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PubMed2002

Assessment of solid-state interactions of naproxen with amorphous cyclodextrin derivatives by DSC.

A microcalorimetric method based on differential scanning calorimetry (DSC) of drug-additive binary systems to assess kneading-induced interactions was applied to naproxen (NAP) in combinations with amorphous hydroxypropyl beta-cyclodextrin (HPbetaCd), beta-cyclodextrin sulfobutyl ether, sodium salt ((SBE)(7m)-betaCd), acetyl beta-cyclodextrin (AcbetaCd) and acetyl gamma-cyclodextrin (AcgammaCd). Modifications of thermal parameters of NAP in DSC curves of physical mixtures indicate heating-induced interactions which resulted in a broadening of the NAP melting endotherm in the combinations with HPbetaCd, AcbetaCd and AcgammaCd. The effect of kneading on the interaction was particularly pronounced for the NAP-HPbetaCd and NAP-(SBE)(7m)-betaCd systems, which show a similar drug-to-carrier interaction ratio (1:2 by weight) as that of the other systems. Drug-to-carrier ratios, calculated considering the amount of NAP which recrystallizes from the melted mixtures equivalent to NAP not bound to the carrier, show a distinctly lower affinity in solid-state of the drug for the anionically charged (SBE)(7m)-betaCd with respect to other neutral carriers. The similar affinity of NAP for AcbetaCd and AcgammaCd demonstrates that the geometry of the cavity, which is a determinant factor for the inclusion complexation in liquid state, does not influence the interaction process in solid-state.

Calorimetry, Differential Scanning↗
PubMed2004

Study of freeze-dried quercetin-cyclodextrin binary systems by DSC, FT-IR, X-ray diffraction and SEM analysis.

The inclusion behavior of 2-hydroxypropyl beta-cyclodextrin (HPbetaCD) and beta-cyclodextrin (betaCD), in solution and solid-state was studied towards a poorly water-soluble bioflavonoid, quercetin (QURC), chemically 3,3',4',5',7-pentahydroxy flavone. Drug-cyclodextrin solid systems were prepared by freeze-drying. Phase solubility study was used to evaluate the complexation in solution, of two cyclodextrins, i.e., betaCD and HPbetaCD. The stoichiometry and stability constants of QURC-betaCD (1:1 and 402M(-1)) and QURC-HPbetaCD (1:1 and 532M(-1)) complexes were calculated by phase solubility method. The formation of inclusion complexes with betaCD and HPbetaCD in the solid-state were confirmed by infrared spectroscopy, differential scanning calorimetry, X-ray diffractometry, and scanning electron microscopy (SEM).

Calorimetry, Differential Scanning↗
PubMed1996

Resolution improvement by use of carboxymethyl-beta-cyclodextrin as chiral additive for the enantiomeric separation of basic drugs by capillary electrophoresis.

Three beta-cyclodextrin derivatives--carboxymethyl-, dimethyl- and hydroxypropyl-beta-cyclodextrin--were tested as chiral selectors for the enantioseparation of seven basic drugs in free solution capillary electrophoresis, using buffers made of 100 mM phosphoric acid adjusted to pH 3.0 with triethanolamine in fused silica capillaries thermostatted at 15 degrees C. The best results with respect to chiral resolution were obtained with carboxymethyl-beta-cyclodextrin (CMCD): the enantiomers of all compounds examined were completely resolved with this beta-cyclodextrin derivative. The influence of the CMCD concentration on the migration times, the apparent electrophoretic mobility difference and the resolution of the drug enantiomers was investigated thoroughly. Particularly impressive resolution values, up to 23.7, were obtained for several compounds in these capillary electrophoretic systems, using CMCD in the 5-15 mM concentration range.

Anesthetics, Local↗
PubMed1998

An improved HPLC method overcoming Beer's law deviations arising from supramolecular interactions in tolfenamic acid and cyclodextrins complexes.

Inclusion complexes of tolfenamic acid (TA), a non-steroidal anti-inflammatory drug, with methyl-beta cyclodextrin and hydroxypropyl-beta cyclodextrin were prepared and characterised. Spectrophotometric, chromatographic (RP-HPLC) and 1H NMR studies of the complexes were conducted. It was observed that cyclodextrins influence TA's molar absorptivity leading to Beer's law deviation. Consequently, the accuracy problem arose, urged for the application of specific chromatographic conditions for the determination of TA in the presence of CDs. A new HPLC method was developed and validated. TA was analysed on a C18 column 5 microm (150 x 4.6 mm), using a column thermostat regulated at 30 degrees C. The mobile phase consisted of methanol-phosphate buffer solution (pH 3.2; 0.07 M) (90:10 v/v) and the flow rate was set at 2.0 ml min(-1). The detector was operated at 286 nm. TA was successfully determined, overcoming the problems arising from the presence of cyclodextrins.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2002

Determination of the free/included piroxicam ratio in cyclodextrin complexes: comparison between UV spectrophotometry and differential scanning calorimetry.

Few analytical techniques allow to evaluate the inclusion yield of cyclodextrin-drug complexes, because most manufacturing processes give amorphous products. In this study, we have developed an alternative method to differential scanning calorimetry, to accurately determine the free/complexed piroxicam ratio by UV spectroscopy. This method is based on the differential solubility of the piroxicam-beta-cyclodextrin 1:2.5 mol/mol complex in water-acetonitrile (1:1, v/v) (Solvent A) or in anhydrous acetonitrile (Solvent B), both containing 0.05 M HCl. In anhydrous acetonitrile, beta-cyclodextrin is insoluble and the included drug remains entrapped, allowing the free piroxicam determination, while with 50% of water, the complex is totally dissolved, allowing the determination of the total guest content. This method was validated for linearity, precision and accuracy. The presence of cyclodextrin does not influence the assays, but more than 0.5% of water in Solvent B significantly affects the determination of the free piroxicam content. In comparison with differential scanning calorimetry, both detectability and precision were improved. It is now possible to analyse complexes with an inclusion purity greater than 99%.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2002

On the specificity of cyclodextrin complexes detected by electrospray mass spectrometry.

Alpha-cyclodextrin complexes with linear alpha,omega-dicarboxylic acids were investigated by electrospray mass spectrometry. These hydrophobic complexes are known to have an equilibrium binding constant that increases with the diacid chain length. However, the electrospray mass spectrometry (ES-MS) spectra showed that the relative intensity of the complex did not vary significantly with chain length. This contradiction is caused by a contribution of nonspecific adducts to the signal of the complex in ES-MS. In order to estimate the contribution of nonspecific adducts to the total intensity of the complexes with alpha-cyclodextrin, the comparison was made between alpha-cyclodextrin and maltohexaose, the latter being incapable of making inclusion complexes in solution. The signal observed for complexes between diacids and maltohexaose can only result from nonspecific electrostatic aggregation, and is found to be more favorable with the shorter diacids. This is also supported by MS/MS experiments. A procedure is described which allows estimation of the contribution of the nonspecific complex in the spectra of the complexes with alpha-cyclodextrin by using the relative intensity of the complex with maltohexaose. The contribution of the specific complex to the total signal intensity is found to increase with the diacid chain length, which is in agreement with solution behavior.

Cyclodextrins↗
PubMed1996

Application of sulfated cyclodextrins to chiral separations by capillary zone electrophoresis.

Mixtures of randomly substituted sulfated cyclodextrins (degree of substitution, approximately 7-10) were successfully used as chiral additives for the enantioseparation of 56 compounds of pharmaceutical interest, including anesthetics, antiarrhythmics, antidepressants, anticonvulsants, antihistamines, antihypertensives, antimalarials, relaxants, and bronchodilators. The separations were accomplished at pH 3.8, with the anode at the detector end of the column. Under these conditions, in which electroosmotic flow is directed toward the injection end of the column and the electrophoretic mobility of the negatively charged cyclodextrin is toward the detector, none of the analytes reached the detector in the absence of the sulfated cyclodextrin. Most (40) of the successfully resolved enantiomers contained basic functionality and a stereogenic carbon. However, the versatility of this sulfated cyclodextrin additive was also demonstrated by the fact that three atropisomers, 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate, 1.1'-binaphthyl-2,2'-diol, and Troger's base, and several neutral analytes were also successfully enantioresolved under these conditions. The separation mechanism seems to involve inclusion complexation.

Cyclodextrins↗
PubMed1997

Chiral discrimination of inhalation anesthetics and methyl propionates by thickness shear mode resonators: new insights into the mechanisms of enantioselectivity by cyclodextrins.

The discrimination of the enantiomers of methyl lactate, methyl 2-chloropropionate, and the inhalation anesthetics enflurane, isoflurane, and desflurane in the gas phase has been performed using thickness shear mode resonators. The selective coating was a modified perpentylated gamma-cyclodextrin derivative dissolved in a polysiloxane matrix. A new model for the sorption of the chiral compounds into the cyclodextrin cavities and into the polymer matrix was established for the purpose of characterizing the sensor responses. This characterization included the fitting of the sensor responses (preferential and nonpreferential sorption) according to the model and extracting the characteristic parameters. In particular we attempted to explain the observed variation of the chiral discrimination factor alpha with changing analyte or cyclodextrin concentrations and search for an invariable parameter, characteristic for a certain analyte-cyclodextrin combination. The process of chiral or "molecular" recognition was thoroughly investigated.

Anesthetics, Inhalation↗
PubMed2001

Cyclodextrin-based molecular machines.

Cyclodextrins have been used as a cyclic component in the construction of supramolecular architectures. Recently they have been studied as a component in the construction of rotaxanes and catenanes. A cyclodextrin ring can translocate in some rotaxane and catenane structures. Therefore, much attention has been given to cyclodextrins as a component of molecular shuttles, motors, and machines. Attempts to design and synthesize molecular-level machines using cyclodextrins as a cyclic component are described.

Cyclodextrins↗
PubMedDate not supplied

Synthesis, hybridization properties, nuclease stability, and cellular uptake of the oligonucleotide--amino-beta-cyclodextrins and adamantane conjugates.

Synthesis of the oligonucleotides conjugated with amino derivatives of beta-cyclodextrin and adamantane, at the 3'-end of host oligonucleotide, has been described. The oligonucleotide conjugates were examined for their nuclease stability, hybridization properties, and cellular uptake. The oligonucleotide conjugates had increased nuclease resistance compared to their parent oligonucleotides. Conjugation of adamantane to the oligonucleotides did not adversely affect the ability of the oligonucleotides to hybridize with their complementary RNA. Conjugation with amino derivatives of beta-cyclodextrin, however, significantly destabilized the duplex formation. In the cellular uptake studies, we found that amino derivatives of beta-cyclodextrin attached at 3'-end of the oligonucleotides did not help to increase the uptake by cells. Cellular uptake of oligonucleotide-adamantane conjugates in association with 2-(hydroxypropyl)-beta-cyclodextrin (HPCD) as a "carrier" was significantly higher than that of control oligonucleotides.

Adamantane↗
PubMedDate not supplied

Specific antitumor targetable beta-cyclodextrin-poly(ethylene glycol)-folic acid drug delivery bioconjugate.

The tumor targeting properties of a new drug carrier synthesized by bioconjugation of folic acid (FA) to beta-cyclodextrins through a poly(ethylene glycol) (PEG) spacer (CD-PEG-FA) were investigated. Surface plasmon resonance demonstrated that CD-PEG-FA specifically interacts with immobilized folate binding protein (FBP) while the naked beta-cyclodextrins do not display any specific interaction. In vitro studies demonstrated that CD-PEG-FA was devoid of cell toxicity. [(3)H]-folic acid/CD-PEG-FA competition binding investigations performed with folate receptor overexpressing human epidermal carcinoma KB cells showed that CD-PEG-FA had about 14 times lower tumor cell binding capacity than free folic acid. The carrier cell trafficking properties were investigated using rhodamine-B as fluorescent probe, which possesses 3000 and 4580 M(-)(1) inclusion constants for CD-PEG-FA and beta-cyclodextrins, respectively. Cell-associated fluorescence measurements showed that CD-PEG-FA does not promote the rhodamine-B uptake into non-folate receptor expressing human lung carcinoma MCF7 cells while 19% higher accumulation in KB cells was found with respect to rhodamine-B loaded beta-cyclodextrins. Confocal laser scanning microscopy indicated the presence of cytosolic red fluorescent spots after 2 h of incubation of KB cells with rhodamine-B included CD-PEG-FA. The fluorescent dye resided primarily in small spots, namely, endosomes and multivesicular bodies. At 1 h after pulsed incubation, wider red fluorescent cellular structures appeared as a fusion of previous structures.

Antineoplastic Agents↗
PubMedDate not supplied

Synthetic biocompatible cyclodextrin-based constructs for local gene delivery to improve cutaneous wound healing.

The localized, sustained delivery of growth factors for wound healing therapy is actively being explored by gene transfer to the wound site. Biocompatible matrices such as bovine collagen have demonstrated usefulness in sustaining gene therapy vectors that express growth factors in local sites for tissue repair. Here, new synthetic biocompatible materials are prepared and shown to deliver a protein to cultured cells via the use of an adenoviral delivery vector. The synthetic construct consists of a linear, beta-cyclodextrin-containing polymer and an adamantane-based cross-linking polymer. When the two polymers are combined, they create an extended network by the formation of inclusion complexes between the cyclodextrins and adamantanes. The properties of the network are altered by controlling the polymer molecular weights and the number of adamantanes on the cross-linking polymer, and these modifications and others such as replacement of the beta-cyclodextrin (host) and adamantane (guest) with other cyclodextrins (hosts such as alpha, gamma, and substituted members) and inclusion complex forming molecules (guests) provide the ability to rationally design network characteristics. Fibroblasts exposed to these synthetic constructs show proliferation rates and migration patterns similar to those obtained with collagen. Gene delivery (green fluorescent protein) to fibroblasts via the inclusion of adenoviral vectors in the synthetic construct is equivalent to levels observed with collagen. These in vitro results suggest that the synthetic constructs are suitable for in vivo tissue repair applications.

Biocompatible Materials↗
PubMedDate not supplied

Binding behavior of aliphatic oligopeptides by bridged and metallobridged bis(beta-cyclodextrin)s bearing an oxamido bis(2-benzoic) carboxyl linker.

beta-Cyclodextrin dimers bearing an oxamido bis(2-benzoic) carboxyl linker (1) or its metal complexes (2 and 3) were newly synthesized, and their inclusion complexation behavior with a series of representative aliphatic oligopeptides, i.e., Leu-Gly, Gly-Leu, Gly-Pro, Glu-Glu, Gly-Gly, Gly-Gly-Gly, and Glu(Cys-Gly), was elucidated by means of UV/vis, circular dichroism, fluorescence, and 2D NMR spectroscopy in Tris-HCl buffer solution (pH 7.4) at 25 degrees C. The results obtained indicated that metallobridged bis(beta-cyclodextrin)s 2 or 3 could significantly enhance the original molecular binding abilities of parent bis(beta-cyclodextrin) 1 toward model substrates through the cooperative binding of two cyclodextrin moieties and the additional chelation effect supplied by the coordinated metal centers. It is interesting that hosts 2 and 3 displayed an entirely different fluorescence behavior upon complexation with guest oligopeptides. Among the guest peptides examined, 3 showed the highest complex formation constant of 68 200 M(-)(1) for Glu-Glu, up to 510-fold as compared with 1 (135 M(-)(1)), while 1 gave excellent molecular selectivity for Glu(Cys-Gly)/Glu-Glu pair, up to 51-fold. The molecular binding ability and selectivity were discussed from the viewpoints of the induced-fit and multiple recognition mechanism between host and guest.

Amides↗
PubMedDate not supplied

A synthetic cysteine oxidase based on a ferrocene-cyclodextrin conjugate.

We report a novel synthetic cysteine oxidase consisting of a ferrocene-beta-cyclodextrin conjugate in which the ferrocene moiety is bound to the secondary hydroxyl side of the cyclodextrin cavity through an ethylenediamine linker. Cysteine oxidation occurs after the ferrocene group is electrochemically oxidized to the ferricinium form, and this generates a voltammetric electrocatalytic wave, the magnitude of which is related to the rate constant for cysteine oxidation. Comparison of cysteine oxidation rates for the primary and secondary beta-cyclodextrin derivatives (105 and 1470 M-1 s-1, respectively) shows that the secondary derivatives are more effective synthetic enzymes. Substrate selectivity of the secondary derivative is demonstrated by comparison of oxidation rates for cysteine (1470 M-1 s-1) and glutathione (260 M-1 s-1) at pH 7.0. The rate constant for cysteine oxidation was 3-fold higher at pH 8.0. With a constant synthetic enzyme concentration, electrocatalytic limiting currents increased linearly with increasing cysteine concentration to a maximum at 6 mM cysteine; above this concentration, the current decreased significantly. These and other results suggest that product inhibition of the catalytic cycle occurs as a result of cystine binding more strongly to the cyclodextrin than cysteine.

Catalysis↗
PubMed2003

Pilot-scale demonstration of cyclodextrin as a solubility-enhancement agent for remediation of a tetrachloroethene-contaminated aquifer.

The limitations associated with conventional pump and treat technology have generated interest in using enhanced in-situ flushing as an alternative for remediating source zones contaminated with immiscible liquid. This research investigates the effectiveness of cyclodextrin as a solubility-enhancement agent to enhance the removal of tetrachloroethene (PCE) from a physically isolated section of an aquifer. An important component of this project was the implementation of reagent recovery and reuse. This field experiment presented the rare opportunity, under strict regulatory guidance, to inject PCE into the surficial aquifer cell created with two sets of sheet piles driven into an underlying clay unit. The well-controlled conditions specific to this experiment allowed quantification of mass balances, which is problematic for many contaminated field sites. The fact that mass balances can be obtained provides the ability to determine remediation effectiveness with unusual accuracy for a field project. The saturated zone within the test cell was flushed with a 15 wt % cyclodextrin solution. The cyclodextrin solution increased the aqueous concentration of PCE in the extraction-well effluent to as much as 22 times the concentrations obtained during the water flush conducted prior to the complexing sugar flush (CSF). The seven pore-volume CSF removed the equivalent of approximately 33 L of PCE from the subsurface. This equates to 48% of the total initial mass, based on the volume of PCE present prior to the CSF (68.6 L). Conversely, the seven pore-volume water flush conducted prior to the CSF removed the equivalent of 2.7 L of PCE. The use of cyclodextrin as a flushing agent, especially in a recycling configuration, appears to hold promise for successful remediation of chlorinated-solvent-contaminated source zones.

Aluminum Silicates↗
PubMed2004

Synthesis of readily modifiable cyclodextrin analogues via cyclodimerization of an alkynyl-azido trisaccharide.

A convergent strategy for the synthesis of beta-cyclodextrin analogues is reported, utilizing preferential cyclodimerization of an azido-alkyne trisaccharide via Cu(I)-catalyzed [3 + 2] dipolar cycloaddition of the alkyne and azide functional groups. The resultant oligosaccharide macrocycle retains the binding propensity of cyclodextrins, as demonstrated by the similar ANS association constants measured for macrocycle 1 and beta-cyclodextrin. This new synthetic strategy opens up new avenues for modular preparation of functionally diverse cyclodextrin analogues that are otherwise inaccessible.

Alkynes↗
PubMed2005

Remarkable supramolecular catalysis of glycoside hydrolysis by a cyclodextrin cyanohydrin.

(6AR,6DR)-6A,6D-di-C-cyano-beta-cyclodextrin (3) was synthesized and shown to catalyze hydrolysis of nitrophenyl glycosides with the reaction following Michaelis-Menten kinetics. At pH 7.4 and 25 degrees C, hydrolysis of 4-nitrophenyl-beta-glucopyranoside (2) was catalyzed with KM = 15 mM, kcat = 8.2 x 10-6 s-1, and kcat/kuncat = 1217. Catalysis was observed with concentration of 3 as low as 10 muM. Hydrolysis of the corresponding alpha-glucoside, alpha-galactoside, alpha-mannoside, and 2-nitrophenyl-beta-galactoside was also catalyzed by 3, with kcat/kuncat ranging from 283 to 2147. A series of analogues of 3 was prepared and investigated for catalysis of the hydrolysis of 2: (6AR,6DR)-6A,6D-di-C-propyl-beta-cyclodextrin (9) was not catalytic, while 6A,6D-di-C-cyano-6A,6D-dideoxy-beta-cyclodextrin (12) had a low catalytic activity (kcat/kuncat = 4). A kcat/kuncat = 48 was found for 6A,6D-dialdehydo-beta-cyclodextrin dihydrate (11). It was proposed that 3 acts by general acid catalysis on the bound substrate.

Biomimetic Materials↗
PubMed2002

Complexation of several benzimidazole-type fungicides with alpha- and beta-cyclodextrins.

The potential increase in water solubility of three benzimidazole-type fungicides (thiabendazole, carbendazim, and fuberidazole) due to complexation with alpha- and beta-cyclodextrins was investigated. Fluorescence emission spectra of the fungicides in the presence of different concentrations of the cyclodextrins were measured. Analysis of these spectra by the method of principal components global analysis (PCGA) yielded precise values for the association constants and the emission spectra of the fungicide-cyclodextrin inclusion complexes. Phase-solubility diagrams confirmed the formation of inclusion complexes between each of the fungicides and beta-cyclodextrin and showed significant increases of their solubilities due to complexation.

Benzimidazoles↗