Study on Interactions of Several Psychopharmaceutical Drugs with β-Cyclodextrin by Affinity Capillary Electrophoresis and their Application in Separation

The binding of psychopharmaceutical drugs by -cyclodextrin (-CD) changed their effective electrophoretic mobilities. Based on this phenomenon the interactions between some psychopharmaceutical drugs and -cyclodextrin were studied and the binding constants of -CD with tiapride, imipramine, clomipramine, amitriptyline, trifluoperazine, perphenazine and carbamazepine were determined by affinity capillary electrophoresis. The presence of -CD improved the separation of these psychopharmaceutical drugs. Organic modifier was used as another kind of additive to be added in the running buffer to improve further the separation. 70 mM pH 7.2 phosphate buffer solution containing 12 mM -cyclodextrin and 15% (v/v) acetone was selected as optimal running buffer for separation by capillary electrophoresis.     

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 -cyclodextrin stationary phases using high performance liquid chromatography. The hydroxypropyl -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 -cyclodextrin and 2,3-dimethyl -cyclodextrin CSPs were also effective in the reverse phase mode. The native -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.     

The effect of inclusion inβ-cyclodextrin on the chemistry of peroxides: Reactions of radicals withβ-cyclodextrin

Studies by electron paramagnetic resonance (EPR), differential scanning calorimetry, thermogravimetric analysis, HPLC and NMR showed that radicals produced by thermolysis and photolysis of benzoyl peroxide,t-butyl peroxide and cumene hydroperoxide included in-cyclodextrin (-CD), undergo significant reaction with the-CD. The formation of-CD radicals was observed by EPR. Products formed by addition of radicals to-CD were also observed. Such host:guest radical reactions explain the reported stabilization of peroxides, found with-CD inclusion, as being primarily due to the interruption of chain reactions by trapping of the chain carriers. A small increase in activation barrier for cleavage of the included peroxide in-CD was also observed.     

Separation of diastereomers of a 1,3-disubstituted tetrahydro-β-carboline by capillary electrophoresis with β-cyclodextrin

Summary Capillary zone electrophoresis with -cyclodextrin as electrolyte additive has been investigated for the separation of the diastereomers of a 1,3-disubstituted tetrahydro--carboline. The effects of pH, buffer concentration, -cyclodextrin concentration and applied voltage on resolution were investigated. This study shows that optimizing the assay conditions leads to maximum chiral separation or resolution. The method enables further research on the quantitative analysis of these compounds.     

Solubility and molecular modeling of triflumizole-β-cyclodextrin inclusion complexes

Solubility enhancement of the fungicide triflumicole by-cyclodextrin is explained using a thermodynamic approach. The influence of organic cosolvents on the overall equilibrium constants of triflumizole complexation with-cyclodextrin in aqueous solutions has been investigated. Their variance in mixed solvents is only partly explained by a competitive inclusion of substrate and cosolvent molecules in-cyclodextrin. The geometries of host-guest complexes have been estimated by molecular mechanics calculations. Their broad structural variety caused by the flexibility of host and guest molecules and different association possibilities of triflumizole have been analysed by a dynamic Monte Carlo docking method. The hydrophobic effect has been simulated by cominimization of the hydrophobic contributions to the solvation energy, calculated from the solvent accessible surface area of the complex and the conformational (potential) energy.     

Counterion binding by surfactant/β-cyclodextrin inclusion complexes

Sodium ion activities were determined potentiometrically in sodium dodecylsulfate and sodium dodecanoate solutions containing-cyclodextrin. Whereas sodium ion did not bind with-cyclodextrin, its activity decreased noticeably when the 1:1-cyclodextrin/surfactant inclusion complex was formed in solution. When the anionic guest was methyl red or methyl orange, no sodium ion binding occurred. When the guest was the cationic dodecylammonium ion in chloride solutions containing-cyclodextrin, pronounced chloride ion binding to the 1:1 inclusion complex occurred.     

Preparation and physico-chemical study of inclusion complexes between idebenone and modifiedβ-cyclodextrins

The inclusion properties of modified-cyclodextrins (trimethyl--cyclodextrin, dimethyl--cyclodextrin and hydroxypropyl--cyclodextrin) towards idebenone were compared with natural-cyclodextrin. The inclusion complexes were prepared by different methods (coprecipitation, kneading, and freeze-drying) and characterized by differential scanning calorimetry, X-ray diffractometry, UV, CD and NMR spectroscopy. The results obtained by CD and NMR spectroscopy indicate a different orientation of idebenone in dimethyl--cyclodextrin with respect to other cyclodextrins. Stability constants of the complexes were determined in water at various temperatures and consequently thermodynamic parameters were obtained. All cyclodextrins are able to significantly increase the water solubility of idebenone, particularly dimethyl--cyclodextrin and hydroxypropyl--cyclodextrin, as a result of complexation. Consequently, they enhance the dissolution rate of the complexed drug compared to the free drug.     

Use of Unmodified and Aminated β-Cyclodextrins for the Separation of Enantiomers of Amino Acid Derivatives by High-Performance Liquid Chromatography

The separation of enantiomers of amino acid derivatives with modifiers of different structures on -cyclodextrin and aminated -cyclodextrin by reversed-phase high-performance liquid chromatography was studied. The dependence of the capacity factors of adsorbates on the concentration of the organic component in the mobile phase was examined. It was found that the retention of amino acid derivatives on unmodified -cyclodextrin and aminated -cyclodextrin increases with the hydrophobicity of the modifying agent of amino acid. In addition, for aminated -cyclodextrin, electrostatic interactions of ionized adsorbates and protonated surface amino groups substantially contribute to the retention. It was demonstrated that the recognition ability of aminated -cyclodextrin is affected by the structure of amino acid and its degree of dissociation.     

Basic studies of the influence ofβ-cyclodextrin and 2-hydroxypropylβ-cyclodextrin on the photo-oxidation reaction of phenothiazine in inclusion complexes,using fluorescence detection

The photo-oxidation reaction of phenothiazine has been studied in the presence of-cyclodextrin (-CD) and 2-hydroxypropyl-cyclodextrin (HP -CD). The influence of these organized media on the formation of the oxidation photoproduct upon UV irradiation has been investigated. Phenothiazine forms an inclusion complex with the cyclodextrins. The stoichiometry and formation constant of the complex formed with 2-hydroxypropyl -CD have been calculated using the changes of the fluorescence emission signal and of the absorbance of the drug upon inclusion. An increase of the fluorescence intensity of the photogenerated product is attained when it becomes included inside the cyclodextrin cavity.     

Reduction of phytotoxicity of nonionic tensides by cyclodextrins

The effect of nonionic tenside nonylphenylnonylglycolate and its -, -, -cyclodextrin, 2,6-di-O-methyl--cyclodextrin (DIMEB) and 2,3,6-tri-O-methyl--cyclodextrin (TRIMEB) complexes was tested on the potassium influx of wheat seedling roots. Tenside alone inhibited strongly the potassium influx. This noxious effect was alleviated by cyclodextrins. The alleviating effect increased with increasing cyclodextrin: tenside molar ratio, in the order: DIMEB>CD>CD>CDTRIMEB.Presented at the Fourth Internatinal Symposium on Inclusion Phenomena and the Third International Symposium on Cyclodextrins, Lancaster, U.K., 20–25 July 1986.     

The effect of mechanical grinding on the formation and crystallinity changes of the inclusion complex of acetaminophen andβ-cyclodextrin

The effect of mechanical grinding on the physicochemical properties of acetaminophen in the presence of three additives,- or-cyclodextrin and microcrystalline cellulose, was studied by using TLC, powder X-ray diffraction analysis, infrared spectroscopy and differential scanning calorimetry. The results indicate that the crystallinity of physical mixtures of acetaminophen and the described additives decreased with increased grinding time and formed an amorphous state when mixtures containing- or-cyclodextrin were ground with acetaminophen. We also found that the acetaminophen molecules could be included step-by-step into the cavity of-cyclodextrin molecules and formed an amorphous inclusion complex.-Cyclodextrin and microcrystalline cellulose did not form an inclusion complex with acetaminophen, but acted only to decrease the crystallinity of the ground mixtures. The mechanical grinding efficiency for acetaminophen was improved in the order of-cyclodextrin -cyclodextrin > microcrystalline cellulose.This paper is part XI of Drug Interaction in Pharmaceutical Formulations.     

Separation and estimation of lindane from a mixture of hexachlorocyclohexane isomers via formation of an inclusion compound withβ-cyclodextrin

The treatment of a mixture of hexachlorocyclohexane isomers containing 16.03% lindane (-isomer) with-cyclodextrin results in an effective separation of lindane as indicated by a 50.4% lindane content in the total included guest. An assembly for a semimicro quantitative extraction for the separation of guest components in the inclusion compounds of cyclodextrins has been designed. The separation by inclusion has been confirmed by the preparation of an inclusion compound of-cyclodextrin with pure lindane whose guest content has been found to be 10.5% using three independent methods.     

Interaction of cyclodextrins with drugs. Chromatographic investigation using a cyclodextrin bonded-phase and its application to chiral separations

Summary The interaction between cyclodextrin and the drug (1R,2S,3S,4S)-(5Z)-7-(3-((phenylsulfonyl)amino)bicyclo[2.2.1]hept-2-yl)hept-5-enoic acid ((+)-S-145), was studied using -, -, and -cyclodextrin bonded-phase columns. Retention behavior of (+)-S-145 on these columns revealed that the strength of inclusion was -cyclodextrin. Interaction between -cyclodextrin and (+)-S-145 was found to increase as the proportion of carboxylic ion in the (+)-S-145 molecule increased. Comparison of binding capacities of these bondedsilica gels obtained by frontal analysis and surface coverage indicated that availability of the immobilized - and -cyclodextrin was 20–25%. The synthesized -cyclodextrin bonded-phase column was superior to that of commercial columns in terms of chiral separation of (±)-S-145. A typical usage of the -cyclodextrin column is discussed for separation of (±)-S-145 in plasma samples.     

Binding of vitamin A byβ-cyclodextrin and heptakis(2,6-O-dimethyl)-β-cyclodextrin

Inclusion complexation of all-trans-retinol, retinal and retinoic acid with -cyclodextrin (-CD) and heptakis(2,6-O-dimethyl)--cyclodextrin (DM--CD) were investigated by means of UV-vis spectroscopy. The association constants (K _a) obtained for vitamin A with DM--CD is greater than with -CD. On the other hand, for the same host compoundK _a values of retinol, retinal and retinoic acid are very close to each other.     

Liquid chromatographie separation of penicillamine enantiomers derivatized with OPA/2-ME on aβ-cyclodextrin bonded phase

A high performance liquid Chromatographic method has been developed for the resolution of penicillamine enantiomers on a -cyclodextrin (-CD) column. Fluorogenic derivatives of the D,L-penicillamine were first formed by usingo-phthaldehyde/2-mercaptoethanol (OPA/2-ME) as derivatizating reagent. These chiral derivatives were then chromatographed on a commercially available chiral stationary phase of -CD with 50/50 ethanol/1% triethylammonium acetate (pH 4.5) as a mobile phase, and detected fluorimetrically at 450 nm (_ex = 355 nm). After careful optimization of the classical Chromatographic parameters good resolution was achieved between the d and l enantiomers. The method proposed here is simple and rapid and can detect the presence of 0.5% of the L-enantiomer in D-penicillamine pharmaceutical preparations (tablets).     

Monolithic silica columns with chemically bonded β-cyclodextrin as a stationary phase for enantiomer separations of chiral pharmaceuticals

An enantioselective silica rod type chiral stationary phase (CSP) is presented; a novel combination of the well known enantiomer separation properties of -cyclodextrin and the unique properties concerning the flow behavior of silica monoliths. Two different synthesis routes are described, and it was found that the in situ modification of a plain silica rod column turned out to be the best. The chromatographic behaviour of the -cyclodextrin silica rod was studied and compared with a very similar commercially available -cyclodextrin bonded particulate material (ChiraDex^®). Even if the amount of -cyclodextrin bound to the silica rod was only about half of the amount of -cyclodextrin bound to ChiraDex^® particles, good resolutions were achieved for a set of chiral test components like Chromakalin, Prominal, Oxazepam, Methadone and some other drugs. By taking advantage of the unique features of the silica rods relating to their flat H/u (Van Deemter) curves, fast enantiomer separations could be demonstrated.     

Stabilization and Solubilization of Lipophilic Natural Colorants with Cyclodextrins

The paper provides data on the practical utilization of the benefits of the molecular encapsulation of natural colorants by cyclodextrins. Experimental results on the stability of cyclodextrin complexed curcumin, curcuma oleoresin, -carotene and carotenoid oleoresins against light-, heat- and oxygen prove the benefits of molecular encapsulation of colorants. The parent -cyclodextrin stabilized most effectively the curcumines, while the stability of carotenoids was most effectively achieved by -cyclodextrin complexation. Methylated -cyclodextrin was found to be the most potent solubilizing agent for both carotenoids and curcuminoids.     

Complex formation of some nonionic surfactants with hydroxypropyl-β-cyclodextrin and with heptakis (2,6-di-O-methyl)-β-cyclodextrin

The interaction of six nonionic surfactants -[4-(1,1,3,3-tetra-methylbutyl)phenyl]--hydroxypoly(oxy-1,2-ethanediyl) with hydroxypropyl--cyclodextrin (HPCD) and dimethyl--cyclodextrin (DIMEB) was studied by reversed-phase thin-layer chromatography in the presence and absence of sodium chloride. Each surfactant formed complexes with both cyclodextrin derivatives; however, the strength of interaction varied considerably. DIMEB formed more stable inclusion complexes with the surfactants than did HPCD. A longer ethyleneoxide chain decreased the strength of interaction, whereas sodium chloride exerted a negligible impact. Principal component analysis indicated that both the hydrophobicity and the specific hydrophobic surface are of the surfactant influenced the complex formation indicating the hydrophobic character of the interaction.Dedicated to Professor József Szejtli.     

Syntheses of 6N(N′-formyl-D-phenylalanyl)-deoxyamino-β-cyclodextrin and 6N(N′-formyl-L-phenylalanyl)deoxyamino-β-cyclodextrin and their inclusion behavior

6N(N-formyl-D-phenylalanyl)-deoxyamino--cyclodextrin and 6N(N-formyl-L-phenylal-anyl)-deoxyamino--cyclodextrin (I andII) were prepared. These new hosts formed intramolecular host-guest complexes and included naphthyl derivatives preferentially with a stoichiometry of 1:1. The inclusion behavior was different between I and II because the cavity shape formed with the CD cavity and the phenylalanine moiety of I was different from that of II.     

Interactions of Nabumetone with Cyclodextrins in Solution and in the Solid State

The interactions of nabumetone (NAB) with -cyclodextrin (-CD) and-cyclodextrin (-CD) were studied in aqueous solution by meansof phase-solubility analysis. Solid dispersions of NAB with -cyclodextrin(-CD), -cyclodextrin (-CD), methyl- (M-CD),hydroxypropyl-cyclodextrin (HP-CD) were prepared by coevaporationand kneading and also by coprecipitation in the case of -CD. X-ray diffractometry, thermal analysis and infrared spectroscopy (FTIR) were used to study the possibility of complexation of the drug with the different cyclodextrins. Solid dispersions of nabumetone with -CD showed a remarkable improvement in the dissolution rate of nabumetone.