyl-β-CD (HP-β-CD) and methyl-β-CD(M-β-CD) was studied. The stoichiometry of the complexes and their apparent formation constants were estimated. The excitation wavelengths were at 335nm for hesperidin in β-CD, HP-β-CD and M-β-CD media. The emission wavelengths were at 444, 436 and 434 nm, respectively; The fluorescence enhancement of hesperidin was observed in different cyclodextrin media. The linear calibration plots between fluorescence intensity and hesperidin concentration were determined in the 10^?7 ～10^?5 M range. The mechanism for the enhanced fluorescence was attributed to protection of the excited state within the cyclodextrin cavity.     

Enhanced fluorimetric determination of procaine in pharmaceutical preparations by aqueous β- cyclodextrin inclusion and non-aqueous competitive action

The effects of changes in polarity and dielectric constant of the solvent on the fluorescence of procaine hydrochloride in different solvents, and in β-cyclodextrin (β-CD) and micellar media (cetylpyridium chloride and sodium dodecyl sulphate), are described in detail. It is shown that, with N,N-dimethylformamide as solvent procaine is better incorporated in β-CD and micelles. Methods are developed under these conditions based on normal, synchronous first- and second- derivative fluorimetry. The linear dynamic range is 10–680 ng ml^-1 and the detection limit is 2.5 ng ml^-1; the relative standard deviation is 0.68% for the β-CD method with normal fluorimetry. The methods are applied directly to the determination of procaine in different pharmaceutical preparation with recoveries of 88–108%.     

Improvement in the fluorimetric detection of 5-methoxypsoralen by using β-cyclodextrin in the mobile phase and a cross-linked β-cyclodextrin column

In liquid chromatography with a cross-linked β-cyclodextrin column, the addition of 10^?2 M β-cyclodextrin to the methanol/water (25:75) mobile phase produces a 6-fold increase in the fluorescence signal of 5-methoxypsoralen (5-MOP), an important skin photosensitizer. An inclusion compound is formed between 5-MOP and β-cyclodextrin. For 20-μl injections, the limit of detection is 2.25×10^?9 M 5-MOP; calibration plots are linear in the range 10^?3–10^?8 M.     

Host–guest system of Vitamin B10 in β-cyclodextrin: characterization of the interaction in solution and in solid state

Conventional drugs are usually formulated for the immediate release of the medicinal substances and for obtaining the desired therapeutic effect. The aim of this paper was to investigate the possible interactions between Vitamin B10 and β-cyclodextrin (β-CD), to determine the physical-chemical characteristics and the interactions present in the corresponding inclusion compound. The so-obtained compounds were characterized by X-ray diffraction, DSC and FTIR spectroscopy. ¹H NMR and UV–vis spectroscopic methods were employed to study the inclusion process in aqueous solution. The X-ray powder diffraction patterns demonstrate the inclusion compound formation, especially for the lyophilized product where the amorphous phase dominates. The existence of the inclusion compounds obtained by different methods was confirmed by comparing with DSC and FTIR data of the pure compounds and the (1:1) Vitamin B10:β-CD physical mixture (pm). ¹H NMR measurements on aqueous solutions of Vitamin B10 and β-CD in D₂O allowed us to establish the corresponding Vitamin B10’s and cyclodextrin’s protons implied in the complexation process. 2D NMR spectroscopy established the geometry of the inclusion complex. ¹H NMR, UV–Vis and fluorescence data were used to obtain the stoichiometry and the stability constant of the complex.     

Mono(6-N-allylamino-6-deoxy)perphenylcarbamoylated β-cyclodextrin: synthesis and application as a chiral stationary phase for HPLC

A novel cyclodextrin derivative: mono(6^A-N-allylamino-6^A-deoxy)perphenylcarbamoylated β-cyclodextrin was synthesized. Hydrosilylation with (EtO)₃SiH and then reaction of the reactive siloxane with pristine silica gel afforded a facile entry into a durable, structurally well-defined chiral stationary phase capable of enantioseparation of a variety of racemic drugs.     

The Use of β-Cyclodextrin Inclusion Complexes for the Analysis of Bisphenol a Residues in Water by Spectrofluorimetry

Abstract

The application of β-cyclodextrin inclusion complexes to determine trace levels of bisphenol A (BPA) in aqueous solution by spectrofluorimetry was investigated. A 1:1 stoichiometry of the host-guest complex between β-CD and BPA, as well as the association constant was determined by using the changes in the fluorescence of BPA that occur when it is included in the hydrophobic cyclodextrin cavity. A simple and sensitive spectrofluorimetric method for the determination of BPA residues is presented; the applicable concentration range was 10.0 to 200.0 μgL^?1. The detection limit obtained was 0.5 μg.L^?1. The accuracy of the proposed method, was checked in the analysis of water samples from different sources previously spiked with different amounts of BPA.     

A kinetic and thermodynamic study of the α-cyclodextrin mediated reaction of a range of p-substituted phenyl methyl sulfides with binding and non-binding peroxyacids

This paper presents a thermodynamic study of the rate and equilibria processes involved in the α-cyclodextrin mediated reaction of a range of 4-substituted phenyl methyl sulfides with two peroxyacids of different binding affinities. The results for the inclusion processes show that the formation of 1:1 and 2:1 (host:guest) complexes between α-cyclodextrin and phenyl methyl sulfides are generally enthalpically controlled, particularly so for the 2:1 complexes, as might be expected for a ternary complex. The data from this series of sulfides is presented as enthalpy-entropy compensation plots, yielding slopes of unity for each inclusion process. The formation of a 1:1 complex between cyclodextrin and the strongly associating 3-chloroperbenzoic acid (MCPBA) is also enthapically controlled. The other peroxyacid used, peroxomonosulfate, does not bind to α-cyclodextrin to any measurable degree. As described in our original study of this reaction system (Davies and Deary in J Chem Soc Perkin Trans 2:2423–2430, 1996), catalysis by α-cyclodextrin is effected by activation of the peroxide as a result its inclusion within the cyclodextrin cavity; hence for reactions of phenyl methyl sulfides with MCPBA, catalysis is observed, but is absent for PMS. In this study the reaction rates are analysed using the transition state pseudo-equilibrium approach of Tee (Carbohydr Res 192:181–195, 1989), whereby the transition state pseudoequilibrium constant K _TS reflects the stabilisation imparted to the transition state by the association with one molecule of cyclodextrin. Enthalpy- entropy compensation plots for K _TS give slopes close to unity; this is the first reported example of such plots being applied to transition state pseudoequilibrium constants.     

Binding behaviors of scutellarin with α-, β-, γ-cyclodextrins and their derivatives

A series of cyclodextrin/scutellarin inclusion complexes were prepared from α-cyclodextrin, β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin with scutellarin (SCU), and their inclusion complexation behaviors, such as stoichiometry, complex stability constants and inclusion mode, were investigated by means of UV/Vis spectroscopy, ¹H NMR and 2D NMR. The results showed that the SCU could be efficiently encapsulated in the cyclodextrin cavity in aqueous solution to produce complexes that were more soluble than free SCU. The enhanced binding ability of cyclodextrins towards SCU was discussed from the viewpoint of the size/shape-fit and multiple recognition mechanism between host and guest.     

Fluorescent properties of aflatoxins in organized media based on surfactants,cyclodextrins, and calixresorcinarenes

Fluorescent properties aflatoxin B1 (AfB1) and its metabolites, aflatoxins B2, G1, and G2 in the presence of surfactants, cyclodextrins, and calix[4]resorcinarenes are studied. It is found that surfactants and cyclodextrins enhance the fluorescence of aflatoxins B1 and G1. Using the example of AfB1, it is shown that the fluorescence intensity in solution attains a maximum in the presence of 2-hydroxypropyl-β-cyclodextrin. The effects observed increase the sensitivity of the fluorimetric determination of AfB1: the detection limit in water is 3.1 × 10^?8 M and decreases to 2.1 × 10^?9 M in a solution of cyclodextrin.     

Time-Resolved Study of the Sensitized Formation and Decay of 1O2(1δg) in the Presence of Cyclodextrins*

The effect of β-cyclodextrin and β-hydroxypropyl-cyclodextrin on some properties of the aromatic ketone 1-H-phenalen-1-one and its sulfonate derivative 1-H-phen-alen-1-one-2-sulfonic acid was measured in aqueous solution. From the changes in the UV-visible range of the absorption spectra, the association equilibrium constants for the formation of inclusion complexes were determined. Because these ketones are very efficient sensitizers for the generation of singlet oxygen, time-resolved infrared luminescence was used to measure the lifetime of singlet oxygen in D₂O. Cyclodextrins are weak deactivating agents of singlet oxygen; the upper limits for the bimolecular deactivation constants are 2 times 10⁵M^?1s^?1 and 1 times 10⁵M^?1s^?1 for β-cyclodextrin and β-hydroxypropyl-cyclodextrin, respectively. Besides, they do not affect noticeably the extent of formation of singlet oxygen; this result is explained in terms of relocation of the sensitizer (exit from the cyclodextrin cavity) in the triplet excited state.     

Stereoselective inclusion mechanism of ketoprofen into β-cyclodextrin: insights from molecular dynamics simulations and free energy calculations

The host–guest inclusion mechanism formed between β-cyclodextrin and those poorly water-soluble drug molecules has important applications in supramolecular chemistry, biology and pharmacy. In this work, the chiral recognition ability of β-cyclodextrin to one of nonsteroidal anti-inflammatory drugs, ketoprofen, has been systematically investigated using molecular dynamics and free energy simulation methods. The R- and S-enantiomers of ketoprofen were explicitly bound within the cyclodextrin cavity in our simulations, respectively. In consistent with experimental observations, tiny structural difference between two isomers could be observed. Calculated absolute binding free energies using adapted biasing force (ABF) method and MM/GBSA approach for both isomers are comparable to experimental values. Significant binding fluctuations along the MD trajectory have been observed. The free energy profiles calculated using two different approaches reveal that the ketoprofen prefers binding in the cavity with the carboxylate group facing the wider edge of β-cyclodextrin. Similar free energy profiles for two enantiomers obtained using ABF calculations indicate that it is very hard to separate and identify the chiral conjugates within the framework of the natural β-cyclodextrin.     

Determination of the stereoisomers in aqueous medium and serum and validation studies of racemic aminoalkanol derivatives of 1,7‐dimethyl‐8,9‐diphenyl‐4‐azatricyclo[5.2.1.02,6]dec‐8‐ene‐3,5,10‐trione,potential new anticancer drugs,by capillary electrophoresis

A new method for the determination of the stereoisomers, in aqueous medium and serum, of the racemic aminoalkanol derivatives I and II of 1,7‐dimethyl‐8,9‐diphenyl‐4‐azatricyclo[5.2.1.0^2,6]dec‐8‐ene‐3,5,10‐trione, which were found in earlier studies to be potential anticancer drugs, was developed and validated. The optimized conditions included 25 mM phosphate buffer adjusted to pH 2.5, containing γ‐cyclodextrin at a concentration of 5% m/v, as background electrolyte, an applied voltage of +10 kV, and a temperature of 25°C. Separations were carried out using a fused‐silica capillary. The developed method of determining the enantiomers of compounds I(S), I(R) and II(S), II(R) was characterized by the following parameters: a detection time within 10.8 min, a detection limit in the range of 141.2–141.7 ng/mL using the UV absorption detection at 200 nm. Good linearity (R² = 0.9989–0.9998) was achieved within the range of concentrations studied. A very good extraction yield of 95.4–99.7% was achieved, and recoveries were carried out from both aqueous solutions and matrix serum. The repeatability of the method for peak areas with an accuracy of the determined concentrations of the analytes in the range of 1.43–1.89%, and limits of quantitation in the range of 432.4–436.3 ng/mL were achieved.     

Sustained release applications of a fluoroalkyl ester-functionalized amphiphilic cyclodextrin by inclusion complex formation with water-soluble drugs in supercritical carbon dioxide

An amphiphilic γ-cyclodextrin, selectively functionalized with perfluorobutanoyl group, octakis(6-O-perfluorobutanoyl)-γ-cyclodextrin (γ-CyD-F), was investigated as a potential sustained release carrier for hydrophilic drugs, taking molsidomine (MOL) as a model drug. Supercritical carbon dioxide, an environmentally benign solvent, was used for the preparation of MOL/γ-CyD-F inclusion complexes. The molecular encapsulation of MOL by the amphiphilic cyclodextrin was confirmed by differential scanning calorimetry (DSC) and powder X-ray diffraction (XRD) studies. Additionally, ¹H NMR spectroscopy was used to investigate the inclusion mode of drug with the γ-CyD-F. The in-vitro release of MOL from the peanut oil suspensions into aqueous phase was found to be significantly retarded by the complexation with γ-CyD-F, mainly due to the hydrophobic properties associated with the γ-CyD-F.     

Use of hydroxypropyl β-cyclodextrin hybrid monolithic material as adsorbent for dispersive solid-phase extraction of fluoroquinolones from environmental water samples

In this study, the hydroxypropyl β-cyclodextrin hybrid monolithic material was fabricated and firstly applied as an adsorbent for dispersive solid-phase extraction coupled with high-performance liquid chromatography to detect trace-level seven fluoroquinolones in water samples. The prepared hydroxypropyl β-cyclodextrin hybrid monolithic material was characterized by Fourier-transform infrared spectroscopy, scanning electron microscopy, and adsorption experiments, which showed excellent specific adsorption to the target fluoroquinolones. Under the optimized conditions, the extraction methodology showed satisfactory precision with relative standard deviations between 2.6% and 5.6%, good linearity (R² ≥ 0.9990), and satisfactory recoveries (82.5–91.8%). The limits of detection and limits of quantification of the method were in the range of 0.4–1.2 and 1.4–4.0 ng/mL, respectively, which confirmed the possibility of quantifying trace levels. Furthermore, the material could be reused at least five times. These results demonstrated that the hydroxypropyl β-cyclodextrin hybrid monolithic material was a promising adsorbent for fluoroquinolones, and the established method combined dispersive solid-phase extraction with high-performance liquid chromatography was suitable for the determination of fluoroquinolones in aqueous samples.     

Characterization of the complexation of tauro- and glyco-conjugated bile salts with γ-cyclodextrin and 2-hydroxypropyl-γ-cyclodextrin using affinity capillary electrophoresis

The complexation of seven bile salts, present in the small intestine of rat, dog and man, (taurocholate, tauro-β-muricholate, taurodeoxycholate, taurochenodeoxycholate, glycocholate, glycodeoxycholate and glycochenodeoxycholate) with γ-cyclodextrin and the chemically modified 2-hydroxypropyl-γ-cyclodextrin, was studied using affinity capillary electrophoresis (ACE). The cyclodextrins (CDs) were investigated due to their use in drug formulation as excipients for solubilisation of poorly soluble drugs and drug candidates. Using mobility shift ACE, the bile salt cyclodextrin interactions were characterized demonstrating 1:1 binding stoichiometry with stability constants ranging from 2 × 10³ to 8 × 10⁴ M^?1. The binding constants showed a systematic dependence on the number and position of hydroxyl groups on the steroid skeleton and the stability constants were in general higher for complexation with the native cyclodextrin than with the modified cyclodextrin. Based upon the size of the complexation constants, it was suggested that the interaction between the CDs and the bile salts takes place at the C and D ring of the steroid skeleton. The complexation of bile salts with the γ-cyclodextrins may compete with drug-γ-cyclodextrin complex formation and, thus, potentially affect drug absorption and efficacy.