Hydroxypropyl chitosan bearing beta-cyclodextrin cavities: synthesis and slow release of its inclusion complex with a model hydrophobic drug

Hydroxypropyl chitosan-graft-carboxymethyl beta-cyclodextrin (HPCH-g-CM beta-CD) was synthesized by grafting CM beta-CD onto HPCH using water soluble 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) as the condensing agent. Due to the presence of hydrophobic beta-CD rings onto the HPCH backbone, this polymer can be used as a matrix for controlled drug release. The adsorption of a hydrophobic model drug, ketoprofen, by HPCH-g-CM beta-CD microparticles (using tripolyphosphate as an ionic crosslinking agent) fitted well in the Langmuir isotherm equation. The drug dissolution profile showed that HPCH-g-CM beta-CD microparticles provided a slower release of the entrapped ketoprofen than chitosan, and the release behavior was influenced by the pH value of the medium. These results suggest that beta-CD grafted with chitosan derivatives may become a potential biodegradable delivery system to control the release of hydrophobic drugs with pH-responsive capability.     

The effect of beta-cyclodextrin on liquid chromatography/electrospray-mass spectrometry analysis of hydrophobic drug molecules

Cyclodextrins (CDs) are widely used in the pharmaceutical industry for their capability of improving bioavailability, solubility, or stability of drugs via the formation of soluble inclusion complexes. CDs have also been widely used in various chemical analysis methods. In this work, liquid chromatography/electrospray mass spectrometry (LC/ESI-MS) analysis for four different drugs (imipramine, desipramine, propranolol, and naproxen) that form inclusion complexes with CDs was performed in the presence and absence of beta-CD. These drugs are subject to nonspecific adsorption when brought into contact with plastics, such as HPLC tubing, sample collection and preparation apparatus, etc. Inclusion of the CD in the samples reduces this nonspecific adsorption due to competitive complex formation between the CD and the analyte. ESI-MS ion intensities increased when beta-CD was included in the sample with concentrations up to 1% (w:v), with a diverter valve installed post LC column. The degree of increased ion signal correlated with the beta-cyclodextrin:analyte binding constant. beta-CD appeared to elute within the void volume time and was observed in a full spectrum scan among the different analyte samples with up to 0.01% beta-CD injected directly to the LC/MS system with the diverter valve switched inline with the mass spectrometer. The use of the diverter valve allowed for direct injection of samples containing up to 1% beta-CD to the LC/MS without any deterioration of analyte ion signal.     

Micellization and solubilization of a model hydrophobic drug nimesulide in aqueous salt solutions of Tetronic T904

The micellar and phase behavior of an ethylene oxide-propylene oxide branched octablock copolymer Tetronic T 904 (hereafter written as T904) in water and NaCl solutions was examined. The copolymer shows a cloud point (CP) ranging from 74-65°C in the concentration range of 1-10% and forms aggregates (micelles) with a hydrodynamic diameter around 10-12nm in the temperature range 30-40°C. Stable, bluish solutions containing aggregates of variable size (several hundred nm in some cases) were observed even at temperatures much less than the critical micellization temperature (CMT=30°C for a 2% solution in water). The CP and the CMT markedly decrease in the presence of NaCl due to the dehydration of the polyethylene oxide shell. The size of the micelles in water or salt solutions increases at temperatures close to the CP as inferred from viscosity measurments. A model drug compound (nimesulide, NIM) was solubilized in T904 micelles which showed a remarkable increase in solubilization at higher temperature; however, a decrease in solubilization was observed in salt solutions. The thermodynamic parameters for solubilization were obtained, and the location of NIM in the copolymer micelles was investigated by UV-Visible spectroscopy.     

Cooperative hydration effect on the binding of organic vapors by a cross-linked polymer and beta-cyclodextrin

A cooperative hydration effect being favorable for the binding of organic vapors by cross-linked poly(N-6-aminohexylacrylamide) and beta-cyclodextrin was observed in ternary systems in the absence of liquid phase. For these systems the vapor sorption isotherms were determined by the static method of headspace gas chromatographic analysis at 298 K. The obtained isotherms show an increase of binding affinity for vapor of hydrophobic sorbates above a threshold value of receptor hydration. Further hydration gives a saturation of this affinity for the studied hydrophilic polyacrylamide derivative, while the affinity of beta-cyclodextrin for the hydrophilic sorbate ethanol even decreases. A similar behavior of this polymer and beta-cyclodextrin at the change of their hydration helps to explain the observed cooperative hydration effect in terms of clathrate formation.     

In vitro release modulation and conformational stabilization of a model protein using swellable polyamidoamine nanosponges of β-cyclodextrin

New swellable cyclodextrin-based poly(amidoamine) nanosponges, named PAA-NS10 and PAA-NS11, were synthesized by crosslinking β-cyclodextrin with either 2,2-bisacrylamidoacetic acid or with polyamidoamine segments deriving from 2,2-bisacrylamidoacetic acid and 2-methylpiperazine, respectively. Water uptake studies showed a tremendous swelling capacity of both nanosponges, forming hydrogels. Time dependent swelling experiments in various aqueous media showed that the nanosponge hydrogels were stable over a period of at least 72 h maintaining their integrity. Thermal analysis showed that the two nanosponges were stable up to 250 and 300 °C, respectively. Both PAA-NS10 and PAA-NS11 were converted to aqueous nanosuspensions using the High Pressure Homogenization technique. Bovine serum albumin (BSA) was used as model protein to study the encapsulating capacity of these new β-cyclodextrin-based PAA-nanosponges. High protein complexation capacity was observed, as confirmed by UV spectroscopy. BSA encapsulation efficiency was greater than 90% on w/w basis for both nanosponges. In vitro BSA release studies were carried out showing a prolonged release of albumin from the two swollen BSA loaded β-CD PAA-NS over a period of 24 h.     

The inclusion compound of a new ionizable derivative of beta-cyclodextrin with ferrocenium drug.

A new beta-cyclodextrin (beta-CD) derivative, mono[6-deoxy-6-(2-butenedinitrile-2,3-dimercapto sodium salt)]-beta-CD (6-mnt-beta-CD), and its inclusion compound with a ferrocenium drug, have been prepared and characterized by IR, UV, 13C-NMR spectroscopy, and mass spectrometry, elemental analysis, thermogravimetry, and cyclic voltammetry (CV). The interplay between the side-arm anion of beta-CD and the ferrocenium (guest) in the inclusion compound 6-mnt-beta-CD-/Fc+ has been investigated by 13C-NMR, UV, IR, and thermogravimetric methods. Charge transfer from the anion to the cation in 6-mnt-beta-CD-/Fc+ was then experimentally identified. The interaction between the guest and the host with side-arm in 6-mnt-beta-CD-/Fc+ resulted in smaller positive potential shifts compared to that in the inclusion compound [beta-CD/Fc+]BF4-.     

Structural effect of ligand chirality and its spectroscopic consequences

Two series of pure and diluted lanthanide crystals with l and dl-isoleucine of formula [Ln(Ile)₂(H₂O)₄]₂(ClO₄)₆ (Ln=Eu, Nd) isomorphic for Eu and Nd ions were synthesised. The europium complex with l-isoleucine (1) and the neodymium one with the dl form (2) have been studied by single-crystal X-ray diffraction. The space groups are monoclinic C2 and triclinic P1̄ for l and dl isoleucine, respectively, and Z=2 and 1. The crystal structures consist of non-centrosymmetric and centrosymmetric dimer units for the l and dl ligand forms, respectively. Thus, the structural effect of ligand chirality was found and its spectroscopic consequences are reported. An attempt has been made to show the relation between the symmetry of the dimeric units and splitting of the electronic transitions. Well resolved absorption spectra down to 5 K are measured. Concentration effects on the intensities of electronic transition are examined. The vibronic coupling and cooperative interaction are analysed and confronted for complexes with l-handed and racemic ligand form. Following the vibrational analysis of the Raman spectra the assignment of [Nd(Ile)₂(H₂O)₄]₂(ClO₄)₆ vibronics are given. The nature of observed phenomena is briefly discussed.     

Inhibiting effect of beta-cyclodextrin on thymine dimerization photosensitized by para-aminobenzoic acid

Beta-cyclodextrin can act as an efficient inhibitor of the photosensitized dimerization of thymine by para-aminobenzoic acid (PABA) in aqueous solution. This can be explained by considering the formation of an inclusion complex between PABA and beta-cyclodextrin.     

Mechanism of pellet coat rupture and its effect on drug release.

In the formation of a coated controlled release preparation with functional coat layers, hydroxypropyl-methylcellulose was used to form a diffusion layer which swelled immediately upon wetting. Eudragit RS30D was used to form the outer retention layer. The rupture of pellet coat occurred when the Eudragit RS30D was unable to withstand the expansion in volume due to the influx of water and swelling of the hydroxypropylmethylcellulose diffusion layer. The sucrose core was able to contribute an osmotic effect. The hydrostatic pressure built up within the pellet can cause the pellet coat to rupture. Sodium chloride deposited in the diffusion coat was able to delay the bursting of the pellet coat. This was due to the competition for the imbibed water between sodium chloride and hydroxypropylmethylcellulose. The rupture of the pellet coat did not result in a total failure of the controlled drug delivery mechanism. Similar drug release rates were obtained irrespective whether there was a puncture in the pellet coat or not. Pressure built-up in the region away from the puncture pushed the core material towards the point of puncture and sealed the puncture point. In addition, the swelling of polymer around the point of rupture ensured continuity in the drug diffusion barrier.     

Temperature effect on solubilization of n-alkylbenzenes into sodium cholate micelles

The solubilization of n-alkylbenzenes (benzene, toluene, ethylbenzene, n-propylbenzene, n-butylbenzene, n-pentylbenzene, n-hexylbenzene) into an aqueous micellar solution of sodium cholate was carried out. Solubilizate concentrations at equilibrium were determined spectrophotometrically at 293.2, 298.2, 303.2, 308.2, and 313.2 K. The first stepwise association constants (K(1)) between solubilizate monomers and vacant micelles were evaluated from the equilibrium concentrations and found to increase with increasing hydrophobicity of the solubilizate molecules. From the Gibbs energy change for solubilization at different micelle aggregation numbers and from the molecular structure of the solubilizates, the function of sodium cholate micelles as solubilizer was discussed. Enthalpy and entropy changes of solubilization were calculated from the temperature dependence of the K(1) values, and the solubilization was found to be enthalpy-driven for the solubilizates with shorter alkyl chains. The results obtained were also compared with those for conventional aliphatic micelles.     

The effect of counterions on coacervation and solubilization in oil-external and middle-phase microemulsions

The effect of hydrated radii, valency, and concentration of counterions on the coacervation of aqueous petroleum sulfonate solutions and on the solubilization capacity of oil-external and middle-phase microemulsions was investigated. The critical electrolyte concentration (CEC) for coacervation increased with Stokes' hydrated radii of monovalent counterions. The CEC for CaCl₂ was much lower than that predicted by either the Stokes' hydrated radii or the ionic strength. For mixed electrolytes containing NaCl and CaCl₂, it was concluded from the shift in CEC that 1 mole of CaCl₂ is equivalent to 16 to 19 moles of NaCl. The changes in relative concentrations of NaCl and CaCl₂ for coacervation exhibited additive behavior. The maximum solubilization of brine in oil-external microemulsions occurred at a specific salt concentration. For mixed electrolytes containing NaCl and CaCl₂, the shift in electrolyte concentration for maximum solubilization showed that 1 mole of CaCl₂ is equivalent to about 4 moles of NaCl. These results suggest that the equivalence ratio of CaCl₂ to NaCl is strikingly different in aqueous solutions and oil-external microemulsions. For solubilization in middle-phase microemulsion containing mixed NaCl and CaCl₂, it was concluded from the shift in optimal salinity that 1 mole of CaCl₂ is equivalent to about 16 moles of NaCl. Here also the changes in NaCI and CaC1₂ concentrations showed additive behavior. The equivalence ratio of CaCl₂ and NaCl appears to be independent of oil chain length in the present study. As shown by the equivalence ratio of CaCl₂ to NaCl, the formation of middlephase microemulsions appears to be similar to coacervation of aqueous surfactant solutions and quite different from the solubilization of water in oil-external microemulsions.     

Structural change in Li and Na aluminophosphate glasses: evidence of a "structural mixed alkali effect"

The short- and long-range structure of a series of single and mixed aluminophosphate glasses with the general composition [xNa(2)O (46 - x)Li(2)O], [yAl(2)O(3) (54 - y)P(2)O(5)] is analyzed using (31)P and (27)Al magic-angle spinning (MAS) NMR as well as small-angle X-ray scattering. These series of glasses allow analyzing both the effect of alumina incorporation in these glasses, for small alumina content (y = 0, 4, 8), and the structural changes associated with the so-called mixed alkali effect (x = 0, 11.5, 23, 34.5, 46). Our results indicate that aluminum is mainly octahedrally coordinated in these glasses and that there is most likely some segregation of the Al(OP)(6) species. In the pure phosphate glasses, we observe a "classical" continuous variation of the structural properties with the relative alkali content, but in the aluminophosphate, both local and long-range structural results reveal for the first time some nonlinear change as a function of the relative alkali content.     

Diverse motifs of mannoside clustering on a beta-cyclodextrin core

[reaction: see text] A new method for the synthesis of beta-cyclodextrin-based cluster mannosides by application of the Sonogashira cross-coupling reaction is described. The method allows for the persubstitution of the beta-cyclodextrin at either 2- and 3-positions to give two types of heptavalent clusters, at both 2- and 6-positions to give clusters with 14 mannopyranoside units and at 2-, 3-, and 6-positions to obtain clusters with 21 mannopyranoside ligands.     

Cyclodextrin nanosponges: a potential catalyst and catalyst support for synthesis of xanthenes

The nanoporous framework of a cyclodextrin nanosponge was used as catalyst for accelerating the one-pot, three-component reaction of dimedone, aldehyde, and phenols for synthesis of xanthene derivatives. Moreover, the nanocavities of cyclodextrin nanosponges were exploited for immobilization of heteropolyacids through the wet impregnation method. This catalyst exhibited superior catalytic performance compared to the bare cyclodextrin nanosponge. Despite the good catalytic activity, the leaching of the catalytic species did not allow efficient recovery and reusability. To circumvent this problem, the cyclodextrin nanosponge was amine-functionalized prior to heteropolyacid immobilization. The results proved that the amine functionalities had an effective role in preserving the catalytic species and improving the reusability through decreasing the leaching time. This catalyst was used for synthesis of a variety of xanthenes in aqueous media. The catalytic amount of catalyst afforded the desired product in excellent yields and with a relatively short reaction time. The results suggested cyclodextrin nanosponge-based catalysts as potential candidates for promoting chemical reactions.     

点电荷模型分析结构

用穆斯堡尔核电四极分裂的点电荷模型计算了四极裂距,计算与实测结果符合良好,利用点电荷模型可以迅速有效地对具有一定对称的穆斯堡尔原子的大量化合物的结构和化学键性质作半经验分析。本文汇总了二十八种结构形式的点电荷模型表达式,计算了一些铁、锡化合物的四极裂距,并分析其异构体、配位数、构型和构型畸变。