Interactions of cyclodextrins with aromatic compounds studied by vibrational circular dichroism spectroscopy

The host/guest complexation between cyclodextrins (CDs) and aromatic compounds was studied by vibrational circular dichroism (VCD) spectroscopy in mid-IR region. Benzoic acid, 4-aminobenzoic acid, and 2,6-naphthalene-dicarboxylic acid acting as the guests with aromatic skeleton, cause the significant changes in VCD patterns of CD, which indicate that the secondary hydroxyl groups of the CDs are involved in the host/guest complexation. In addition, the intensities and dissymmetry factors (deltaA/A) of the VCD bands, which belong to skeletal CD vibrations, depend on the sizes of the guest molecules. Our results indicate that the formation of the CD inclusion complexes can be followed by VCD spectroscopy.     

Preference Prediction for the Stable Inclusion Complexes between Cyclodextrins and Monocyclic Insoluble Chemicals Based on Monte Carlo Docking Simulations

Cyclodextrins (CDs) are useful functional excipients, which are being used to camouflage undesirable pharmaceutical characteristics, especially poor aqueous solubility, through the inclusion complexation process with insoluble drugs. The selection of more efficient cyclodextrin is important to improve the bioavailability of drugs. In this study, the complexing and solubilizing abilities toward poorly water-soluble monocyclic molecules of natural CDs (α-CD, β-CD, and γ-CD) were investigated using Monte Carlo (MC) docking simulations studies. These theoretical results closely agree with the experimental observation of the complex stability in water of the various guests–CD complexes. Host preferences, based on the experimentally determined stability constants between host CDs and guest molecules, show excellent correlation with the calculated interaction energies of corresponding complexes. The inclusion complex with the lower MC docking interaction energy shows a higher value of stability constant than that of the other complex, and the prediction accuracy of the preferred complex for 21 host–guest pairs is 100%. This result indicates that the MC docking interaction energy could be employed as a useful parameter to select more efficient cyclodextrin as a host for the bioavailability of insoluble drugs. In this study, β-CD shows greater solubilizing efficacies toward guest molecules than those of α-CD and γ-CD, with the exception of one case due to the structure of a guest molecule containing one lipophilic cyclic moiety. The surface area change of CDs and hydrogen bonding between the host and guest also work as major factors for the formation of the stable complex.     

β-Cyclodextrin and folic acid host–guest interaction binding parameters determined by Taylor dispersion analysis and affinity capillary electrophoresis

The thermodynamic properties of molecular recognition in host–guest inclusion complexes can be studied by Taylor dispersion analysis (TDA). Host–guest inclusion complexes have modest size, and it is possible to get convergent results fast, achieving greater certainty for the obtained thermodynamic properties. Cyclodextrins (CDs) and their derivatives can be used as drug carriers that can boost stability, solubility, and bioavailability of physiologically active substances. A simple and effective approach for assessing the binding properties of CD complexes that are critical in the early stages of drug and formulation development is needed to fully understand the process of CD and guest molecules’ complex formation. In this work, TDA was successfully used to rapidly determine interaction parameters, including binding constant and stoichiometry, between β-CD and folic acid (FA) along with the diffusivities of the free FA and its complex with β-CD. Additionally, the FA diffusion coefficient obtained by TDA was compared to the results previously obtained by nuclear magnetic resonance. Affinity capillary electrophoresis (ACE) was also used to compare the binding constants obtained by different methods. The results showed that the binding constants obtained by ACE were somewhat lower than those obtained by the two TDA procedures.     

Study of the retention of aroma components by cyclodextrins by static headspace gas chromatography

The process of encapsulation is widely employed in the flavour industry to protect volatile and/or labile flavouring materials during storage. A variety of commercial practices are currently followed, but those involving the formation of flavour/cyclodextrin (CD) molecular inclusion complexes afford some of the greatest potential for increased product shelf life. The determination of the stability of inclusion complexes is of critical importance to take advantage of the complexation potential of CDs. Hence, we investigated the interactions between five CDs and thirteen aroma components. Relevant for, the retention of these compounds in presence of different CDs has been determined. The stability constants of the inclusion compounds have been calculated by static headspace gas chromatography in aqueous solution at 30 °C. The results indicate the formation of 1:1 inclusion complex for all the studied compounds. The binding between CDs and the aroma compounds depends on both hydrophobicity of the guest molecule and their geometric accommodation into the CD cavity. The results show that β-CDs are the most versatile CDs for the inclusion of the studied molecules.     

The binding behavior of cyclodextrins toward a nitroxide spin probe in the presence of different alcohols as studied by EPR

Stability constants, rates of association and dissociation, and thermodynamic and activation parameters for the formation of inclusion complexes between the radical guest, N-benzyl- tert-butyl- d 9-nitroxide and beta- or 2,6- O-dimethyl-beta-cyclodextrin (CDs), have been determined by EPR spectroscopy in water in the presence of 14 different alcohols, differing in size and lipophilicity. In all cases, it was found that addition of alcohol, depending on its structure and concentration, causes a reduction of the stability of the paramagnetic complex. Global analysis of EPR data allowed us to explain the CDs binding behavior: we discarded the formation of a ternary complex, where alcohol and radical guest are coincluded into CD cavity, while data were found more consistent with the formation of a binary complex alcohol:CD competing with the monitored complex nitroxide:CD. Both kinetic and thermodynamic analysis of the experimental results have revealed that the presence of alcohols affects to a larger extent the dissociation rather then the association of radical probe and CD and that the former process is of greater importance in determining the stability of the complex, this confirming the reliability of the competition model proposed. This competition has been used for the indirect determination of the stability constants of complexes between CD and examined alcohols. By using a similar approach, we showed EPR spectroscopy can be considered a rapid and accurate technique to investigate the CDs binding behavior toward different nonradical guest.     

Inhibition of acid‐induced decomposition of diphenyltriazenes by complexation with cyclodextrins

Acid‐promoted N? N bond cleavage in 1,3‐diphenyltriazenes (X‐Ph‐N=N‐NH‐Ph‐X; X = H, 4‐OCH₃), leading to formation of diazonium ions and anilines, is strongly inhibited in aqueous solutions in the presence of cyclodextrins (CDs). The inhibition is ascribed to the formation of inclusion complexes that render the guest diphenyltriazene significantly less basic as a result of the less polar nature of the CD cavity (a microsolvent effect). Association equilibrium constants for 1:1 host–guest complexes increase in the order α‐CD <β‐CD ～ permethyl‐β‐CD < hydroxypropyl‐β‐CD, with values for X = 4‐OCH₃ being larger than those for X = H. In the case of α‐CD, formation of 2:1 host–guest complexes is also involved. © 2010 Wiley Periodicals, Inc. Int J Chem Kinet 42: 567–574, 2010     

Non-covalent columnar cyclodextrin-based structures

Examples of the formation of ordered ensembles of α-, β-, and γ-cyclodextrins (CDs) molecules with a columnar packing of macrocycles are reported. These ensembles are formed by (1) the supramolecular dissociation of polymer inclusion complexes under the action of organic solvents that are selective with respect to a polymer guest and (2) the fixation of columnar CD aggregates self-organized in aqueous solutions at high temperatures upon the precipitation from water into organic solvents. Specific features of the organization of cyclodextrins in the thus-synthesized structures are studied by X-ray diffraction. Preliminarily oriented polymer inclusion complexes based on corresponding CDs are used as a model with the columnar arrangement of macrocycles.     

Kinetic control of threading of cyclodextrins onto axle molecules

We report here, for the first time, kinetic control of the face-direction of cyclodextrin (CD) in the construction of a pseudo-rotaxane with an alkyl chain bearing pyridyl end caps. The yields of complexes of CDs with guest alkyl derivatives were controlled by the simple change of the position and the number of methyl groups bound to the pyridyl moiety. Single-substituted pyridyl groups attached to the ends of the alkyl chain regulated the rate for CDs passing them. Two methyl substituents could clearly govern the degree of complex formation of CD with guest molecules and resulted in the distinction of face-direction of CD molecules entering the gates at guest ends.     

Investigation on the inclusions of PCB52 with cyclodextrins by performing DFT calculations and molecular dynamics simulations

The effective enrichment and identification of lowly concentrated polychlorinated biphenyls (PCBs) in the environment is attracting enormous research attention due to human health concerns. Cyclodextrins (CDs) are known to be capable of forming inclusion complexes with a variety of organic molecules. The purpose of this study is to provide theoretical evidence of whether CDs as host molecules can include the guest molecules PCBs to form stable host-guest inclusion complexes, and if so, whether the general infrared and Raman techniques are suitable for the direction of CD-modified PCBs. Focusing on a representative PCB molecule, 2,2',5,5'-tetrachlorobiphenyl (PCB52), we carried out density functional theory calculations and molecular dynamics (MD) simulations on its complexes with α-, β-, and γ-CDs with different host-guest stoichiometry ratios, including 1:1, 1:2, 2:1, and 2:2. On the basis of both the optimized geometries and calculated energy changes raised from encapsulating the guest molecule into the cavities of CDs, the CDs are believed to be suitable hosts for accommodating PCB52 guest molecules. The stability of inclusion complexes depends on both the type of CD and host-guest stoichiometry ratio. MD simulations give a clear picture of the scene on how the PCB52 molecule enters the cavity of β-CD. The vibrational analyses on the 1:1 complexes of CDs provide information for the spectral characterization of the inclusion complexes: Raman spectroscopy can deliver the characteristic bands of PCB52, whereas IR spectroscopy cannot uniquely assign them, implying that Raman spectroscopy is a useful technique for the identification of CD-modified PCBs. The present theoretical results are expected to provide guidance for the relevant experimental research.     

Complexation of capsaicin with β-cyclodextrins to improve pesticide formulations: effect on aqueous solubility, dissolution rate, stability and soil adsorption

The binary systems of capsaicin (CP) and β-cyclodextrin (βCD) or hydroxypropyl-β-cyclodextrin (HPβCD) were investigated in an attempt to improve formulations of this pesticide. UV spectral shift methods indicated guest–host complex formation between CP and the two cyclodextrins (CDs). Phase solubility analysis showed B_s type diagrams with βCD, A_L type with HPβCD indicating the formation of an inclusion complex at 1:1 stoichiometric ratio in solution state. Solubility profiles indicated a 50-fold enhancement of CP solubility could be achieved in the presence of 60 mM HPβCD with respect to CP alone. Solid co-evaporated systems (CES) with 1:0.5–1:5 molar ratios of CP/CDs were physicochemically characterized, revealing that the true inclusion complexes could be formed in the solid CP/βCD systems with 1:5 molar ratio and in the solid CP/HPβCD systems with the molar ratios more than 1:3, respectively. In contrast, crystalline drug was detectable in all other systems. Compared with corresponding physical mixtures (PMs), the CES exhibited significant enhancement with regard to CP dissolution and the protection from CP degradation under the accelerated conditions. It was also revealed that complexation of CP with HPβCD had a pronounced improved effect on the pesticide formulations and greatly reduced the amount of CP adsorbed in the soil. These results demonstrate that HPβCD may be a preferred excipient, enabling more efficient and intelligent use of CP/CDs inclusion complexes in the development of pesticide formulations.     

1H NMR study of the inclusion of Costa-type organocobalt(III) complexes in cyclodextrins

The inclusion behavior between Costa-type complexes and cyclodextrins (CDs) was studied by 1H NMR in aqueous solution. The results indicated that 1:1 inclusion complex was formed, in which the alkyl group of the guest was included in the cavity of CDs. The stability constants of the inclusion complexes were determined by the quantitative 1H NMR method. The effects on stability constants were discussed when various host and guest compounds were used.     

Influence of the presence of methyl cyclodextrins in high-performance liquid chromatography mobile phases on the separation of beta-carboline alkaloids

The presence of cyclodextrins (CDs) in the mobile phase alters the chromatographic equilibria and induces a secondary chemical equilibrium associated to the chromatographic separation by HPLC. In this study the influence of the presence of CDs in the mobile phase as chemically modified beta-CDs, i.e. 2,3-di-O-methyl-beta-cyclodextrin (DMbeta-CD) and 2,3,6-tri-O-methyl-beta-cyclodextrin (TMbeta-CD) on the separation of the alkaloids norharmane, harmane and harmine is described. These beta-carboline alkaloids are chemically and structurally related and their quantitation by RP-HPLC is of interest due to their biological and pharmacological properties. Two stationary phases (methyl-, C(1) and octadecyl-, C(18)) were employed, with methanol:buffered aqueous solution and ethanol:buffered aqueous solution as mobile phases. The role of tert-butyl alcohol as a mobile phase modifier and also as an inclusion complex stabiliser was also considered. The concentrations of DMbeta-CD and TMbeta-CD vary from 0 to 17 mM. The presence of increasing amounts of CDs in the mobile phase reduces the retention factor. The changes observed in the retention factor allow the determination of the alkaloid/CD apparent association constants, whose magnitude is influenced by the chemical and structural properties of the guest molecules but also by the composition of the mobile phase. Assuming a 1:1 stoichiometry for the inclusion complexes, the apparent association constants obtained were higher for norharmane and for both DMbeta-CD and TMbeta-CD. The strength of the complexes is higher for DMbeta-CD than for TMbeta-CD and this behaviour can be explained considering the steric problems associated to the permethylated-beta-CDs. Besides significant differences in the magnitude of the apparent association constants were observed for the two stationary phases employed and thus can be related to the adsorption of CDs on the stationary phase. A significant reduction in the proportion of organic solvent in the mobile phase (50%) without a decrease in the selectivity or resolution of the separation is a favourable consequence of the presence of the CDs in the mobile phase.     

Molecular electrostatic potentials and hydrogen bonding in alpha-, beta-, and gamma-cyclodextrins

Cyclodextrins (CDs) are cyclic oligomers of glucose having the toroid of sugars elaborating a central cavity of varying size depending on the number of glucoses. The central hydrophobic cavity of CD shows a binding affinity toward different guest molecules, which include small substituted benzenes to long chain surfactant molecules leading to a variety of inclusion complexes when the size and shape complementarity of host and guest are compatible. Further, interaction of guest molecules with the outer surface of alpha-CD has also been observed. Primarily it is the electrostatic interactions that essentially constitute a driving force for the formation of inclusion complexes. To gain insights for these interactions, the electronic structure and the molecular electrostatic potentials in alpha-, beta-, and gamma-CDs are derived using the hybrid density functional theory employing the three-parameter exchange correlation functional due to Becke, Lee, Yang, and Parr (B3LYP). The present work demonstrates how the topography of the molecular electrostatic potential (MESP) provides a measure of the cavity dimensions and understanding of the hydrogen-bonded interactions involving primary and secondary hydroxyl groups. In alpha-CD, hydrogen-bonded interactions between primary -OH groups engender a "cone-like" structure, while in beta- or gamma-CD the interactions from the primary -OH with ether oxygen in glucose ring facilitates a "barrel-like" structure. Further, the strength of hydrogen-bonded interactions of primary -OH groups follows the rank order alpha-CD > beta-CD > gamma-CD, while the secondary hydrogen-bonded interactions exhibit a reverse trend. Thus weak hydrogen-bonded interactions prevalent in gamma-CD manifest in shallow MESP minima near hydroxyl oxygens compared to those in alpha- or beta-CD. Furthermore, electrostatic potential topography reveals that the guest molecule tends to penetrate inside the cavity forming the inclusion complex in beta- or gamma-CD.     

New SPE loading material for affinity‐based separation of cyclodextrins from drug:CD complexes in order to overcome Beer's law deviations

Molecular inclusion of guest molecules within CDs is known to alter guest molecule spectrophotometric absorptivity, making their determination, based on spectrophotometric data, inaccurate. Therefore specific analytical methods capable of quantifying the drugs as free molecules must be developed and validated. SPE was selected to simplify sample and avoid more time‐consuming alternatives. A new solid phase was synthesized and characterized by infrared spectrometry, differential scanning calorimetry and elemental analysis. The competitive complexation of adamantane groups immobilized on the silica substrate facilitates drug:CD complex dissociation and elimination of CD from samples. The drug molecules, now free from CD, can be easily analysed by an already available HPLC method. This new SPE loading material was employed in the determination of ketoprofen in its CD complex as a representative example of the utility of this novel material. The calculated analytical errors were reduced from a maximum of 20.79% (without SPE) to a minimum of 3.99%.     

Experimental and theoretical studies on the inclusion complexation of syringic acid with alpha-, beta-, gamma- and heptakis(2,6-di-O-methyl)-beta-cyclodextrin

Intermolecular interactions of alpha-, beta-, gamma- and heptakis(2,6-di-O-methyl)-beta-cyclodextrin (CD) with syringic acid (Syr) in aqueous solution are investigated by fluorescence spectroscopy. The fluorescence intensity of Syr gradually increases with the addition of the CDs. The formation constants (K) of the host-guest inclusion complexes are determined using a nonlinear analysis. The association abilities of Syr with the CDs decrease in the order gamma->beta->alpha- approximately DMbeta-CD. Both the intrinsic binding abilities of the CDs and the structural effect of Syr are taken into consideration when comparing the K values. Based on the results of NMR experimental and theoretical PM3 calculations both in vacuo and in water, it is found that Syr stays near the wider rim of alpha-CD cavity. Both the number of substituted groups (NSG) in a guest and the molar volume ratio of the guest to host cavity (MVR) play an important role in forming the CD supramolecular complexes of a homologous series of phenol derivatives, such as 2-methoxylphenol (2-Mop), eugenol (Eug) and Syr, i.e., an appropriate NSG or MVR in an inclusion system, such as in 2-Mop-alpha-CD, Eug-beta-CD and Syr-gamma-CD systems, can maximize the intermolecular interaction between host and guest.     

Solubilization of Polycyclic Aromatics in Water by γ‐Cyclodextrin Derivatives

A series of hydrophilic per‐6‐thio‐6‐deoxy‐γ‐cyclodextrins (CDs) were synthesized from per‐6‐iodo‐6‐deoxy‐γ‐CD. These new hosts are able to solubilize polycyclic aromatic guests in aqueous solution to much higher extents than native CDs. Phase‐solubility diagrams were mostly linear in accordance with both 1:1 and 1:2 CD–guest complexes in aqueous solution. The stoichiometry of the inclusion complexes was further investigated by fluorescence spectroscopy, which revealed very pronounced Stokes shifts typical for 1:2 complexes. This finding was further consolidated by quantum mechanical calculations of dimer formation of the guests and space‐filling considerations by using the cross‐sectional areas of the CDs and guests. The calculated dimerization energies correlated well with the binding free energies measured for the 1:2 complexes, and provided the main contribution to the driving force of complexation in the γ‐CD cavity.     

Study on Supramolecular Systems of Cyclodextrins and Magnolol,Honokiol by Thin Layer Chromatography

The interactions between magnolol, honokiol and six cyclodextrins (CDs) have been studied by reversed-phase thin-layer chromatography. The NH 3 H 2 O-NH 4 Cl buffer containing various CDs (pH 9.7, 20C) and polyamide plate are selected, respectively, as mobile and stationary phases. CDs except for f -CD and CM- g -CD can form inclusion complex with magnolol. However, the strong space resistance between honokiol and CD makes it difficult for them to form inclusion complex. The comparison of inclusion capacity of different CDs indicates that for the ionic CDs the charge interaction plays an important role in the inclusion procedure. The thermodynamic parameters of interaction imply that the inclusion process shows the enthalpy-entropy compensation effect. The j H - T j S plot for CDs displays an excellent linear relationship, affording a very large slope ( f =1.1) and intercept ( T j S 0 0 =16.3), which exhibits that the enthalpic gain from the inclusion complexation is completely canceled out by the entropic loss from the conformational changes caused upon guest inclusion. The marked influence of CDs on the hydrophobicity of magnolol suggests that this interaction may modify the biological properties of magnolol.     

Nucleation effect of cyclodextrin inclusion complexes on the crystallization of isotactic poly(1‐butene)

The β‐cyclodextrin (β‐CD) and γ‐cyclodextrin (γ‐CD) inclusion complexes (ICs) with four kinds of polyolefin were prepared. The crystallization behavior of isotactic poly(1‐butene) (iPB‐1) blended with these CDs and ICs was investigated by differential scanning calorimetry, polarized optical microscopy, and wide‐angle X‐ray diffraction. The iPB‐1 blended with the ICs was found to exhibit higher crystallization temperature (T_C), smaller spherulites, and faster crystallization rate than neat iPB‐1. These results indicate that the ICs can act as nucleating agent on the crystallization of iPB‐1 and induce the accelerated crystallization. The guest molecules of ICs play an important role in the nucleation effect of ICs on the crystallization of iPB‐1. ICs with polyolefin having higher T_C as guest molecules have higher nucleation effect than the one with polyolefin having lower T_C as guest molecules. And, the CDs and ICs induce different crystal form of iPB‐1. The crystal of iPB‐1 blended with CDs is defective, whereas the crystal of iPB‐1 blended with ICs is more perfect. © 2010 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 48: 389–395, 2010     

Molecular recognition in cyclodextrin complexes of amino acid derivatives. 2. A new perturbation: the room-temperature crystallographic structure determination for the N-acetyl-p-methoxy-L-phenylalanine methyl ester/beta-cyclodextrin complex

Cyclodextrins (CDs) are cyclic oligosaccharides that encapsulate various small organic molecules, forming inclusion complexes. Because CD complexes are held together purely by noncovalent interactions, they function as excellent models for the study of chiral and molecular recognition mechanisms. Recently, room-temperature crystallographic studies of both the 2:2 N-acetyl-L-phenylalanine methyl ester/beta-CD and 2:2 N-acetyl-L-phenylalanine amide/beta-CD complexes were reported. The effect of changes in carboxyl backbone functional group on molecular recognition by the host CD molecule was examined for the nearly isomorphous supramolecular complexes. A new perturbation of the system is now examined, specifically perturbation of the aromatic side chain. We report a room-temperature crystal structure determination for the 2:2 N-acetyl-p-methoxy-L-phenylalanine methyl ester/beta-CD inclusion complex. The complex crystallizes isomorphously with the two previously reported examples in space group P1; the asymmetric unit consists of a hydrated head-to-head host dimer with two included guest molecules. The crystal packing provides both a nonconstraining extended hydrophobic pocket and an adjacent hydrophilic region, where hydrogen-bonding interactions can potentially occur with primary hydroxyl groups of neighboring CD molecules and waters of hydration. The rigid host molecules show no sign of conformational disorder, and water of hydration molecules exhibit the same type of disorder observed for the other two complexes, with a few significant differences in locations of water molecules in the hydrophilic region near guest molecules. There is evidence for modest disorder in the guest region of an electron density map. In comparing this system with the two previously reported complexes of phenylalanine derivatives, it is found that the packing of the guest molecules inside the torus of the CD changes upon substitution of a methoxy group at the para position of the aromatic phenyl ring. Backbone hydrogen-bonding interactions for the guest molecules with the CD primary hydroxyls and waters also change. This structure determination is a new and revealing addition to a small but growing database of amino acid and peptidomimetic interactions with carbohydrates.     

Preparation and characterization of the crystalline inclusion complexes between cyclodextrins and poly(1,3-dioxolane)

The preparation and characterization of the crystalline inclusion complexes between a polymeric guest, poly(1,3-dioxolane) (PDXL), and small-molecular hosts, cyclodextrins (CDs) are reported. It is observed that the polymer guest can form crystalline inclusion complexes with three kinds of cyclodextrins, which may be attributed to the high oxygen atom density in PDXL chain. The crystalline inclusion complexes were characterized with FTIR , TGA, X-ray diffraction, SEM, 1H NMR and 13C CP/MAS NMR spectroscopes. It was found that the crystalline inclusion complexes have higher temperature stability than the pure CDs. The X-ray powder diffraction patterns of the crystalline inclusion complexes proved that they have columnar structures. 13C CP/MAS NMR spectra of the crystalline inclusion complexes indicate that CDs adopt a more symmetrical conformation in the complexes, while pure CDs assume a less symmetrical conformation in the crystal without a guest inside their cavities. The morphology of the crystal was