Complexation of natural and methylated β-cyclodextrins with long-chain Carboxylic acids in aqueous solutions. Calorimetric studies at 298 K

The formation of complexes between β-cyclodextrin or methyl-β-cyclodextrin and monocarboxylic acids from C₅ to C₁₂ has been studied calorimetrically at 298 K in aqueous buffer phosphate, pH 11.3. When a complex forms, calorimetry enables the calculation of both the enthalpy and the association constant, from which the Gibbs free energy and the entropy of the process can be obtained. The forces involved in the association process are then discussed in the light of the signs and values of the thermodynamic parameters obtained. For β-cyclodextrin, 1:1 inclusion complexes form, characterized by an irregular variation in the values of enthalpies, entropies and association constants at increasing alkyl chain length. A model is proposed to explain this unusual behaviour for acids longer than ten carbon atoms. The association involving methyl-β-cyclodextrin shows, instead, a regular variation of the thermodynamic parameters up to the C₁₂ term. An elongation of the cavity effect is discussed: the cavity behaves as it were deeper than that of the natural cyclodextrins. Association is characterized prevailingly by hydrophobic interactions; for the longer terms, the high and almost invariant entropic contribution determines the large association constants, notwithstanding the positive, unfavorable enthalpic contribution. This is an indication that the relaxation of water molecules from the hydrophobic hydration shells of the external methyl groups is the contribution that mainly determines the association process.     

Noncovalently-Bound Cyclodextrin Dimers and Related Compounds. (Review)

In the review noncovalently-bound cyclodextrin (CD) dimers, i. e., CD host-guest 2:1 complexes as well as CD self-assembled inclusion oligomers, are briefly characterized, showing methods of their investigations; the properties and possible applications of these species are also described. __________ Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1603–1624, November, 2005.     

Characterization of Alkane Diol-CD Complexes. Acid Denitrosation of N-Methyl-N-Nitroso-p-Toluenesulphonamide as a Chemical Probe

A study was carried out on the acid denitrosation of N-methyl-N-nitroso-p-toluenesulfonamide (MNTS) in mixed systems made up of linear (geminal and terminal) alkyl diols and β-cyclodextrin (CD). The alkyl diols used allowed us to vary the length of the hydrocarbon chain from 2 to 6 carbon atoms. The observed rate constant, k _obs, decreases in the presence of CD. The inhibition profile decreases as the as the number of carbons in the chain is increased. This behaviour can be interpreted as a consequence of a balance between the complexation processes of MNTS and the alkyl diols by the CD. At a constant CD concentration and increase in the diols concentration decreases the concentration of free cyclodextrin available to complex with MNTS molecules and therefore produces an increases in the observed rate constant. The results were interpreted in terms of two different models; trough the presupposition and non-presupposition of a stoichiometry for the CD-diols complex. Both models agreed quite well and allow us to determine the uncomplexed cyclodextrin concentration in each case as well as the stoichiometry of the complexes. The binding constant for both types of alkane diols increase with increasing the number of carbon in the chain. Besides, the binding constant of the α,ω-alkane diols is higher than for the analog α,β-alkane diols. One of the main consequences of this study is that the acid denitrosation of MNTS can be use to obtain the stochiometry of the CD-diol complexes and to monitor the free cyclodextrin concentration.Electronic Supplementary Material Supplementary material is available for this article at     

Sulphamethizole-Cyclodextrin-Hydroxy Propylmethyl Cellulose Multicomponent Complexes

The effect of cyclodextrin complexation of sulphamethizole (SM) was studied. Two systems were prepared with two cyclodextrin derivatives, β-cyclodextrin (BCD) and hydroxypropyl-β-cyclodextrin (HPBCD): binary complexes and multicomponent systems (cyclodextrins and a hydroxylpropylmethyl cellulose K4M). Inclusion complexes were prepared by freeze-drying and characterized by thermal analysis (DSC) and X-ray diffractometry. The presence of the polymer in the solution increases the effect of cyclodextrins – specially BCD – on the solubility of SM. In solid state, binary inclusion complexes enhance the dissolution behaviour of SM but, from the multi-component complexes, the polymer controls the release of the drug. This revised version was published online in August 2006 with corrections to the Cover Date.     

Electrochemical carboxylation of β-cyclodextrin/1-(3-phenoxyphenyl)-1-chloroethane inclusion complex on a glassy-carbon cathode in anhydrous dimethylformamide

Inclusion complexes of β-cyclodextrin with 1-(3-phenoxyphenyl)-1-chloroethane in the “guest-host” molar ratio of 1: 2 are synthesized, isolated, and characterized. It is shown that preparative electrocarboxylation of β-cyclodextrin/1-(3-phenoxyphenyl)-1-chloroethane inclusion complex on a glassy-carbon cathode in dimethylformamide leads to the formation of S-form of 2-(3-phenoxyphenyl)propionic acid (S-Phenoprofen) with an optical yield of ～20%. In addition to the acid, a dimer of electrochemically generated intermediates forms.     

Calorimetry to Evaluate Inclusion Mechanism in the Complexation Between 2-hydroxypropyl-β-cyclodextrin and Barbiturates in Aqueous Solution

Two different types (structures) of inclusion complexes with a 1:1 stoichiometry between barbiturates and 2-hydroxypropyl-β-cyclodextrin (HPCyD) were realized in aqueous solution using isothermal titration calorimetry and molecular dynamics simulation. The first type of complex with a higher association constant was entropy driven and the substituent R ₂ was inserted into the HPCyD cavity by hydrophobic interaction. The barbituric acid ring contributed to the second type of complex, which was characterized by large negative values of ΔH and small positive ΔS reflecting van der Waals interaction and/or hydrogen bonding formation between the hetero atoms in the barbituric acid ring and the secondary hydroxyl groups of HPCyD. This revised version was published online in July 2006 with corrections to the Cover Date.     

Influence of the Cyclodextrin Size Cavity in the Complexation of Tetrahydroharmane

The interactions between cyclodextrins and tetrahydroharmane, 1-methyl-1,2,3,4-tetrahydro-9H-pyrido/3,4-b/indole, have been investigated in pH 10.1 aqueous media. Absorption and fluorescence studies, together with lifetime measurements show that tetrahydroharmane forms ground state inclusion complexes with -CD and -CD but not with -CD. Steady state experiments detect only one kind of tetrahydroharmane--CD complex, whereas time resolved measurements reveal the existence of two different types of 1:1 association complexes. The results in -CD are very similar to those in -CD, but the interactions are much weaker.     

Manufacturing and Assessing the New Orally Disintegrating Tablets,Containing Nimodipine-hydroxypropyl-β-cyclodextrin and Nimodipine-methyl-β-cyclodextrin Inclusion Complexes

The aim of the present study was to manufacture new orally disintegrating tablets containing nimodipine–hydroxypropyl-β-cyclodextrin and nimodipine–methyl-β-cyclodextrin inclusion complexes. For obtaining a better quality of the manufactured tablets, three methods of the preparation of inclusion complexes, in a 1:1 molar ratio, were used comparatively; namely, a solid-state kneading method and two liquid state coprecipitation and lyophilization techniques. The physical and chemical properties of the obtained inclusion complexes, as well as their physical mixtures, were investigated using Fourier transformed infrared spectroscopy, scanning electron microscopy, X-ray diffraction analyses, and differential scanning calorimetry. The results showed that the lyophilization method can be successfully used for a better complexation. Finally, the formulation and precompression studies for tablets for oral dispersion, containing Nim–HP-β-CD and Nim–Me-β-CD inclusion complexes, were successfully assessed.     

Cations in a Molecular Funnel: Vibrational Spectroscopy of Isolated Cyclodextrin Complexes with Alkali Metals

The benchmark inclusion complexes formed by α‐cyclodextrin (αCD) with alkali‐metal cations are investigated under isolated conditions in the gas phase. The relative αCD‐M⁺ (M=Li⁺, Na⁺, K⁺, Cs⁺) binding affinities and the structure of the complexes are determined from a combination of mass spectrometry, infrared action spectroscopy and quantum chemical computations. Solvent‐free laser desorption measurements reveal a trend of decreasing stability of the isolated complexes with increasing size of the cation guest. The experimental infrared spectra are qualitatively similar for the complexes with the four cations investigated, and are consistent with the binding of the cation within the primary face of the cyclodextrin, as predicted by the quantum computations (B3LYP/6‐31+G*). The inclusion of the quantum‐chemical cation disrupts the C₆ symmetry of the free cyclodextrin to provide the optimum coordination of the cations with the ‐CH₂OH groups in C₁, C₂ or C₃ symmetry arrangements that are determined by the size of the cation.     

A novel differential scanning calorimetric method to study the complexation of β-cyclodextrin with steroid in solid state

This communication demonstrates that, by simply minotiring the evaporation of water molecules included in β-cyclodextrin cavity, complexation of β-cyclodextrin with steroid in solid state can be studied. The reported method is simple, rapid and novel.     

Cyclodextrin-based Nanosponges for Drug Delivery

Nanosponges were prepared from β-cyclodextrins as nanoporous materials for possible use as carriers for drug delivery. The structure of β-cyclodextrin-based nanosponges was principally investigated by FT-IR, DSC and RX analyses. Sizes, morphology and toxicity were also examined. The capacity of the nanosponges to incorporate molecules within their structure was evaluated using drugs with different structures and solubilities. The nanosponges were found capable of carrying both lipophilic and hydrophilic drugs and of improving the solubility of poorly water-soluble molecules.     

Synthesis and electrochemical behavior of inclusion complexes based on β-cyclodextrin and alkylaromatic compounds: Electrochemical carboxylation of the β-cyclodextrin-1-(4-isobutylphenyl)ethylchloride inclusion complex on a glassy-carbon cathode in anhydrous dimethylformamide

Inclusion complexes of β-cyclodextrin with alkylaromatic compounds β-cyclodextrin-1-(4-isobutylphenyl)ethylchloride in the “guest-host” molar ratio of 1 : 2 and β-cyclodextrin-methyl-(4-isobutylphenyl)ketone in the “guest-host” molar ratio of 1 : 1, are synthesized, isolated, and characterized. It is shown that preparative electrocarboxylation of the inclusion complex β-cyclodextrin-1-(4-isobutylphenyl)ethylchloride on a glassy-carbon cathode with a dissolving magnesium anode in dimethylformamide affords S-forms of 2-(4-isobutylphenyl)propionic acid (S-Ibuprofen) in a high enantiomeric excess (97%). In addition to the acid, a dimer and a hydride form from the corresponding intermediates.     

Complexation of Fluvastatin Sodium with β-Cyclodextrin: NMR Spectroscopic Study in Solution

¹H NMR spectroscopic study of fluvastatin sodium (FLU), β-Cyclodextrin (β-CD) and their mixtures confirmed the formation of FLU/β-CD inclusion complex in solution. The stoichiometry of the complex was determined to be 1:1 and the overall binding constant (K _s) was calculated to be 340 M⁻¹. Two dimensional COSY, ROESY and DEPTO experiments were performed for the unambiguous assignment of aromatic proton resonances and it was found that two isomeric forms of FLU are present in solution. It was confirmed with the help of ROESY spectral data that only F-substituted aromatic ring penetrates the β-CD cavity and there is chiral differentiation by the β-CD as one of the isomer binds more strongly, which is indicated by the intensity of correlation peaks. The mode of penetration of the guest into the β-CD cavity was also established and structure of the complex has been proposed.     

NMR Investigations of Inclusion Complexes between β-Cyclodextrin and Naphthalene/Anthraquinone Derivatives

A ¹H and ¹³C NMR study on the inclusion complex between β-cyclodextrin and naphthalene, 1,5-dichloronaphthalene and 9,10-anthraquinone was carried out in order to define the stoichiometry of the association and the possible conformations. The upfield variation of the chemical shifts from the protons locate inside the cavity (H-3, H-5) coupled with the downfield variation of the other protons which locate outer sphere of the β-CD (H-1, H-2, H-4 and H-6,6′) provided clear evidence of the inclusion phenomena. The NMR spectra revealed the formation of 1:1 inclusion complex in which aromatic ring of the guest is tightly held by the host cavity. The signal degeneration of ¹H & ¹³C NMR spectra still exist for naphthalene and 1,5-dichloronaphthalene upon complexation revealed a symmetrical conformation of the guest molecules in the cavity of β-cyclodextrin, respectively. However, in 9,10-anthraquinone, the signal degeneration of ¹H & ¹³C NMR spectra was removed upon complexation which revealed an unsymmetrical conformation of the guest molecule inside the cavity. According to theoretical calculations and NMR studies, the possible conformations of the inclusion complexes are given here.     

Prominent Solubilizing Effect of 2-Hydroxypropyl-β-cyclodextrin on a New Thiazolidine Derivative (FPFS-410) with Antidiabetic and Lipid-lowering Activities through Inclusion Complex Formation

2-(N-Cyanoimino)-5-{(E)-4-styrylbenzylidene}-4-oxothiazolidine (FPFS-410) is a newly synthesized thiazolidine derivative having not only antidiabetic but also lipid-lowering activities. However, this compound has an extremely low aqueous solubility (2.8×10⁻⁸ M in phosphate buffer at 25 °C). In this study, we attempted to improve the solubility of FPFS-410 in water, by means of the complexation with 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD). Further, the interaction of FPFS-410 with HP-β-CyD in 50% v/v methanol/water mixed solution was investigated by ultraviolet and ¹H-nuclear magnetic resonance (NMR) spectroscopic methods, because the solubility of FPFS-410 in water was too low to study quantitatively the interaction. The results of the solubility method indicated that HP-β-CyD had a markedly high solubilizing ability to FPFS-410, e.g., the solubility of the compound was increased 200,000-fold by the addition of 40 mM HP-β-CyD. The continuous variation plot of the FPFS-410/HP-β-CyD system in 50% v/v methanol/water solution gave a maximum at a host/guest molar ratio of 1:1. ¹H-NMR spectroscopic studies suggested that the stilbene moiety of FPFS-410 is preferably included in the HP-β-CyD cavity to form the 1:1 complex in 50% v/v methanol/water solution. The present results suggest that HP-β-CyD is useful for improvement of the oral bioavailability of FPFS-410.     

Spectral Studies on the Cyclodextrin Inclusion Complexes of Toluidine Blue O and Meldola's Blue in Aqueous Solution

The absorption and emission spectral properties of toluidine blue O (TBO) and Meldola's blue (MDB) in the presence of cyclodextrins (CDs) were studied. Formation of 1 : 1 and 1 : 2 (CD-Dye) inclusion complexes were observed with -CD and -CD, respectively. An increase in the emission intensity was noticed in the presence of -CD due to the formation of 1 : 1 (CD-Dye) inclusion complexes. However, a decrease in the emission intensity was observed in the presence of -CD due to the formation of 1 : 2 (CD-Dye) inclusion complexes. Dimerization of dye molecules in the presence of -CD lead to a decrease in the emission intensity. The formation constants for the 1 : 1 and 1 : 2 (CD-Dye) inclusion complexes were calculated.     

Experimental and Theoretical Study on the Inclusion Capability of a Fluorescent Indolizine β-Cyclodextrin Sensor Towards Volatile and Semi-volatile Organic Guest

Inclusion equilibria of a new fluorescent indolizine modified β-cyclodextrin were studied in aqueous solution to evaluate its use as a fluorescent chemo-sensor for volatile organic compounds (VOCs). The host compound shows a decrease of the fluorescence intensity by adding adamantanol, benzene, toluene, phenol and p-cresol as guest. The sensing parameter (ΔI/I ₀) was used to show the sensing ability of the host. The formation constant values measured using a spectral displacement method and a specific algorithm treatment are reported. Although the guest binding ability of the sensor is not enhanced by the existence of the hydrophobic cap, this new cyclodextrin sensor shows a very strong sensing ability. The experimental values of the constants were in good agreement with the computed complexation energies, ΔE, from molecular mechanics modelling of the inclusion process.     

Inclusion Complex of Podophyllotoxin with γ‐Cyclodextrin: Preparation,Characterization, Anticancer Activity,Water‐Solubility and Toxicity

An inclusion complex of podophyllotoxin (PPT) with γ‐cyclodextrin (γ‐CD) was prepared. The behavior, characterization, and water solubility of the inclusion complex were carefully investigated via fluorescence spectroscopy, thermogravimetry, differential scanning calorimetry, X‐ray diffraction analysis, and ¹H and 2D nuclear magnetic resonance spectroscopy. Furthermore, antitumor activity to human cancer lines and toxicity in mice were studied. Results showed that the inclusion complex formed in a 1:1 ratio with a considerable apparent stability constant K_s (4245.5 L·mol^?1). Water solubility was considerably improved. In addition, the anticancer activity of the inclusion complex was better than that of cis‐platinum (DDP, positive control). Most importantly, the toxicity of podophyllotoxin inclusion complex reduced and became more safety to mice which will be great valuable to research its applications as a kind of antitumor drug to human in the further.     

Molecular Mechanics Study of the Inclusion Complexes of Some 1,2,4-Oxadiazole Derivatives of 3,3′-Bis (1,2,4-Oxadiazol-5(4H)-one) with β-Cyclodextrin

Molecular mechanics calculations were employed to study the inclusion of some 1,2,4-oxadiazol derivatives in β-cyclodextrin in vacuum and in the presence of water as a solvent using MM + force field. The driving forces for complexation in both environments are dominated by nonbonded van der Waals host–guest interactions with little electrostatic contribution. Among 1,2,4-oxadiazole derivatives investigated in this work, 3,3′-bis(1,2,4-oxadiazol-5(4H)-one) (H₂OD) forms the least stable 1:1 complex and the stability increases as the chain length increases.