βCD Cavity Research Articles

Competition between the Hydrated Fluoride Anion and Hexanoic Acid for Inclusion in β-Cyclodextrin: An 1H-NMR Study in Aqueous Solution

β-cyclodextrin (βCD) and two guests (hexanoic acid and the hydrated fluoride ion) are considered as a system in the NMR chemical shift fast exchange regime. The measured chemical shift variations for the βCD H5 protons are expressed as functions of the mole fractions for the free and complexed states, and their slopes, $$\Delta \delta^{0}_{i} = (\partial \Delta\delta/\partial x_{i})_{xj(j\neq i)}$$ , are evaluated. When the NaF concentration is varied ([NaF]0/mM = {50,100, 150, 200, 250}) for a defined value of the hexanoic acid concentration ([Hex]0/mM = {5, 7.5, 10, 12.5, 15}), the chemical shift variations of the βCD H5 protons for 2.5 mM βCD solutions in D2O present a second order polynomial variation with a minimum, suggesting two opposing trends. The first trend corresponding to the decrease of Δδ values (relative shielding) is traced to increasingly negative values of $$\Delta \delta^{0}_{\beta{\rm CD} \cdot {\rm Hex\_F^{-}}}$$ . Corresponding to the increase of Δδ values (relative deshielding), the second trend is mainly associated with the increase of the mole fraction for the inclusion complex βCD·F(H2O) 6 − , as the concentration of NaF increases. The kosmotropic, stabilizing features of the fluoride ion are consistent with the results of HF/6–31G* single point energy calculations showing that βCD·F(H2O) 6 − is energetically favourable, in contrast with βCD·Cl(H2O) 6 − and βCD·Br(H2O) 8 − . Due to its smaller size, F(H2O) 6 − is not appreciably distorted inside the βCD cavity as compared with Cl(H2O) 6 − and Br(H2O) 8 − .

Surface Plasmon Resonance Study of the Interaction of a β-Cyclodextrin Polymer and Hydrophobically Modified Poly(N-isopropylacrylamide)

Surface plasmon resonance (SPR) technique is used to follow, both in real time and in situ, the association between a physically adsorbed polymer of beta-cyclodextrin (pbetaCD) and different hydrophobically modified poly(N-isopropylacrylamide) (PNIPAM) copolymers containing either adamantyl or dodecyl groups. This association is due to the complex formation between the hydrophobic groups and the betaCD cavities. Therefore, the adsorbed amount of PNIPAM onto the pbetaCD layer depends on the substituent and on its substitution level. The association and dissociation rate constants are evaluated from the kinetics of PNIPAM adsorption. An estimation of the association constants leads to values higher than 10(4) M(-1), reflecting the strong interaction between these polymers.

Solid-state inclusion compounds of small amphiphilic molecules (CnEm) in β-cyclodextrin: a study at defined relative humidities

Solid-inclusion compounds of ethylene glycol butyl ether (C4E1), di(ethylene glycol) butyl ether (C4E2) and di(ethylene glycol) hexyl ether (C6E2) in β-cyclodextrin (βCD), with general formula represented by the notation {βCD·CnEm}, were prepared from aqueous solution and characterized by powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), FT-Raman and 13C CP MAS NMR spectroscopies, at ambient humidity, as true hydrated microcrystalline inclusion compounds, pointing to a cage structure for {βCD·C4E1} and a channel structure for both {βCD·C4E2} and {βCD·C6E2}. In addition, the inclusion compounds were investigated at several defined relative humidities (RHs). Several relative intensities of βCD Raman bands generally ascribed to C–O stretching and CH2 bending vibrations are found to be influenced by the presence of guests in the βCD cavity or the increase of ambient humidity, or by both of these factors. PXRD patterns show that crystalline structures are preserved for RHs equal or above 20%. Interestingly, important changes on the multiplicity of resonances and in the dispersions of 13C CP MAS NMR chemical shifts values for all the carbon atoms of the βCD macrocycle are observed in passing from RH 15% to 20%, suggesting amorphous structures below RH 20%. Overall, the above findings converge to stress the structural relevance of hydration water in the βCD inclusion compounds, either with a cage packing arrangement or with a channel structure.

Influence of Host's Substitution on the Orientation of the Guest: Pseudo-rotaxanes of Charged Cyclodextrins with Methyl Orange in Solution

Methyl Orange (MO), an azo-dye molecule with an inherent dipole moment, has been used as a probe to explore the influence of anionic or cationic substituents of cyclodextrins (CDs) on the mode of insertion to form pseudorotaxanes, using NMR spectroscopy. MO is oriented in a single mode inside the βCD cavity, with the dimethylamino group localized at the secondary side. This orientation is completely reversed when MO enters the anionic sodium heptakis[6-deoxy-6-(3-thiopropionate)]-βCD (βpsp) cavity, whereas inside the cationic heptakis(6-deoxy-6-amino)-βCD hydrochloride, MO flips once more, to adopt the same orientation as in βCD. In the latter case the water solubility of MO is significantly lowered. The disposition of the guest in βCD and in each βCD derivative in a single mode was attributed principally to anti-parallel dipole-dipole stabilization. In the wider γCD, the availability of more cavity space leads to 1:2 and 2:2 host/guest stoichiometries and the effect of dipoles is of secondary significance. In the anionic sodium octakis[6-deoxy-6-(3-thiopropionate)]-γCD, MO is positioned as in βpsp, but a 1:2 adduct is also detected. Finally, MO does not dissolve in octakis(6-deoxy-6-amino)-γCD hydrochloride solution.

How humidity affects the solid-state inclusion of 2-phenoxyethanol in β-cyclodextrin: a comparison with β-cyclodextrin

The solid-state inclusion compound ({βCD·PhE}) of 2-phenoxyethanol (PhE) in β-cyclodextrin (βCD) was prepared from aqueous solution and studied by powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), FT-Raman and 13C CP MAS NMR, at ambient humidity and several defined relative humidites (RHs). It is shown that {βCD·PhE} is a true inclusion microcrystalline compound whose PXRD pattern best matches that of an isostructural channel compound. The studies at defined RHs show that its crystalline structure is preserved for RHs equal or above 20% and that its hydration water is not as strongly bound as in βCD. Relative intensities of βCD Raman bands generally ascribed to C–O stretching and CH2 bending vibrations are found to be influenced by the presence of the guest in the βCD cavity or the increase of ambient humidity, or by both of these factors. Comparison of the 13C CP MAS NMR spectra for {βCD·PhE} with those for βCD, at RHs equal or higher than 20%, reveals a decrease in the multiplicities of the carbon atoms resonances and in the dispersions of chemical shift values of the various types of carbon atoms, thus pointing to an improved symmetrization of the βCD macrocycle in the channel structure of {βCD·PhE}.

Molecular structures of the inclusion complexes beta-cyclodextrin-1,2-bis(4-aminophenyl)ethane and beta-cyclodextrin-4,4'-diaminobiphenyl; packing of dimeric beta-cyclodextrin inclusion complexes.

The present investigation is part of an ongoing study on the influence of the long end-functonalized guest molecules DBA and BNZ in the crystal packing of beta-cyclodextrin (betaCD) dimeric complexes. The title compounds are 2:2 host:guest complexes showing limited host-guest hydrogen bonding at the primary faces of the betaCD dimers. Within the betaCD cavity the guests exhibit mutual pi...pi interactions and between betaCD dimers perpendicular NH...pi interactions. The DBA guest molecule exhibits one extended and two bent conformations in the complex. The BNZ guest molecule is not planar inside betaCD, in contrast to the structure of BNZ itself, which indicates that the cavity isolates the molecules and forbids the pi...pi stacking of the aromatic rings. NMR spectroscopy studies show that in aqueous solution both DBA and BNZ form strong complexes that have 1:1 stoichiometry and structures similar to the solid state ones. The relative packing of the dimers is the same in both complexes. The axes of two adjacent dimers form an angle close to 20 degrees and have a lateral displacement approximately 2.45 A, both of which characterize the screw-channel mode of packing. Although the betaCD/BNZ complex indeed crystallizes in a space group characterizing the latter mode, the betaCD/DBA complex crystallizes in a space group with novel dimensions not resembling any of the packing modes reported so far. The new lattice is attributed to the three conformations exhibited by the guest in the crystals. However, this lattice can be transformed into another, which is isostructural to that of the betaCD/BNZ inclusion complex, if the conformation of the guest is not taken into account.

Inclusion of carvone enantiomers in cyclomaltoheptaose (β-cyclodextrin): thermal behaviour and H→D and D→H exchange

The inclusion compounds of carvone enantiomers in cylcomaltoheptaose (β-cyclodextrin, βCD) are studied at defined temperatures above room temperature and in relation to H→D and D→H exchanges. Loss of water molecules and release of carvone molecules from the βCD cavity are caused by increase of temperature above room temperature and are measured by the integrated intensities of the OH and CH Raman stretching bands, respectively. In turn, H→D and D→H exchanges are monitored by the integrated intensities of the OH and OD Raman stretching bands, respectively. All of these processes were followed in real time with a Raman spectrometer equipped with CCD detection. The results indicate that distinct carvone enantiomers lead to the formation of different βCD inclusion hydrates that have different water content and hydration structures. In particular, the results suggest that SCarv–βCD has a greater water content, dehydrates strongly for temperatures above room temperature, and exchanges protons faster than the RCarv–βCD complex.

The influence of β‐cyclodextrin on goaty flavour ‐ Characterization of synthetic inclusion complexes with capric acid and caprylicacid

Sensory analysis shows that the addition of 0.4 per cent (w/v) of the macrocyclic β‐cyclodextrin (βCD) to goat’s milk improves the flavour and reduces its goaty taste, due to encapsulation of molecules responsible of this flavour. In vitro studies of the inclusion of formed complexes between βCD and short‐chain fatty acids, caprylic (C8...) and capric acid (C10...), were carried out by differential scanning calorimetry (DSC) and proton magnetic resonance (...1HNMR). Complex formation was confirmed by DSC, through the disappearance of the signs due to melting of C10 and C8 after the encapsulation process. The 1H NMR technique shows that C10... is included in the βCD cavity. The results suggest that βCD can encapsulate short‐chain fatty acids, making possible its use for masking of these compounds in goat’s milk and derivatives.

Enhancement of Ibuprofen Dissolution via Wet Granulation with β-Cyclodextrin

The purpose was to investigate the effect of wet granulation with β-cyclodextrin (βCD) on the enhancement of ibuprofen (IBU) dissolution. The effect of the granulation variables on the physical properties as well as the dissolution of tablets prepared from these granules was also examined. Granulation was performed using three granulating solvents: water, ethanol (95 vol%), and isopropanol. Granules were either oven-dried for 2 h or air-dried for 3 days. The granules or respective physical mixtures were compressed into tablets. Powder X-ray diffraction showed that oven-dried granulation resulted in less amorphous entities that facilitated IBU– βCD complexation in solution and enhanced the dissolution of the corresponding tablets compared to the physical mixture with or without oven drying. In contrast, air-dried granulation did not cause any differences in the X-ray diffraction pattern (crystallinity) or the dissolution compared to the physical mixture without drying. Isopropanol and water, as granulating solvents, enhanced the dissolution of the oven-dried batches more than ethanol. The Differential scanning calorimetry (DSC) and Thermogravimetric analysis (TGA) data showed that tablets prepared from oven-dried granules, but not air-dried granules, had lower ΔH values and percent loss in weight, respectively, than those prepared from the physical mixture as a result of the expulsion of the water molecules from the βCD cavity and enhancement of the complexation in solution. These results showed that oven-dried granulation of IBU and βCD provided faster IBU dissolution than the physical mixture; air-dried granulation did not substantially affect the dissolution of IBU.

Elucidation of Solution State Complexation in Wet-Granulated Oven-Dried Ibuprofen and β-Cyclodextrin: FT-IR and 1H-NMR Studies

The effect of oven-dried wet granulation on the complexation of β-cyclodextrin with ibuprofen (IBU) in solution was investigated using Fourier transform infrared spectroscopy (FT-IR), proton nuclear magnetic resonance (1H NMR), and molecular modeling. Granulation was carried out using 5 mL of three different granulating solvents; water, ethanol (95% v/v), and isopropanol and the granules were oven-dried at 60°C for 2 h. The granules were compared to oven-dried physical mixture and conventionally prepared complex. Phase solubility study was performed to investigate the stability of the granulation-formed complexes in solution. FT-IR was used to examine the complexation in the granules while 1H NMR, and molecular modeling studies were carried out to determine the mechanism of complexation in the water-prepared granules. The solubility studies suggested a 1:1 complex between IBU and βCD. It also showed that the stability of the complex in solution was in the following order with respect to the granulating solvents: ethanol > water > isopropanol. The FT-IR study revealed a shift in the carboxylic acid stretching band and decrease in the intensities of the C-H bending bands of the isopropyl group and the out-of-plane aromatic ring, of IBU, in granules compared to the oven-dried physical mixture. This indicated that granules might have some extent of solid state complexation that could further enhance dissolution and the IBU–βCD solution state complexation. 1H NMR showed that water prepared oven-dried granules had a different 1H NMR spectrum compared to similarly made oven-dried physical mixture, indicative of complexation in the former. The 1H NMR and the molecular modeling studies together revealed that solution state complexation from the granules occurred by inclusion of the isopropyl group together with part of the aromatic ring of IBU into the βCD cavity probably through its wider side. These results indicate that granulation process induced faster complexation in solution which enhances the solubility and the dissolution rate of poorly soluble drugs. The extent of complexation in the granules was dependent on the type of solvent used.

Reversal of charge selectivity in transmembrane protein pores by using noncovalent molecular adapters.

In this study, the charge selectivity of staphylococcal alpha-hemolysin (alphaHL), a bacterial pore-forming toxin, is manipulated by using cyclodextrins as noncovalent molecular adapters. Anion-selective versions of alphaHL, including the wild-type pore and various mutants, become more anion selective when beta-cyclodextrin (betaCD) is lodged within the channel lumen. By contrast, the negatively charged adapter, hepta-6-sulfato-beta-cyclodextrin (s(7)betaCD), produces cation selectivity. The cyclodextrin adapters have similar effects when placed in cation-selective mutant alphaHL pores. Most probably, hydrated Cl(-) ions partition into the central cavity of betaCD more readily than K(+) ions, whereas s(7)betaCD introduces a charged ring near the midpoint of the channel lumen and confers cation selectivity through electrostatic interactions. The molecular adapters generate permeability ratios (P(K+)/P(Cl-)) over a 200-fold range and should be useful in the de novo design of membrane channels both for basic studies of ion permeation and for applications in biotechnology.

Interaction of p-hydroxybenzoic esters with beta-cyclodextrin

In the present investigation, the complex formation of beta-cyclodextrin (βCD) with p-hydroxybenzoic esters (parabens) was studied by mixing βCD with methyl, ethyl, propyl and butyl parabens, respectively, in aqueous solutions and subjecting the resultant mixtures individually to the following processes: occasional shaking for 24 h at 25°C, continuous shaking using shaker bath for 24 h at 25°C, intermittent ultrasonification for 90 min at 25°C, autoclaving at 115°C for 30 min and freeze-drying followed by reconstitution with distilled water. The degrees of interaction between βCD and the parabens subjected to the various processes were evaluated, using the membrane dialysis method. The difference in the method of processing did not affect the degree of interaction significantly. However, the degree of interaction was found to increase proportionally with the concentration of βCD. The alkyl group of the parabens was also found to affect the extent of interaction. Compared to methyl paraben, the degree of interaction of ethyl paraben was observed to be lower. Interestingly, further increase in the size of the alkyl group significantly enhanced the extent of interaction. Studies using 1H-NMR showed that the extent of interaction depended on how well the parabens could fit into the βCD cavity.

Preparation and Electrochemical Characterization of a β-Cyclodextrin-Based Chemically Modified Electrode

The preparation and the voltammetric characterization of a chemically modified electrode (CME) based on a suitable thiolate β-cyclodextrin (βCD) derivative in the form of self-assembled monolayer (SAM) is described. The quality of SAM was studied by double layer capacitance measurements, reductive desorption and cyclic voltammetry. Species unable (hexacyanoferrate) or able (ferrocenecarboxylic acid and hydroquinone) to permeate the βCD cavity were used to test the CME by cyclic voltammetry. The CME can work as channel sensor so it can be used for the detection of nonelectroactive analytes forming a strong inclusion complex with βCD if a suitable marker able to permeate the βCD cavity is used. This approach was also used for the evaluation of the conditional constants of the surface host-guest complexes formed by βCD with analytes in test (trimethyilcetylammonium ion and ursodeoxycholic acid).

Experimental Thermodynamics and Molecular Mechanics Calculations of Inclusion Complexes of 9-Methyl Anthracenoate and 1-Methyl Pyrenoate with β-Cyclodextrin

Steady-state fluorescence and molecular mechanics calculations were used to study the inclusion complexes of 9-methyl anthracenoate (MA) and 1-methyl pyrenoate (ΜP) with β-cyclodextrin (βCD). Binding constants of 1:1 complexes at different temperatures were obtained from the analysis of the fluorescence enhancement of the βCD solutions with respect to the MA or MP free chromophores. The thermodynamic parameters ΔH and ΔS were also obtained. Molecular mechanics calculations were applied to study both inclusion processes in vacuo and in the presence of water as a solvent. Complexation is mainly due to nonbonded van der Waals host−βCD interactions. Both MA and MP penetrate only partially into the βCD cavity.

Molecular, crystal and solution structure of a β-cyclodextrin complex with the bromide salt of 2-(3-dimethylaminopropyl)tricyclo[3.3.1.1 3,7]decan-2-ol, a potent antimicrobial drug

The pharmacological properties of a cyclomaltoheptaose (β-cyclodextrin) series of adamantane-group-bearing compounds that exhibit potent antibacterial activity have been studied, both isolated and in complex with β-cyclodextrins (βCDs). In this work, the structure of the bromide salt of 2-(3-dimethylaminopropyl)tricyclo[3.3.1.1 3,7]decan-2-ol (ADM-10) complexed with βCD and ten water molecules was studied in the solid state by X-ray crystallography and in solution by NMR spectroscopy. X-ray crystallographic studies of the complex were performed both at room and cryogenic temperatures. The long aliphatic chain of ADM-10 adopts a single conformation at low temperature in contrast to what is observed at room temperature, where two side chain conformations are seen. Both NMR and X-ray crystallography studies indicate that the adamantane moiety of ADM-10 is buried in the βCD cavity. Chemical shifts in NMR experiments can be explained on the basis of the crystal structure of the complex.

Modelling of molecular interactions and inclusion phenomena in substituted β‐cyclodextrin: From simple probes to proteins

AbstractThe ability of β‐cyclodextrin (βCD) to form stable complexes with α‐interferon was investigated. By using simple molecular mechanics approach interaction energy profiles of simple probes passing the center of βCD ring cavity along the main molecular symmetry axis were evaluated first. A computational study of host‐guest inclusion complexes between βCD and L‐α‐aminoacids and some selected pentapeptides was also carried out and aimed at understanding the nature of the driving forces and mechanism, leading to their formation. Relative complexation energies for the complexes and the solvation Gibbs free energies for single L‐α‐aminoacids were calculated. Both the aminoacid residue inside the βCD cavity and neighbouring residues were found to contribute to the stabilization of βCD complexes with the side‐chain of aminoacids present on the surface of α‐interferon. The most appropriate number of host βCD molecules for the encapsulation in the first shell of one α‐interferon molecule resulted to be 25.

Effects of the Host Cavity Size and the Preparation Method on the Physicochemical Properties of Ibuproxam-Cyclodextrin Systems

The effect of cyclodextrin (Cd) complexation on ibuproxam (IBUX) dissolution properties was studied by evaluating both the influence of Cd cavity size and the preparation method used for obtaining solid inclusion complexes. Binary systems of IBUX with natural Cds, prepared using different techniques (kneading, sealed-heating, spray-drying), were studied by differential scanning calorimetry (DSC), hot-stage microscopy (HSM), Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), and their dissolution behavior was evaluated according to the dispersed amount method. The nature and the dissolution performance of the end product appeared to be related to both steric factors of host molecule and preparation method of the solid system. The αCd cavity size was less suitable for accommodating the IBUX molecule, whereas spray-drying and sealed-heating methods led to a true inclusion complex of IBUX in the βCd and γCd cavity. In contrast, the kneading method did not lead in any case to a real inclusion complex. Spray-dried systems with βCd and γCd were the most effective in achieving the enhancement of the IBUX dissolution rate.

Structure of Neohesperidin Dihydrochalcone/β-Cyclodextrin Inclusion Complex: NMR, MS, and X-ray Spectroscopic Investigation

The inclusion complex between the semisynthetic sweetener neohesperidin dihydrochalcone (1) and β-cyclodextrin (βCD) has been investigated in solution, in the gas phase and in the solid state. In aqueous solution they form a 1:1 complex having a Kbinding of 1.6 × 103 M-1 at 315 K. The nuclear Overhauser effects show that the terminal isovanillin ring of 1 is included in the hydrophobic cavity of βCD from the narrower rim of the truncated cone. The peak at m/z 1747 corresponding to the supramolecular entity [βCD + 1 + H]+ was detected by MS−FAB measurements. The fragmentation pattern of 1 is different in the presence and in the absence of βCD, suggesting that the disaccharide moiety of 1 and the external polar surface of the host are tightly associated. In the solid state evidence of the formation of the βCD/1 complex is obtained from the X-ray powder diffractograms which show diffraction peaks differing in position and intensity from those of native guest 1 and host βCD. Keywords: Neohesperidin dihydrocha...

Fast-atom bombardment mass spectrometric and tandem mass spectrometric study of (—)-menthol-β-(D)-glucopyranoside, neohesperidin dihydrochalcone and their non-covalent association with β-cyclodextrin. Two examples of interaction of a carbohydrate host with glycoconjugate guests

(−)-Menthol-β-(D)-glucopyranoside 1 and neohesperidin dihydrochalcone 2 are glycoconjugates of practical interest. Compound 1 releases (−)-menthol in foods by slow hydrolysis and 2 is a sweetener used as an alternative to sucrose for diet food and beverages. Their molecular encapsulation in β-cyclodextrin (βCD) is currently under investigation with the purpose of obtaining long lasting properties in the final product. From a mass spectrometric point of view, the study of the protonated gaseous 1:1 host–guest complexes of 1 and 2 with βCD is of particular interest, since the guest molecules possess an apolar aglycon, likely to interact with the lipophilic cavity of βCD, and a saccharidic part, whose capability of interaction with the polar external surface of βCD has not been investigated so far. We carried out a fast-atom bombardment (FAB) mass spectrometric and tandem mass spectrometric (MS/MS) study in thioglycerol on 1 and 2 and their gaseous protonated 1:1 association complexes with βCD. The FAB and t...

AM1 calculations on inclusion complexes of cyclomaltoheptaose (β-cyclodextrin) with 1,7-dioxaspiro[5.5]undecane and nonanal, and comparison with experimental results

Semiempirical calculations on cyclomaltoheptaose (βCD), 1,7-dioxaspiro[5.5]undecane ( 1), nonanal ( 2), and the inclusion complexes of βCD with 1 and 2 were carried out using the AM1 method. The structure of βCD after complete geometry optimization was in very good agreement with crystallographic structures. Moreover, the calculated dipole moment of βCD was found to depend strongly upon the orientation of the primary hydroxyl groups. Different possible positions of the guest molecules in the βCD cavity were examined, a few of them resulting in a gain of energy. These corresponded to partial inclusion of 1 from the secondary side but total inclusion of 2. Conclusions regarding the geometries of the complexes were in satisfactory agreement with the dominant structures in aqueous solutions as derived from NMR experiments. Thermodynamic data ( ΔH 0, ΔS 0) in aqueous solutions were obtained from van't Hoff plots using 1H NMR, and were compared with the computed heats of formation. The forces responsible for host-guest association are discussed in the light of the above results.