Betulonic acid—cyclodextrins inclusion complexes

Journal of Thermal Analysis and Calorimetry - Betulonic acid (BA) is a pentacyclic lupane-type triterpenoid possessing valuable pharmacological activities, exhibiting very low water solubility....     

Microenvironmental effects of cyclodextrins I: Enhancement of intramolecular excimer formation of polymethylene-bisβ-naphthoate via inclusion with cyclodextrins

The effects of α-, β- and γ-cyclodextrins (CDs) on the fluorescence spectra of a series of polymethylene-bis-β-naphthoates (Bn) have been studied. It is observed that β-CD and γ-CD enhance Bn intramolecular excimer fluorescence, indicating the formation of two-to-one guest host inclusion complexes. The possible conformation of these inclusion complexes is discussed.     

Inhibition of cyclodextrins on the activity of α-amylase

α-amylase activity influences both flour fermentation process and the quality of the fermented products due to its ability of breaking starch into smaller units. The inhibition of cyclodextrins on α-amylase activity was investigated in this paper. Experiment results showed that hydrophobic cavity size was an intrinsic factor during the inhibition processing. Among three types of cyclodextrin (α-, β- and γ-), β-type exhibited the most significant inhibitory activity toward α-amylase. The optimal inhibitory parameters were indicated to be pH 5.9, concentration of β-cyclodextrins 1 mmol/L, reaction temperature 45 °C and reaction time 60 min. Results suggested that the endogenous fluorescence of α-amylase was inhibited by cyclodextrins. Circular dichroism spectrum indicated that the secondary structure of α-amylase, including α-helices, β-sheets and random coils, was changed by cyclodextrins. All the results in this paper aim to provide a further understanding for α-amylase in the industry application.     

Inclusion complex of α-lipoic acid and modified cyclodextrins

The solubility of α-lipoic acid (LA) with the addition of modified cyclodextrins was investigated using the solubility method. The solubility of LA in the presence of β-cyclodextrin (β-CD), hydroxypropyl-β-cyclodextrin (HP-β-CD), mono-6-O-glucopyranosyl-β-cyclodextrin (mono-G₁-β-CD), methyl-β-cyclodextrin (Me-β-CD), 2,6-di-O-methyl-β-cyclodextrin (DM-β-CD), and sulfobutylether-β-cyclodextrin (SBE-β-CD) was higher than that of LA itself. In particular, the solubility of LA in the presence of SBE-β-CD was 20 times higher than that of LA alone. The structure of the inclusion complex of SBE-β-CD and LA in aqueous solution was examined by ¹H-¹H ROESY NMR spectroscopy. The 1,2-dithiolane moiety of LA was included from the secondary hydroxyl face of SBE-β-CD. The solid complexes of LA and SBE-β-CD were prepared by the kneading and freeze-drying methods. Formation of the solid complexes was confirmed by X-ray diffraction patterns (XRD), differential scanning calorimetry (DSC), and infrared spectroscopy (IR). The kneading and freeze-drying methods were successful for obtaining the solid inclusion complexes with improved thermal stability.     

Solid-state characterization and dissolution properties of ezetimibe–cyclodextrins inclusion complexes

The objectives of this research were to prepare and characterize inclusion complex of Ezetimibe (EZE) with cyclodextrins (β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HPβ-CD)) and to study the effect of complexation on the dissolution rate of EZE, a water insoluble drug. Phase solubility curve was classified as A _P -type for both cyclodextrins, indicating the 2:1 stoichiometric ratio for β-CD–EZE and HPβ-CD – EZE inclusion complexes. The inclusion complexes in the molar ratio of 2:1 (β-CD–EZE and HPβ-CD–EZE) were prepared by various methods such as kneading, coevaporation and physical mixing. The molecular behaviors of drug in all samples were characterized by fourier-transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) studies. The results of these studies indicated that complex prepared by kneading and coevaporation methods showed inclusion of the EZE molecule into the cyclodextrins cavities. The highest improvement in in-vitro dissolution profiles was observed in complex prepared with hydroxypropyl-β-cyclodextrin using co-evaporation method. Mean dissolution time and similarity factor indicated significant difference between the release profiles of EZE from complexes and physical mixtures and from pure EZE.     

Enantioseparation of β-substituted tryptophan analogues with modified cyclodextrins by capillary zone electrophoresis

Direct capillary zone electrophoretic methods were developed for the separation of the enantiomers of unnatural β-substituted tryptophan analogues such as erythro- and threo-β-methyl-, β-2-propyl-, β-3-pentyl-, β-phenyl- and β-2,5-dimethoxyphenyltryptophan. Cyclodextrins (CDs) were chosen as chiral selectors because of their favorable properties (stability, commercial availability, low cost, UV transparency, inertness, etc.). Capillary zone electrophoresis was carried out using sulfopropylated-α-CD (SP2-α-CD), sulfopropylated-β-CD (SP2-β-CD) both with a degree of substitution of 2 moles/mole cyclodextrin, and sulfopropylated-β-CD (SP4-β-CD) with a degree of substitution of 4 moles/mole β-cyclodextrin. With this technique all compounds investigated are baseline resolved using different background electrolytes and chiral additives. The elution sequence was determined in all cases.     

Aggregation of cyclodextrins: An explanation of the abnormal solubility ofβ-cyclodextrin

-,- and -Cyclodextrins have been shown to exist as aggregates in solution bound together by a network of hydrogen bonds. Removal of this network by ionisation of the hydroxyl groups leads to a greatly increased solubility and removal of aggregation. The presence of aggregates in solution of structure breaking solutes in which the solubility of-cyclodextrin is greatly enhanced, leads to a proposal that the abnormally low solubility of-CD may be explained by the presence of aggregates and the unfavourable interaction of these aggregates with the hydrogen bonded structure of water.     

UV-induced self-assembly of the inclusion complexes formed between a long-chain photochromic spiropyran and cyclodextrins

Photochromic spiropyran with a long chain alkyl substitute can form axial complexes with α-, β-, and γ-cyclodextrin, respectively. The complexes show normal photochromism. The novel property of the colored forms of the inclusion complexes is that they can assemble into dimers at relatively low concentration or J-aggregates at relatively high concentration. For α-, β-, and γ-cyclodextrin, λ_(max) of the J-aggregates appear at 700 650, and 630 nm, respectively. The sizes of the cavities of cyclodextrins have very little effect on the spectra and decoloration kinetics of the dimers, but have great effects on the spectra of the J-aggregates. Unlike the charge transfer complex of Krongauz, the decoloration process of the dimers or J-aggregates cannot be described by an exponential or a two-exponential kinetics, but obey half-order kinetics very well. Another result that can be deduced from the kinetic analysis is that unlike the dimers formed in apolar solvents or in polymers, which consist of a color     

Pattern recognition methods as supplementary techniques for identification of salicylamide — cyclodextrins inclusion complexes

The objective of this study was to learn whether or not the pattern recognition methods, such as agglomerative cluster analysis (CA) and principal component analysis (PCA), can be used as supplementary techniques for identification of salicylamide (SAA) inclusion complexes with β-cyclodextrin (β-CD) and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD). To do this, phase-solubility of SAA in the presence of the cyclodextrins was studied by the Higuchi-Connors method, which showed that the cyclodextrins enhanced the solubility of SAA in water as compared to that of the drug. Next, the solid phase complexes of the drug with β-CD and HP-β-CD were prepared by using the coprecipitation, precipitation-evaporation, and kneading methods. Identification of the inclusion complexes was performed by using thermal analysis, infrared spectroscopy, and wide angle X-ray scattering. Two multivariate statistical methods, CA and PCA, were used as the supplementary techniques for identification of the inclusion complexes. The results of the statistical analysis have shown that CA and PCA are helpful for interpretation of the thermoanalytical and spectral data. Moreover, these methods enabled proper classification of the products in all doubtful cases. They can be used as supplementary techniques to verify the conclusions of the above-mentioned standard methods.      

The cavity size effect on the fluorescence properties of 4′-dimethylaminoacetophenone complexed with cyclodextrins

Fluorescence properties of excited 4^′-dimethylaminoacetophenone (DMAAP) complexed with α-, β-, and γ-cyclodextrins (CDs) were studied by means of steady state and time-resolved laser spectroscopy. The 1:2 DMAAP–α-CD and 1:1 DMAAP–β-CD complexes exhibited dual fluorescence in neutral aqueous solutions while only the fluorescence from the locally excited state was observed in the case of DMAAP complexed with γ-CD. The CD cavity size effect on the excited state dynamics of DMAAP–CD complexes was further discussed. It revealed that polarity effect introduced by the hydrophobic cavity is more important in controlling of the photochemistry of DMAAP than the restriction of molecular motion inside the CD cavity.     

Can the presence of chemically inert species modify the face selectivity in asymmetric induction by cyclodextrins?

Reduction of-cyclodextrin (-CD) aromatic ketone (acetophenone and acetonaphthones) inclusion compounds were carried out in the presence of a large number of chemically inert species as potential co-guests. In several cases, it was observed that stoichiometric molar ratios of these compounds to ketone significantly modify the chiral induction yielding the inverted alcohol enantiomer and increasing the face selectivity. The results were found to depend strongly on the respective structure and shape of both the ketone and the additive, and on the molar ratio of-CD:ketone:third compound. These observations suggest the formation of a three-component inclusion complex in which the geometry of binding of the substrate and its mobility are changed with respect to the binary system.     

“Surface water” and “strong-bonded water” in cyclodextrins: a Karl Fischer titration approach

Cyclodextrins are some of the most used carriers for bioactive compounds (as host–guest complex) and many factors influence the association–dissociation of this complex, some of them being related to hydrophobicity. In the solid state, cyclodextrins contain two types of water molecules: “surface” water molecules (especially close to the crystal surface) and “strong-bonded” water molecules (especially from the cyclodextrin cavity), but the classification is hard to do, and the concentration of these water molecules are relatively difficult to estimate by simple methods. In the present study we used the volumetric Karl Fischer titration to estimate these types of water molecules in cyclodextrins by means of the rate of water reaction (related to diffusion from cyclodextrin crystals). “Surface” water molecules are titrated with rates between 1.8–2.8 mM/s for α-cyclodextrin, while for β-cyclodextrin these rates are little bit higher (2.9–3.4 mM/s). The rates corresponding to “strong-bonded” water molecules are approximately tens fold lower (0.05–0.3 mM/s for α-cyclodextrin and 0.15–0.33 mM/s for β-cyclodextrin). The approximate ratio between “surface” and “strong-bonded” water molecules could also be estimated by this simple and rapid method.     

Host–guest complexation of a nitroheterocyclic compound with cyclodextrins: a spectrofluorimetric and molecular modeling study

Nitroheterocyclic compounds (NC) were candidate drugs proposed for Chagas disease chemotherapy. In this study, we investigated the complexation of hydroxymethylnitrofurazone (NFOH), a potential antichagasic compound, with α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), Hydroxypropyl-β-cyclodextrin (HP-β-CD), Dimethyl-β-cyclodextrin (DM-β-CD) and γ-cyclodextrin (γ-CD) by fluorescence spectroscopy and molecular modeling studies. Hildebrand–Benesi equation was used to calculate the formation constants of NFOH with cyclodextrins based on the fluorescence differences in the CDs solution. The complexing capacity of NFOH with different CDs was compared through the results of association constant according to the following order: DM-β-CD > β-CD > α-CD > HP-β-CD > γ-CD. Molecular modeling studies give support for the experimental assignments, in favor of the formation of an inclusion complex between cyclodextrins with NFOH. This is an important study to investigate the effects of different kinds of cyclodextrins on the inclusion complex formation with NFOH and to better characterize a potential formulations to be used as therapeutic options for the oral treatment of Chagas disease.     

Selective assembly of cyclodextrins on poly(ethylene oxide)–poly(propylene oxide) block copolymers

This paper presents a computational study on the formation of a molecular necklace formed by specific threading of cyclodextrins (CDs) on block copolymers. Structural as well as energetic principles for the selective complexation of - and -cyclodextrin with poly(ethylene oxide)–poly(propylene oxide) block copolymers (PEO–PPO) are elucidated considering a diblock copolymer of equimolecular composition (PEO)4–(PPO)4 as guest. A non-statistical distribution of CDs, i.e. -CDs primarily located on the PEO chain and -CDs on PPO blocks of the polymer, is based on a variety of structural features and energetic preferences considering both potential as well as solvation energies. This selectivity becomes already obvious considering 1:1 complexes between PEO and PPO monomers and the two CDs, but is increasingly evident when calculating higher order ensembles. Besides the host–guest interaction, docking between CDs themselves is an important, also non-statistical, prerequisite for the self-assembly of highly ordered tubes. The formation of intermolecular hydrogen bonds between adjacent CDs in a tubular aggregate gives an important contribution to the overall stability of the molecular necklace. The net effect, based on the preferential interaction between host and guest as well as between the host molecules themselves, results in the formation of a stable, highly ordered macromolecular, multicomponent aggregate.     

Inclusion of neutral guests by water-soluble macrocyclic hosts – a comparative thermodynamic investigation with cyclodextrins,calixarenes and cucurbiturils

Abstract

The driving forces of association between three different families of macrocycles as hosts, namely cyclodextrins (α-, β-, and γ-), p-sulfonatocalix[n]arenes (n = 4–6) as well as cucurbit[n]urils (n = 6–8), and three different bicyclic azoalkane homologues as guests, namely 2,3-diazabicyclo[2.2.1]hept-2-ene (DBH), 2,3-diazabicyclo[2.2.2]oct-2-ene (DBO) as well as 2,3-diazabicyclo[2.2.3]non-2-ene (DBN), were examined by means of calorimetric titrations, NMR spectroscopy and molecular dynamics simulation, all in aqueous solution. The small, spherical and uncharged guests preferably bind inside the cavities of the medium sized hosts. The inclusion complexation by β-cyclodextrin and p-sulfonatocalix[4]arene shows medium binding affinities (millimolar), while cucurbit[7]uril macrocycle shows very strong binding (micromolar). For all types of macrocycles, the complex formation is enthalpically driven (ΔH° < 0), accompanied by slightly unfavourable entropy changes (ΔS° < 0). The results are discussed in terms of the flexibility of the hosts, the hydrophobic character of their cavities and the release of high-energy water upon binding, and generalised by including two additional guests, the ketones cyclopentanone and (+)-camphor.     

NMR study of host–guest complexes of disulfonated derivatives of 9, 10-diphenylanthracene and corresponding endoperoxides with cyclodextrins

Disulfonated derivatives of 9,10-diphenyl anthracene (dsDPA) are known carriers of singlet oxygen. DsDPA and corresponding endoperoxides (dsDPAO₂) form host–guest complexes with native cyclodextrins (i.e. β-CD and γ-CD). The modes of host–guest interaction were studied by ¹H NMR and 2D-NMR (ROESY). Specific inclusions of phenyl groups of dsDPA/dsDPAO₂ into the cyclodextrin cavities were found for both β-CD and γ-CD. The mode of interaction depends on the size of the CD cavity and the position of the sulfonate group.     

Solvent effects on the complexation of 1-alkanols by parent and modified cyclodextrins. Calorimetric studies at 298 K

The formation of complexes of parent and alkylated cyclodextrins (CDs) with 1-heptanol and 1-octanol has been studied calorimetrically at 298 K in water and in concentrated aqueous solutions of urea. The forces involved in the association process are discussed in the light of the signs and values of the thermodynamic parameters obtained: association enthalpy, binding constant, Gibbs free energy, and entropy. It was inferred that: (i) in water, the formation of complexes for parent and substituted α-cyclodextrins (αCDs) is determined by enthalpy. For parent and substituted β-cyclodextrins (βCDs), instead, hydrophobic interactions are the prevailing forces determining complexation, as indicated by the small and negative or positive enthalpies and by the high and positive entropies. (ii) In urea, hydrophilic interactions are attenuated. The formation of complexes with alkylated CDs does not occur. (iii) The analysis of the thermodynamic properties confirms that inclusion is a process dominated by hydration phenomena. Modifications experienced by the solvent water in the hydration shells of the interacting substances upon association determine the formation of the complexes.     

Interaction of naproxen with α-, β-, and γ-hydroxypropyl cyclodextrins in solution and in the solid state

Solid combinations of naproxen with amorphous hydroxypropyl derivatives of -, -, and -cyclodextrin with an average substitution degree per anhydroglucose unit of 0.6 were investigated for thermal behaviour (differential scanning calorimetry), drug crystallinity (X-ray diffractometry), and dissolution rate (dispersed amount and rotating disc methods). Phase-solubility analysis and computer-aided molecular modelling were carried out to study the inclusion complexation of naproxen with hydroxypropyl cyclodextrins. The cavity size of the host is a selective factor for the solubilizing effect, complexing ability, and dissolution rate enhancement on naproxen, hydroxypropyl -cyclodextrin being markedly the most effective derivative. No relationship was found between the decrease in crystallinity of the drug dispersed in the amorphous carrier matrix and the geometrical features of the cyclodextrin macrocycle.