Native Β-cyclodextrin Research Articles

A Combined Theoretical−Experimental Study of the Inclusion of Niobocene Dichloride in Native and Permethylated β-Cyclodextrins

Inclusion complexes comprising niobocene dichloride, Cp2NbCl2, and either native β-cyclodextrin (β-CD) or permethylated β-CD (TRIMEB) were prepared with a host:guest molar ratio of 1:1. The adducts were characterized in the solid state by powder X-ray diffraction (XRD), thermogravimetric analysis (TGA), 13C{1H} CP/MAS NMR, FTIR, and FT Raman spectroscopies. Ab initio calculations were performed in order to elucidate the possible inclusion geometries and calculate vibrational frequencies for Cp2NbCl2 in the region 100−1800 cm-1. The vibrational spectra indicated that neither the hosts nor the guest were chemically modified upon inclusion complexation. Small wavenumber shifts in C−H, C−C, and metal−ligand vibrational modes were attributed to the effect of the host−guest interaction. Powder XRD showed that the β-CD adduct was of low crystallinity, while the TRIMEB adduct was quite crystalline. The powder XRD pattern of the TRIMEB adduct could be satisfactorily indexed in the monoclinic system with the space group P21. A hypothetical structural model for the crystal packing was obtained through Monte Carlo optimizations using a reported TRIMEB geometry comprising a distorted elliptical cavity. An unrestrained Rietveld refinement of the structural model could not be carried out due to the relatively low quality of the experimental powder XRD pattern. However, the plausibility of the host−guest interaction geometry, involving inclusion of one of the guest Cp ligands inside the CD cavity, was fully supported by the ab initio calculations.

Per- O-(3-hydroxy)propyl-β-cyclodextrin: a cyclodextrin derivative bearing only primary hydroxyl groups

Natural β-cyclodextrin (cyclomaltoheptaose) was treated with sodium hydride and allyl bromide to form the per- O-allyl-β-cyclodextrin. 9-BBN, sodium hydroxide and hydrogen peroxide were then added to form, after adequate treatments, the desired per- O-(3-hydroxy)propyl-β-cyclodextrin in yields close to 65%. This modified cyclodextrin, which bears only primary hydroxyl groups, can be used as a macro-initiator of the anionic polymerisation of ethylene oxide to form star-shaped polymers. The presence of only primary hydroxyl groups allows us to expect identical initiation kinetics for all the hydroxyl groups of the modified glucopyranosyl units.

NMR Spectroscopy on the Complexation of 3,6-Anhydro-β-cyclodextrin with 2,6-Naphthalenedicarboxylate Ion

Abstract The 2,6-naphthalenedicarboxylate ion (2,6-NDC) was included into the interior cavity of 3A,6A-anhydro-β-cyclodextrin (1) in D2O containing 0.1 mol dm−3 Na2CO3 and caused a shift in the 1H NMR signals due to the C3- and C5-H’s of 1 to different directions, depending on the positions of glucose units (anisotropic ring-current effect). The decrease in entropy accompanied by the complexation was much larger than that for the complexation of native β-cyclodextrin with 2,6-NDC. These results indicate that the molecular rotation of 2,6-NDC is retarded within the deformed cavity of 1.

Thermodynamics of Molecular Recognition of Bile Salts by 3,6- (Oligoethylenediamino-Bridged) β-Cyclodextrin Dimers

The molecular recognition behaviors of some representative bile salts by three 3,6'-bridged beta-cyclodextrin dimers with oligo(ethylenediamino) linkers in different lengths, i.e. 3,6'-(ethylenediamino-bridged) beta-cyclodextrin dimer (1), 3,6'-(diethylenetriamino-bridged) beta-cyclodextrin dimer (2), and 3,6'-(triethylenetetraamino-bridged) beta-cyclodextrin dimer (3), were investigated in aqueous phosphate buffer solution (pH 7.20) at 25 degrees C by means of 2D NMR spectroscopy and isothermal titration microcalorimetry. Owing to the cooperative host-linker-guest binding mode between host and guest, these 3,6'-bridged beta-cyclodextrin dimers showed significantly enhanced binding abilities and molecular selectivities as compared with native beta-cyclodextrin through the simultaneous contributions of hydrophobic, hydrogen bond, and electrostatic interactions. Thermodynamically, the inclusion complexations of these beta-cyclodextrin dimers with bile salts were mainly driven by large enthalpic gain, accompanied by slight to moderate entropic loss. An enthalpy-entropy compensation analysis demonstrated that these beta-cyclodextrin dimers experienced large conformational changes and extensive desolvation effect upon inclusion complexation with guest molecules.

Photophysical behaviours of some 2-styrylindolium dyes in aqueous solutions and in the presence of cyclodextrins

Host–guest inclusion type association between native β-cyclodextrin and randomly substituted methyl-β-CD and two 2-styrylindolium cationic dyes, e.g. 1,3,3-trimethyl-2-(4-diethylaminostyryl)-3H-indolium iodide (D1) and 1,3,3-trimethyl-2-[4-(N-2-cyanoethyl,N-methyl)-aminostyryl]-3H-indolium iodide (D2), are reported. The described indolium derivatives belong to the rarely investigated class of unsymmetrical polymethines. The complex formation was studied in aqueous buffer solutions with two pH values (7.2 and 3) by means of absorption and steady-state fluorescence spectroscopy. The association equilibrium constant (K), the molar absorptivity and the stoichiometry of the complexes were evaluated using the modified Benesi-Hildebrand approach. The complex stability was affected by the pH of the solution and by the type of CD. The results obtained indicate that D1 forms 1:1 complexes with both β-CD and Me-O-β-CD, whereas D2 does not form stable complexes with Me-O-β-CD and in acidic medium. The fluorescent intensity of D1 in the presence of CDs increases over four times relative to the intensity of the pure dye solutions, presumably via inclusion of the dye into the cyclodextrin cavity due to rigidity of the structure.

Direct synthesis of novel amphiphilic cyclodextrin

A novel amphiphilic cyclodextrin derivative was obtained by controlled esterification of lauric acid chloride on the primary face of the native β-cyclodextrin in a one step synthesis. The characterization of the substitution degree and isomer structure was performed by mass and NMR spectroscopies. A specific purification procedure by sublimation was developed in order to eliminate the excess of lauric acid molecules in the reaction product. The sublimation efficiency was assessed by differential scanning calorimetry (DSC) in quantifying the remaining fatty acid. In this way the duration of the sublimation process could be optimized.

Preparation and physicochemical characterization of omeprazole:methyl-beta-cyclodextrin inclusion complex in solid state

In this work, we illustrate the usefulness of cyclodextrins, namely, methyl-β-cyclodextrin (MβCD), an amorphous, methylated derivative of the natural β-cyclodextrin (βCD), as a tool to form an inclusion complex with omeprazole (OME), a poorly water soluble drug. Solid binary systems between OME and MβCD were prepared experimentally in a stoichiometry 1:1 by different techniques (physical mixing, kneading, spray-drying and freeze-drying). Afterward these products were characterized by Fourier transformation-infrared spectroscopy (FTIR); X-ray diffractometry (XRD) and scanning electron microscopy (SEM). The results obtained suggest that spray-drying and freeze-drying methods yield a higher degree of amorphous entities suggesting the formation of inclusion complexes between OME and MβCD.

Molecular Recognition of a Novel Bridged Bis(<EM>β</EM>-cyclodextrin) Tethered with Aromatic Diamine for Dyes

A novel bridged bis(β-cyclodextrin)with rigid aromatic diamino tethers,3,3'-methylenedianilino-briged-bis(6-aimino-6-deoxy-β-cyclodextrin)(2),was synthesized by the reaction of mono-[6-o-(p-tolysulfonyl)]-β-cyclodextrin with 3,3'-methylenedianiline.The inclusion complexation behaviors of native β-cyclodextrin(1)and the novel briged(β-cyclodextrin)(2)with some organic dyes,i.e.,acridine red(AR),neutral red(NR),sodium 6-toluidino-2-naphthalenes-ulfonate(TNS),ammonium 8-anilino-1-naphthalenesulfonate(ANS),rhodamine B(RhB)and brilliant green(BG)were investigated at 25 ℃ in aqueous phosphate buffer solution(pH=7.20)by means of fluorescence and ultraviolet spectroscopy.The spectral titrations gave the complex stability constants(KS)and Gibbs free energy changes(ΔG0)for the stoichiometry 1∶1 inclusion complexation of hosts examined with dye molecules.The obtained results demonstrated that bis(β-cyclodextrin)2 showed much higher binding ability and molecular selectivity toward these guest dyes than native β-cyclodextrin 1.Typically,dimmer 2 displayed the highest binding ability upon inclusion complexation with BG,affording 22.2 times higher KS value than native β-cyclodextrin.The cooperative binding ability of the bis(β-cyclodextrin)was discussed from the viewpoints of size/shape-fit interaction and multiple recognition mechanism.

New cyclodextrin bioconjugates for active tumour targeting

A new cyclodextrin-based carrier for active targeting of low soluble and degradable drugs has been synthesized and characterized. β-Cyclodextrins were first reacted with excess hexamethylene diisocyanate and the resulting CD–(C6–NCO)5 derivative was reacted with 700 Da diamino-PEG to yield CD–(C6–PEG–NH2)5. About one out of five free amino groups of PEG were functionalised with folic acid (FA) as a tumour targeting moiety. The chemical structures of the intermediates as well as the final product, CD–(C6–PEG)5–FA, were characterized by 1H and 13C NMR, reverse phase and gel permeation chromatography, and UV-Vis spectroscopy. After modification, the haemolytic activity of β-cyclodextrins decreased by about 70%. In the presence of the new carrier, the β-estradiol solubility increased by more than 300 fold and the chlorambucil degradation rate decreased by 50–60%. CD–(C6–PEG)5–FA formed an inclusion complex with curcumin displaying an association constant of 954,732 M− 1. The new carrier increased the curcumin solubility by about 3200 fold as compared to native β-cyclodextrins and reduced its degradation rate at pH 6.5 and 7.2 by 10 and 45 fold, respectively. FA receptor-overexpressing human nasopharyngeal tumour KB cell lines and non-folic acid receptor-expressing human breast cancer MCF7 cells were used to evaluate the targeting properties of the new drug delivery system. The in vitro studies demonstrate that the new carrier possesses potential selectivity for the folate receptor-overexpressing tumour cells as ED50 values of 52 μM, 58 μM and 21 μM were obtained with curcumin-loaded CD–(C6–PEG–NH2)5, curcumin in foetal serum medium and CD–(C6-PEG)5–FA, respectively.

HSP90-like artificial chaperone activity based on indole β-cyclodextrin

Indole β-cyclodextrin (β-1) was found to be able to prevent aggregation of citrate synthase (CS) on heating condition. As a result, β-1 showed anti-CS aggregation in this system by regulating in early stage. The depression mechanism of β-1 for aggregation of CS is as follows: the β-1 formed a complex with hydrophobic parts of the β-sheet structure of CS. From CD spectra, CS was changed own conformation was changed by β-1 addition. So, it was concluded that β-1 works as β-sheet inducer in thermal condition. On the other hand, native β-cyclodextrin (β-CyD) shows small suppression capability for CS aggregation.

Synthesis and characterization of hyperbranched poly (sulfone-amine) modified β-cyclodextrin

AbstractAn economical strategy to prepare hyperbranched poly(sulfone-amine) modified β-cyclodextrins (HPSA-m-CDs) from natural β-cyclodextrin (β-CD) and other commercially available materials has been reported. The final product has many good properties of hyperbranched poly(sulfone-amine)s (good solubility, low viscosity etc.), while its inclusion ability can also be well kept. It is a feasible approach to prepare functionalized modified cyclodextrin at very low cost, and may have potential applications in the fields of catalysis, drug delivery, food additives, etc.

Chiral Separation of Synthetic Vicinal Diol Compounds by Capillary Zone Electrophoresis with Borate Buffer and b-Cyclodextrin as Buffer Additive

The investigation on capillary electrophoretic enantioseparation of six synthetic compounds containing vicinal diol groups has been undertaken to acquire the optimum conditions using native beta-cyclodextrin (beta-CD) as chiral selector and borate as a background electrolyte. The separation was carried out in an uncoated capillary (58.5 cm x 75 microm i.d., effective length 48.5 cm) and the effects of several important factors were investigated in detail. The results showed that beta-CD as a chiral selector exhibited good enantioselectivity and that the enantioseparation was greatly influenced by the structure of the diols, the borate concentration and the buffer pH. The optimum performance was obtained for the chiral vicinal diols under the conditions of 200 mM borate buffer of pH 9.8 containing 1.7% beta-CD at an applied voltage of 15 kV and a capillary temperature of 20 degrees C. Under the conditions, four diols were baseline separated with fast analysis time and the good theoretical plate numbers (above 10 x 10(4)) and favorable migration-time reproducibilities (RSDs below 3.0%) were obtained. The separation results were satisfactory.

Enantiomeric separation of synthetic 2,3-dihydroxy-3-phenylpropionate compounds by β-cyclodextrin-modified capillary electrophoresis

A new capillary electrophoretic method was developed for enantiomeric separation and optical impurity analysis of three synthetic 2,3-dihydroxy-3-phenylpropionate compounds using native β-cyclodextrin (β-CD) as chiral selector and borate as a background electrolyte. The separation was carried out in uncoated capillary (58.5 cm × 75 μm I.D., effective length 48.5 cm). The results showed that β-CD as the chiral selector exhibited good enantioselectivity and the baseline separation was obtained at pH 9.8, 200 mM borate buffer containing 1.7% β-CD at applied voltage 15kV and capillary temperature 20 °C within 15 min. The precision of each tested compound was less than 1.0% at migration time and 5.0% in corrected peak area and the accuracy of the method was in the range of 98.7–105%. Furthermore, the developed method was successfully applied to the determination of the undesirable trace (2 S,3 R)-(+)-form impurity in the synthetic (2 R,3 S)-(−)-2,3-dihydroxy-3-phenylpropionate samples.

Simultaneous effect of cyclodextrin complexation, pH, and hydrophilic polymers on naproxen solubilization

The effect of pH variation on complexation and solubilization of naproxen (p K a 4.2) with natural βCyclodextrin (βCyD) and various neutral, cationic and anionic βCyD-derivatives has been investigated. The combined effect of pH variation and hydrophilic polymer addition on CyD solubilizing and complexing efficiency has also been determined. Phase-solubility analysis in buffered aqueous solutions (pH from 1.1 to 6.5) was used to study the interaction of the drug with each CyD, in the presence or not of the water-soluble polymer. A clear influence of the substituent type was observed, the methylderivative being the most efficient agent; on the contrary, unexpectedly, no influence of the CyD charge in the interaction with the ionizable drug was detected. As expected, total drug solubility increased with increasing pH; however, the solubility increment with respect to drug alone obtained by CyD complexation progressively decreased, with a parallel reduction of the complex stability, attributed to the reduced affinity of charged drug for the hydrophobic CyD cavity. The addition of the polymer in part counterbalanced the destabilizing effect obtained with increasing pH, by improving the CyD complexation power towards naproxen. In particular, the presence of PVP allowed an increase of the complex stability constant with hydroxypropyl βCyD up to 60% with respect to the corresponding drug–CyD binary system. Therefore, the combined strategy of pH control and polymer addition to the CyD complexing medium can be successfully exploited to improve naproxen solubilization and reduce the amount of CyD needed. The construction of theoretical drug solubility curves as a function of pH for any given CyD and polymer concentration enables selection of the best experimental conditions for obtaining the desired drug solubility value.

No delayed temporal response to sample concentration changes during enhanced microdialysis sampling using cyclodextrins and antibody-immobilized microspheres

The temporal response to concentration changes external to a microdialysis probe containing trapping agents in the perfusion fluid was studied. Native beta-cyclodextrin and a water-soluble beta-cyclodextrin polymer were used as trapping agents in the microdialysis perfusion fluid to study the temporal concentration response to carbamazepine, a hydrophobic analyte. The temporal response of microdialysis probes containing antibody-immobilized microspheres against five different cytokines (tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-2 (IL-2), IL-4, and IL-5) to concentration changes outside of the probe was also determined. In both cases, no delayed temporal response of enhanced microdialysis was observed for either carbamazepine or the cytokines as compared to standard microdialysis sampling procedures.

Cyclodextrin Solubilization of the Antibacterial Agents Triclosan and Triclocarban: Effect of Ionization and Polymers

The natural β-cyclodextrin (βCD) and its complexes have limited solubility in aqueous solutions. This low aqueous solubility, as well as low aqueous solubility of the guest molecule (i.e. triclosan or triclocarban (TCC)), can result in low complexation efficiency (CE). The purpose of this study was to enhance the apparent intrinsic solubility (S 0) of the guest molecule and its βCD complexes through ionization and addition of auxiliary compounds such as polymers, amino acids and metal ions. Both triclosan (pK a 7.9) and TCC (pK a 12.7) are weak acids. Addition of ethanol to the complexation medium enhanced S 0 of both triclosan and TCC but at the same time ethanol lowered the stability constant (K c ) of their βCD complexes resulting in overall lowering of CE. Addition of small amount of water-soluble polymers enhanced the βCD solubilization of both guests, and addition lysine enhanced the solubilization of TCC. Ionization of triclosan resulted in significant enhancement of CE and enhanced triclosan release from tablets containing triclosan/βCD complex. The effect of ionization was not as pronounced in the case of TCC.

Cyclodextrin complexes of valdecoxib: properties and anti-inflammatory activity in rat

The influence of natural β-cyclodextrin and its hydrophilic derivatives (HPβCd and SBE7βCd) on the in vitro dissolution rate, in vivo absorption and oral bioavailability of a poorly water soluble anti-inflammatory agent, valdecoxib (VALD) was studied. Equimolar drug–cyclodextrin solid complexes were prepared by kneading and coevaporation methods and characterized by infrared spectroscopy, differential scanning calorimetry, X-ray diffraction. In the liquid state, the cyclodextrin complexes were studied using phase solubility analysis, 1H nuclear magnetic resonance and circular dichroism spectroscopy. Drug solubility and dissolution rate in distilled water were notably improved by employing the βCds. The DP 15 (i.e. percent of dissolved VALD at 15 min) was 10.5% for the pure drug and 50, 91 and 93% for VALD-βCd, VALD-HPβCd and VALD-SBE7βCd complexes, respectively. Moreover, it was found that in the, the cyclodextrin complexes of drug showed significant improvement in the anti-inflammatory activity.

The Use of Cyclodextrin-Based LC Stationary Phases for the Separation of Chiral Dihydrobenzofuran Derivatives

The enantiomeric separation of 12 chiral dihydrobenzofurans is reported on derivatized β-cyclodextrin stationary phases using high performance liquid chromatography. The hydroxypropyl β-cyclodextrin chiral stationary phase (CSP) with acetonitrile/water mobile phases was the most effective combination as it baseline separated 9 of the 12 compounds. The acetyl β-cyclodextrin and 2,3-dimethyl β-cyclodextrin CSPs were also effective in the reverse phase mode. The native β-cyclodextrin was far less effective than the non-aromatic derivatized CSPs. The aromatic functionalized CSPs showed no selectivity in the normal phase mode. Structural characteristics, such as substituent polarity and ring location, were important in the observed enantioselectivity.

Complexation of Monosulfonated Triphenylphosphine with Chemically Modified β-Cyclodextrins: Effect of Substituents on the Stability of Inclusion Complexes

Interactions between the meta-substituted monosulfonated triphenylphosphine and chemically modified β-cyclodextrins were investigated in aqueous solution by NMR and UV–vis spectroscopy. Titration and continuous variation plots obtained from 31P NMR data indicate that the monosulfonated triphenylphosphine forms 1:1 inclusion complexes with the 2-hydroxypropylated β-cyclodextrin, the methylated β-cyclodextrin and the (2-hydroxy-3-trimethylammoniopropyl)-β-cyclodextrin chloride. These inclusion complexes are more stable that those formed with native β-cyclodextrin, confirming that poisoning of the chemically modified β-cyclodextrins by the hydrosoluble phosphine occurs when modified cyclodextrins are used as mass transfer promoters in aqueous-phase organometallic catalysis.

Comparative Study on Co-Ground Products of Rofecoxib with -Cyclodextrin and Its Sulfobutyl Ether-7 Derivative in Solution and in the Solid State

The inclusion behavior of sulfobutyl ether-7 derivative ofβ-cyclodextrin (SBE7βCD), in solution and solidstate was compared with that of natural β-cyclodextrin(βCD) toward a poorly water-soluble anti-inflammatoryagent, rofecoxib (ROFX), chemically 4[4-(methylsulfonyl)phenyl]-3-phenyl-2 (5H)-furazone. Drug-cyclodextrin solidsystems were prepared by cogrinding in a ball mill. A phasesolubility method was used to evaluate the stoichiometries andstability constants of ROFX-βCD (1 : 1 and 62 M-1)and ROFX-SBE7βCD (1 : 1 and 132 M-1) complexes.The formation of inclusion complexes with βCD andSBE7βCD in the solid state were confirmed by infraredspectroscopy, differential scanning calorimetry, X-ray diffractometry,scanning electron microscopy and in the liquid state by phasesolubility analysis, nuclear magnetic resonance spectroscopy andcircular dichroism studies. Dissolution studies using the USP paddlemethod were carried out in phosphate buffer pH 7.2 at 37 °Cfor both βCD and SBE7βCD complexes of rofecoxib.Solubility enhancement was much greater for the rofecoxib-SBE7βCDcomplex compared to drug-βCD complex. The stability constantobtained for the SBE7βCD inclusion complex of rofecoxib wasthe highest. Finally, dissolution profiles obtained suggest thatSBE7βCD is more effective than β-cyclodextrin inimproving the pharmaceutical properties of rofecoxib.