Cyclodextrin Inclusion Complexes Research Articles

Ultrafast reaction dynamics of auramine O in a cyclodextrin nanocavity

The effect of confinement on a barrierless ultrafast chemical reaction is investigated through the ultrafast torsional reaction of the dye Auramine O bound in a cyclodextrin (CD) inclusion complex. The rate of the barrierless reaction is inferred from the ultrafast time evolution of the fluorescence emission. The rate is decreased on formation of the complex but in a highly size dependent fashion, with only β-CD yielding a significant effect. This reflects both the formation constant for the AuO-CD complex and the nature of the confinement. Even in the case of β-CD the effect of adsorption was smaller than was observed for adsorption of the same dye at the surfactant water interface. This shows that the structure and nature of the inclusion complex and is more important in determining the degree of rate retardation than the simple fact of confinement.

An alternative form of melarsoprol in sleeping sickness

Human African trypanosomiasis (HAT), or sleeping sickness, is a major threat to human health throughout sub-Saharan Africa. Almost always fatal if untreated or inadequately treated, a commonly used drug for treating late-stage HAT, and the only drug for late-stage Trypanosoma brucei rhodesiense, is intravenous melarsoprol, which kills 5% of patients receiving it. Melarsoprol cyclodextrin inclusion complexes have been tested in a highly reliable mouse model of HAT. These complexes increase the oral bioavailability of melarsoprol making them effective orally and both curative and nontoxic in doses that are equivalent to those of intravenous melarsoprol. It is argued that a small clinical trial of this drug in HAT is justified to potentially improve the outcome of patients with late-stage rhodesiense disease.

Factors affecting solubilization of a poorly soluble novel tubulin-binding agent

JCA112 is a novel tubulin-binding agent with limited aqueous solubility and high hydrophobicity. Three strategies; cyclodextrin inclusion complexation, solid dispersion (SD) formation, and liposome incorporation were evaluated to enhance the solubility of JCA112. Phase-solubility studies were carried out with hydroxypropyl β-cyclodextrin (HPβCD), SDs were prepared by solvent evaporation method and liposomes were prepared by thin-film hydration method. Saturation solubility of the prepared formulations resulted in a significant increase in the solubility of JCA112 by all three methods. Cyclodextrin complexation resulted in a higher order complex formation increasing the aqueous solubility by 30-fold up to 105 μg/mL. Amongst the selected polymers, Poloxamer 188 (Pluronic® F68) was the most effective polymer in enhancing the aqueous solubility via SD, resulting in an equilibrium solubility of 50 μg/mL, independent of the drug loading. Liposomes were the most effective amongst all three techniques, with a saturation solubility of 1.8 mg/mL contributing to greater than 500-fold increase in the solubility of JCA112. The solubility enhancement by liposome was directly proportional to the drug loading. All the three strategies were successful in enhancing the solubility of the drug. Solubility enhancement by the three techniques can be attributed to the geometry/structure and the lipophilicity of the drug.

Comparative Analysis of Chiral Drugs in View of Chemometrics

With the development of methods for obtaining chiral compounds as potential drugs, there is also need to develop analytical methods for the separation of both enantiomers. Keeping in mind that the physical and chemical properties of both enantiomers are identical, their different nature will only be revealed in a chiral environment that is appropriately designed. Physicochemical systems can be used to predict the differences in biological activity of both enantiomers. The complexity of the problem requires the use of additional tools, which are various chemometric methods. This paper reviews the application of chemometry in the analysis of chiral drugs and discusses the effects of a combination of chromatographic, electrophoretic, and spectroscopic analysis (UV-Vis absorption spectroscopy, and near-IR spectroscopy aided by cyclodextrin inclusion complexes) with chemometrics for improving the methods of enantioseparation (experimental design), explaining the mechanisms of behavior and chiral recognition (quantitative structure-enantioselective retention relationships) and indicating chiral purity (enantiomeric excess).

Polymers coalesced from their cyclodextrin inclusion complexes: What can they tell us about the morphology of melt‐crystallized polymers?

AbstractCyclodextrins (CDs) are cyclic polysaccharides with nano‐size, largely hydrophobic cavities, and exteriors covered with hydrophilic hydroxyl groups, making them water soluble. Threading and filling their cavities with polymer chains produces noncovalently bonded crystalline inclusion compounds (ICs). In this study, we formed fully covered, stoichiometric ICs between guest poly(L‐lactic acid), poly(ε‐caprolactone), and nylon‐6 chains and host α‐CD. Coalesced samples of all three polymers were obtained after appropriately removing the stacked α‐CD host channels from their ICs. Distinct differential scanning calorimetriy (DSC) thermograms were observed for as‐received and coalesced samples, with the coalesced samples crystallizing faster at higher temperatures from their melts, and this distinction was maintained even after extensive, long‐time melt‐annealing (hours, days, and weeks). We believe this is due to the largely unentangled chains with extended conformations that are more densely packed in the initially coalesced samples. When small amounts (∼2 wt %) of the coalesced polymers are used as self‐nucleating agents for their as‐received samples, the resulting self‐nucleated samples show DSC thermograms similar to those of the neat coalesced polymers, including their long‐time stability to melt‐annealing. Coalesced polymers, whether neat or in samples they self‐nucleate, may conserve their organization in the melt (largely extended and unentangled chains) for long periods, because the process of entangling the many chains influenced by a single initially extended unentangled coalesced chain, after it randomly coils, is extremely sluggish. By contrast, in melt‐crystallized or solution‐cast samples, polymer chains generally become fully randomly coiled, interpenetrate, and entangle after being heated and held in their melts for comparatively much shorter times. For example, we have recently observed (DSC) that ultra high molecular weight, gel‐spun spectra polyethylene (PE) fibers® did not conserve or retain any memory of their as‐spun and highly drawn semicrystalline morphology even after spending as little as 2 min in the melt. As a consequence of the comparison to the behavior of coalesced polymer melts, we believe that polyethylene chains in Spectra fibers® must be at least intimately dispersed within their crystalline regions, and likely partially coiled and entangled in their noncrystalline regions, thereby facilitating their rapid transformation into a full entanglement network of randomly coiling chains in the melt. © 2012 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys, 2012

Electrochemically sensitive supra-crosslink and its corresponding hydrogel

In this work, through inclusion complexation between cyclodextrin (CD) host and ferrocene (Fc) guest, a monomer with double bond was incorporated to the surface of CdS quantum dot (QD). The obtained supra-structure could act as a supra-crosslink (Fc-SCL) in its copolymerizing with N,N-dimethylacrylamide (DMA) leading to a hybrid supramolecular hydrogel (Fc-Gel). Fc-SCL inherited satisfactory electrochemical activity from Fc. When the weight percentage of Fc-SCL in Fc-Gel was increased, an apparent increase of elastic modulus (G′) was observed. Furthermore, Fc-Gel also exhibited good fluorescent properties. It was also demonstrated that the inclusion complexation of CD and Fc played a crucial role in constructing the hydrogel; therefore, this Fc-Gel was an organic-inorganic hybrid hydrogel induced by supramolecular interaction.

シクロデキストリンを用いた水溶性1'-Acetoxychavicol Acetate複合体の作製及び抗腫瘍効果に関する研究

シクロデキストリンを用いた水溶性1'-Acetoxychavicol Acetate複合体の作製及び抗腫瘍効果に関する研究

Effect of α- and β-cyclodextrins on the intramolecular charge transfer and intramolecular proton transfer fluorescence of methyl o-hydroxy p-dimethylaminobenzoate

The influence of α- and β-cyclodextrins on the spectral characteristics of methyl o-hydroxy p-dimethylaminobenzoate has been studied using steady-state and time-resolved spectroscopic technique. The stoichiometries and equilibrium constants of the solute molecule–cyclodextrin inclusion complexes have been determined by the steady-state fluorescence measurements. Nonlinear least-squares regression analysis indicates that both 1:1 and 1:2 inclusion complexes were formed between studied compound and α- and β-cyclodextrins. The contribution of the fluorophore in free, 1:1, and 1:2 complexes was calculated for a particular concentration of α- and β-CD. Additionally, the location of the fluorophore inside the cavity was reported, with regard to the intra- and intermolecular proton transfer and intramolecular charge transfer processes.

Supramolecular effects on the antifungal activity of cyclodextrin/di-n-decyldimethylammonium chloride mixtures

Candidiasis infections are growing problem worldwide especially for the immunocompromised individuals. Di-n-decyldimethylammonium chloride is one of the most common antifungal agents used to clean medical devices. The current study examines the antifungal mechanism of di-n-decyldimethylammonium cation and its cyclodextrin inclusion complexes. Depending on the type of cyclodextrin (α-, β- or γ-CD), inclusion complexes can be as active as ammonium alone in terms of microorganism death (fungicidal activity). Moreover, with β-CD inclusion complexes, synergism is observed against fungus growth (fungistatic activity). Based on molecular dynamics, we propose a mechanism supported by cell number, selective electrode and ζ-potential measurements as a function of time. The mechanism involves four steps: (i) the positively-charged complex diffuses through the solution, (ii) it adsorbs onto the fungus membrane surface by electrostatic interaction, (iii) then it dissociates and the ammonium inserts in the microorganism membrane, and (iv) the change of the cell surface charge induces cell lysis.

Isothermal titration calorimetry (ITC) study of natural cyclodextrins inclusion complexes with drugs

Isothermal titration calorimetry (ITC) was used to characterize inclusion complex formation of natural cyclodextrins (α- and β-cyclodextrin) with three drugs ((+)brompheniramine, (±)brompheniramine, cyclopentolate) in aqueous solutions. ITC measurements were carried out at 298.15 K on a Microcal OMEGA ultrasensitive titration calorimeter (MicroCal Inc.). The experimental data were analyzed on the basis of the model of a single set of identical sites (ITC tutorial guide). β-CD forms inclusion complexes of stoichiometry 1:1 with the all investigated drugs. In turn, smaller molecule of α-CD forms inclusion complexes of two different stoichiometry: with bigger molecules ((+)brompheniramine and (±)brompheniramine) of a stoichiometry 2:1 and with smaller molecules (cyclopentolate) of a stoichiometry 1:2. Based on the experimental values of equilibrium constant (K) and enthalpy of complex formation (ΔH), the Gibbs energy of complex formation (ΔG), and the entropy of complex formation (ΔS), have been calculated, for all the investigated systems. Obtained results showed that complex formation of β-CD (bigger molecule with wider cavity compared to β-CD) with both (+)brompheniramine, (±)brompheniramine, and cyclopentolate is enthalpy driven while complexes of α-CD with the all investigated drugs are enthalpy-entropy stabilized. This indicated that the difference in the cavity dimensions is reflecting in different driving forces of complex formation and binding modes what resulted in different stoichiometry of the obtained inclusion complexes.

Enhanced dissolution, stability and physicochemical characterization of ATRA/2-hydroxypropyl-β-cyclodextrin inclusion complex pellets prepared by fluid-bed coating technique

The aim of this work was to prepare stable all-trans-retinoic acid (ATRA)/2-hydroxypropyl-β-cyclodextrin (HPCD) inclusion complex pellets with industrial feasible technology, the fluid-bed coating technique, using PVP K30 simultaneously as binder and reprecipitation retarder. The coating process was fluent with high coating efficiency. In vitro dissolution of the inclusion complex pellets in 5% w/v Cremopher EL solution was dramatically enhanced with no reprecipitation observed, and significantly improved stability against humidity (92.5% and 75% RH) and illumination (4500 lx ± 500 lx) was achieved by HPCD inclusion. Differential scanning calorimetry and powder X-ray diffractometry confirmed the absence of crystallinity of ATRA. Fourier transform-infrared spectrometry revealed interaction between ATRA and HPCD adding evidence on inclusion of ATRA moieties into HPCD cavities. Solid-state 13C NMR spectrometry indicated possible inclusion of ATRA through the polyene chain, which was the main reason for the enhanced photostability. It is concluded that the fluid-bed coating technique has the potential use in the industrial preparation of ATRA/HPCD inclusion complex pellets.

Encapsulation of vanillin/cyclodextrin inclusion complex in electrospun polyvinyl alcohol (PVA) nanowebs: Prolonged shelf-life and high temperature stability of vanillin

► Encapsulation of vanillin/CD-IC in PVA nanowebs was achieved via electrospinning. ► PVA/vanillin/CD-IC nanowebs show prolonged shelf-life and high temperature stability. ► The prolonged shelf-life of vanillin was significantly dependent on the CD type. ► PVA/vanillin/γ-CD-IC nanoweb effectively stabilized vanillin compared to α-CD and β-CD. We produced functional nanowebs, containing vanillin, having prolonged shelf-life and high temperature stability facilitated by cyclodextrin (CD) inclusion complexation. Polyvinyl alcohol (PVA) nanowebs incorporating vanillin/cyclodextrin inclusion complex (vanillin/CD-IC) were produced via electrospinning technique. The vanillin/CD-IC was prepared with three types of CDs; α-CD, β-CD and γ-CD to find out the most favourable CD type for the stabilization of vanillin. PVA/vanillin/CD-IC nanofibres, having fibre diameters around ∼200 nm, were successfully electrospun from aqueous mixture of PVA and vanillin/CD-IC. Our results indicated that vanillin with enhanced durability and high temperature stability was achieved for PVA/vanillin/CD-IC nanowebs due to complexation of vanillin with CD, whereas the PVA nanofibres without CD-IC could not effectively preserve the vanillin. Additionally, we observed that PVA/vanillin/γ-CD-IC nanoweb was more effective for the stabilization and slow release of vanillin suggesting that the strength of interaction between vanillin and the γ-CD cavity is stronger when compared to α-CD and β-CD.

Thermodynamic properties of inclusion complexes of α-cyclodextrin + aliphatic nitriles (H(CH2) n CN: n = 1–8) in aqueous solution

In order to investigate the contribution of the hydrophilic parts of guest molecules of aliphatic complexes to the inclusion reaction, the thermodynamic properties of inclusion complexes of cyclodextrin (α-CD) with aliphatic nitriles [H(CH2) n CN: n = 1–8] into the α-CD cavity in dilute aqueous solutions were measured by a micro-calorimeter at 298.15 K. The thermodynamic properties of inclusion for the octane nitrile system were different from those of others. The inclusion process of aliphatic nitriles to α-CD has two kinds of major driving force of enthalpy and entropy driven inclusion. The interaction energies of inclusion complexes of α-CD and aliphatic nitriles were determined by DFT calculation (B3LYP/6-31++G (d,p)) in water and compared with the experimental results. DFT calculations were performed on the inclusion complexes of α-CD with seven nitriles of each conformer. Both the gas phase interaction and solvent effect were taken into consideration. Also non-polar interactions between aliphatic nitriles + α-CD in aqueous solution were calculated and herein the inclusion energy is discussed.

Vesicles Prepared from Inclusion Complexes Between Cyclodextrins and Ethyl Benzoate

Ethyl benzoate was found to complex with cyclodextrins in formation of vesicles for the first time. These vesicles were characterized by transmission electron microscopy and dynamic light scattering. The complex stoichiometry, the stability constant and conformations of ethyl benzoate · cyclodextrins in aqueous solution were investigated by ultraviolet and nuclear magnetic resonance analyses. The vesicle system was prepared without complicated synthesis. This kind of vesicles prepared by cyclodextrin inclusion complexes could be applied in many fields.

Preparation of Natural Borneol/2-Hydroxypropyl-β-cyclodextrin Inclusion Complex and Its Effect on the Absorption of Tetramethylpyrazine Phosphate in Mouse

Natural borneol (NB)/2-hydroxypropyl-β-cyclodextrin (HP-β-CD) inclusion complex has been prepared, and characterized by differential scanning calorimetry (DSC), X-ray diffractometry (XRD) and Fourier transform infrared spectroscopy (FT-IR). The phase solubility and release of NB, and its effect on the absorption of tetramethylpyrazine phosphate (TMPP) in mice were also measured. The results demonstrated that NB could be efficiently loaded into HP-β-CD to form an inclusion complex at a mass ratio of 1 : 6, and the inclusion complex had different physicochemical characteristics from free NB. The profile of phase solubility displayed a typical A(L)-type, indicating the formation of 1 : 1 stoichiometric inclusion complex. Additionally, the stability of the inclusion complex was greatly improved compared with that of NB. The results of absorption of TMPP in mouse indicated that NB/HP-β-CD enhanced the absorption of TMPP and the concentration of TMPP in brain tissue, especially in the early period. Both TMPP plasma and brain concentration-time courses in mice were fitted to open two-compartment model with first-order absorption after oral administration of TMPP with NB/HP-β-CD. However, the use of NB/HP-β-CD did not change the in vivo behavior of TMPP. Our results suggest the application potential of NB/HP-β-CD inclusion in pharmaceutics.

Investigation on Dissolution Pattern and Mathematical Modeling of Drug Release of UDCA by Complextaion with b-Cyclodextrin-Choline Dichloride Coprecipitate

The objective of the present investigation was to study the effect of presence of choline dichloride (CDC) in β-cyclodextrin (β-CD) on in vitro dissolution of Ursodeoxycholic acid (UDCA) from molecular inclusion complexes. The molecular inclusion complexes of UDCA with β-CD coprecipitated with CDC were prepared using kneading method. In vitro dissolution of pure drug, physical mixtures and cyclodextrin inclusion complexes (UDCA-β-CD- CDC) were carried out. Molecular inclusion complexes of Ursodeoxycholic acid with coprecipitated β-CD showed considerable increase in the dissolution rate in comparison with physical mixture and pure drug in 0.1 N HCl, pH1.2 and phosphate buffer, pH 7.4. Inclusion complexes with 1:2M ratio showed maximum dissolution rate in comparison to other ratios. FT-IR spectroscopy and differential scanning calorimetry studies indicated no interaction between UDCA and β-CD-CDC in complexes in solid state. Dissolution enhancement was attributed to the formation of water soluble inclusion complexes with the precipitated form of β-CD. The in vitro release from all the formulations was best described by first order kinetics followed by Higuchi release model. In conclusion, dissolution of Ursodeoxycholic acid can be enhanced by using the β-CD-CDC coprecipitate as a host st molecolec.

Preparation, characterization and in vitro dissolution study of Nitrazepam: Cyclodextrin inclusion complex

The objectives of this research were to prepare and characterize inclusion complexes of Nitrazepam with Hydroxypropyl-β-cyclodextrin (HPβCD) and Sulfobutyl ether β-cyclodextrin (SBEβCD) to study the effect of complexation on the dissolution rate of Nitrazepam, a water-insoluble drug. The phase solubility profile of Nitrazepam with Hydroxypropyl- β-cyclodextrin and Sulfobutyl ether β-cyclodextrin was an AP-type, indicating the formation of 2:1 stoichiometric inclusion complexes. Gibbs free energy values were all negative, indicating the spontaneous nature Nitrazepam solubilization and their value decreased with increase in the cyclodextrin concentration, demonstrating that the reaction conditions became more favorable as the concentration of cyclodextrins increased. Complexes of Nitrazepam were prepared with cyclodextrin using various methods such as physical mixing, kneading, spray-drying and lyophilization. The complexes were characterized by Differential scanning calorimetry, Fourier-transform infrared, scanning electron microscopy and powder X-ray diffraction studies. These studies indicated that a complex prepared by lyophilization had successful inclusion of the Nitrazepam molecule into the cyclodextrin cavity. Complexation resulted in a marked improvement in the solubility and wettability of Nitrazepam. Among all the samples, a complex prepared with Sulfobutyl ether β-cyclodextrin by lyophilization had the greatest improvement in the in vitro rate of Nitrazepam dissolution. The mean dissolution time for Nitrazepam decreased significantly after preparing complexes. The similarity factor indicated a significant difference between the release profiles of Nitrazepam from complexes, physical mixtures and plain Nitrazepam. To conclude that, the tablets containing complexes prepared with Cyclodextrins had significant improvement in the release profile of Nitrazepam as compared to tablets containing Nitrazepam without cyclodextrin.

A solid-state study of the inclusion of endosulfan in native and derivatised cyclodextrins using X-ray diffraction and thermoanalytical methods

Endosulfan is a highly toxic insecticide used in several countries and known to be relatively persistent in the environment. This recently banned agrochemical is capable of forming solid-state inclusion complexes with both native and derivatised cyclodextrins (CDs). Differential scanning calorimetry and powder X-ray diffraction (PXRD) techniques were used to confirm complexation of β-CD, γ-CD and randomly methylated β-CD (RAMEB) with the technical 7α:3β isomeric sample of endosulfan. The PXRD traces obtained for the inclusion complexes of the native CDs (β-CD and γ-CD) with endosulfan match those of other isostructural CD inclusion complexes. The single crystal X-ray structure of the complex formed between heptakis(2,6-di-O-methyl)-β-CD (DIMEB) and the β-endosulfan isomer is presented and shown to have a novel packing arrangement. The implications of the encapsulation of endosulfan in CDs are discussed with reference to the potential for sequestering the insecticide from contaminated areas.

Effect of Ultra-High Pressure on the Characterization of Ursolic Acid/β-Cyclodextrin Inclusion Complex

To study the characterization of ursolic acid (UA) and β- cyclodextrin(β-CD) inclusion complex which prepared by ultra-high pressure method. Inclusion complex of UA /β-CD was prepared at 100MPa and 500MPa. The inclusion complex was characterized by IR spectra, X-ray diffraction, Differential scanning calorimetry and Scanning electron microscope. It was testified that the inclusion complex was formed between β-CD and UA at ultra-high pressure conditions.

Formulation and Evaluation of Thienorphine Hydrochloride Sublingual Delivery System

Thienorphine hydrochloride (ThH) is a highly insoluble and readily metabolized partial-opioid agonist. It is used for the treatment of pain and heroin addiction. This study aimed to formulate and evaluate sublingual delivery systems containing ThH. Dimethyl-β-cyclodextrin (DM-β-CD) can enhance the solubility and permeability of hydrophobic drugs. In this paper, ThH cyclodextrin inclusion complexes were prepared and administrated sublingually with the objective of improving the drug's aqueous solubility, in vitro permeation rate, and in vivo absorption rate. The formulation was prepared with DM-β-CD using the freeze-dried method and characterized using phase solubility, differential scanning calorimetry (DSC), X-ray and NMR analyses. The results of each test indicated the formation of dynamic inclusion complexes between ThH and DM-β-CD. The inclusion complexes also showed significant increases in in vitro aqueous solubility and mucosal permeability. According to the pharmacokinetic study of the complex in rats, the AUC and C(max) values of the sublingual delivery group were 40 and 46 times higher than those of the gastrointestinal group, whereas t(max) was shorter, which proved that in vivo absorption and metabolism had been improved. It can therefore be concluded that the inclusion technology and sublingual delivery system were suitable for ThH development.