Solubility Study of Nimodipine Inclusion Complexation with α- and β-Cyclodextrin and some Substituted Cyclodextrins

The solubility of nimodipine was measured in aqueous solutions of the following cyclodextrins: -cyclodextrin (-CD), hydroxypropyl--CD (HP--CD), -cyclodextrin (-CD), random substituted methyl--CD (M--CD), three hydroxypropyl--CDs (HP--CD) with mutually different average degree of substitution, and hydroxypropyl--cyclodextrin (HP--CD). From the determined linear solubility diagrams the values of the binding constant K₁₁ of the inclusion complexes of nimodipine with the respective CDs were evaluated. The -CDs efficiently solubilized sparingly soluble nimodipine, the highest value of K₁₁ was found for M--CD (1680 M^-1), followed by -CD (550 M^-1) and HP--CDs, where the higher degree of substitution lowered K₁₁. Only slight solubilization of nimodipine was observed in the solutions of the -CDs and HP--CD.     

Formulation and Preliminary in vivo Testing of Rufloxacin-Cyclodextrin Ophthalmic Solutions

Aim of the present work was to investigate the effect of somecyclodextrins (CDs) on the solubility and ocular bioavailability of rufloxacin base (RUF), with theultimate goal of developing an ophthalmic formulation. Phase solubility studies of RUF inpH 7.4 buffer were carried out in the presence of -cyclodextrin (-CD),hydroxypropyl--cyclodextrin (HP--CD) and -cyclodextrin(-CD). The effect of hydroxypropyl methylcellulose (HPMC) on RUF solubility was evaluated after heating the solutionscontaining HP--CD at 120 °C.A significant enhancement of RUF solubility was achieved by associatingthe drug with CDs, particularly HP--CD. This CD formed with RUF a less stablecomplex than that formed by -CD, but did not suffer the solubility limitations ofthe parent CD, and showed a higher solubilizing capacity than -CD. Addition of 0.25%(w/v) HPMC to solutions containing HP--CD increased the solubilizing effect of this CD,thus allowing reduction of the amount necessary for solubilization of 0.3% (w/v) RUF.Preliminary pharmacokinetic data in rabbits indicated that theocular bioavailability of 0.3% (w/v) RUF solubilized by HP--CD was higher when compared witha 0.3% (w/v) RUF suspension used as reference.     

Interaction of tri-O-methyl-β-cyclodextrin with drugs

Summary The effect of tri-O-methyl--cyclodextrin(methyl--CD) on the partition coefficients of drugs, such as p-nitrophenol, salicylic acid, benzoic acid, and aspirin, was studied at 25°C. The partition coefficients of these drugs were increased linearly with methyl--CD concentration. The increase of partition coefficients was interpreted by the 11 complex formation between methyl--CD and the drug in CHCl₃ phase.The interaction between p-nitrophenol and methyl--CD in solution was studied by UV and PMR spectroscopies. It was concluded that p-nitrophenol is included in the cavity of methyl--CD in both aqueous solution and CHCl₃ solution.Inclusion compounds of these drugs with methyl--CD in the solid state were studied by X-ray diffractometry, IR spectroscopy, and DSC measurements. 11 crystalline inclusion compounds were obtained from hot water. It is also suggested that amorphous inclusion compound was obtained by the grinding of drug with methyl--CD.The dissolution rate and the bioavailability of ketoprofen were significantly increased in the presence of methyl--CD. The bioavailability of ketoprofen after oral administration with methyl--CD to rats was 3.7 times that of ketoprofen alone.     

Synthesis and thermal study of some adducts of morpholine with nickel(II) nitrite,sulphate and perchlorate

The preparations of the nickel-morpholine (Morph) complexes Ni(NO₂)₂·3Morph and Ni(ClO₄)₂·4Morph·2H₂O are described. The thermal treatment of this perchlorate and of NiSO₄·2Morph led to the isolation of Ni(ClO₄)₂·2Morph·2H₂O and NiSO₄·Morph. The magnetic moments, diffuse reflectance spectra and infrared spectra of these compounds are all compatible with a pseudo-octahedral environment around the nickel atom.

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Zusammenfassung Die Darstellung der Nickel-Morpholin(Morph)-Komplexe Ni(NO₂)₂·3Morph und Ni(ClO₄)₂·4Morph·2H₂O wird beschrieben. Die thermische Behandlung dieses Perchlorates und von NiSO₄·2Morph ergibt Ni(ClO₄)₂·2Morph·2H₂O und NiSO₄Morph. Magnetisches Moment sowie diffuse Reflektionsspektren und Infrarotspektren dieser Verbindungen sind kompatibel mit einer pseudooktaedrischen Koordination des Nickelatoms.

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, () : Ni(NO₂)₂·, NiSO₄·2 Ni(ClO₄)₂·4·2H₂O. NiSO₄· Ni(ClO₄)₂·2·2H₂O. , , .

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The authors are indebted to Consejeria de Cultura y Educación de la Comunidad Autónoma de Murcia for financial support.     

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.     

Formation of Supramolecular Polymers Constructed by Cyclodextrins with Cinnamamide

-Cyclodextrin having cinnamamide at 6- or 3-positions (6-CiNH--CD, 3-CiNH--CD) and -cyclodextrin with cinnamamide on 6-position (6-CiNH--CD) have been prepared. Supramolecular structures were formed in the solid state or aqueous solutions and characterized by measurements of NMR and vapor pressure osmometry (VPO). The results indicate that 6-CiNH--CD formed insoluble supramolecular polymers in the solid state, while 6-CiNH--CD and 3-CiNH--CD formed supramolecular complexes in aqueous solutions. 6-CiNH--CD was found to form a dimer in an aqueous solution. 3-CiNH--CD formed intermolecular complexes to give supramolecular polymers. The differences of the position of guest part on cyclodextrins caused to give a variety of supramolecular structures in aqueous solutions.     

Inclusion Complexes of Cyclodextrins with Tetrakis(4-carboxyphenyl)porphyrin and Tetrakis(4-sulfonatophenyl)porphyrin in Aqueous Solutions

In neutral and alkaline solutions, tetrakis(4-carboxyphenyl)porphyrin (TCPP) and tetrakis(4-sulfonatophenyl)porphyrin (TSPP) form 1:1 and 2:1 host–guest inclusion complexes with -cyclodextrin (-CD), -cyclodextrin (-CD), and 6-deoxy-6-diethylamino--CD (DEA--CD), except for DEA--CD in alkaline solution. On the other hand, TCPP and TSPP form only 1:1 inclusion complexes with 6-deoxy-6-dihexylamino--CD (DHA--CD). The limited solubilities of DEA--CD in alkaline solution and DHA--CD are likely responsible for no observation of the 2:1 inclusion complex containing DEA--CD in alkaline solution and that containing DHA--CD. The equilibrium constants (Ks) of TCPP and TSPP for the formation of the inclusion complexes have been estimated from the absorption and/or fluorescence intensity changes in neutral and alkaline solutions. The K₂ values, which are the equilibrium constants for the formation of the 2:1 host–guest inclusion complex from the 1:1 inclusion complex, are about one tenth the corresponding K₁ values, except for the -CD–TSPP system in alkaline solution. In neutral solution, where DEA--CD and DHA--CD are in protonated forms, the electrostatic force operates between DEA--CD (DHA--CD) and TCPP (TSPP), leading to the greater K values than those in alkaline solution, where DEA--CD and DHA--CD exist as neutral species.     

Effects of Cyclodextrins on Deodoration of ``Aging Odor'

Hexenal, octenal and nonenal are known causes of unpleasant body odor and are present at markedly increased levels in the middle-aged and elderly. The odor of such unsaturated aldehydes is therefore called ``aging odor'. The present study investigated the effects of cyclodextrins (CDs) on deodoration of crotonaldehyde, pentenal, hexenal, heptenal, octenal, nonenal, decenal, undecenal and dodecenal. -, - and -CD formed inclusion complexes with the majority of unsaturated aldehydes in aqueous solution. The -CD inclusion complex contained the highest amount of guest molecule. One molecule of -CD was estimated to include 1 molecule of short chain aldehyde and 2 molecules of long chain aldehyde. Deodorant testing was conducted by headspace gas analysis using sealed vials. All CDs decreased the concentrations of unsaturated aldehyde. With nonenal, the deodorant power of parent CDs was -CD > -CD > -CD, and that of chemically modified CD was Me-CD > HP-CD > G2-CD > MCT-CD. CDs were demonstrated to reduce ``aging odor'. Me-CD was the most effective type of CD for the deodoration of ``aging odor'.     

Surface Tension and 1H NMR Studies on Inclusion Complexes of β-Cyclodextrin with Sodium Alkyl Sulfonate

The inclusion complexes of -CD with sodium octylsulfonate (C8As), sodium dodecyl sulfonate (C12As), andsodium hexadecyl sulfonate (C16As) in aqueous solutions havebeen studied by surface tension measurement at the air/water interfaceand 1H NMR spectroscopy at 323 K.At fixed concentrations of the surfactants, the surface tensions firstincrease with the increase of -CD concentrations,then they attain a maximum. The surface tension curves of the surfactantsin the presence of -CD are higher than those in the absence of-CD. The values increase with increasing -CD concentrations foreach surfactant. The apparent critical micelle concentrations (CMC) of thesurfactants vary linearly with -CD concentrations.A 1H NMR study shows that the signals of theinner H-3 and H-5 of -CDshift upfield upon addition of the surfactants.The magnitude of the chemicalshift changes (= CD obs)varies as a functionof the concentrations of the surfactants. From therelationships between the chemicalshift changes of H-3 or H-5 inside the -CD cavityand guest/host molar ratios, a 1:1 stoichiometry foreach inclusion complex is assumed. The associationconstants of the inclusion complexes have beendetermined by 1H NMR spectroscopy.     

A thermal decomposition study of some nickel(II)thioureachloride complexes

TG/DTA and Thermal Degradation Mass spectrometry (TDMS) data are presented for a series of nickel(II)thiourea chloride complexes: NiL₄Cl₂:L=thiourea or methyl-, dimethyl-, tetramethyl-, di-n-butyl, naphthyl-, ethylene- or allylthiourea. Two different thermal decomposition mechanisms are proposed for these complexes, and it is apparent that the thermal decomposition mechanism adopted by a particular complex depends on the structure of the relevant thiourea ligand and not on the nature of the halide ligand or on the existence of geometrical isomerism for these complexes.

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Zusammenfassung Durch TG, DTA und thermodegradative Massenspektrometrie (TDMS) von Nickel(II)-thioharnstoff-chlorid-Komplexen, NiL₄Cl₂ (L=Thioharnstoff oder Methyl-, Dimethyl-, Tetramethyl-, Di-n-butyl-, Naphthyl-, Vinyl- oder Allylharnstoff), erhaltene Daten werden angegeben. Zwei verschiedene Mechanismen werden für die thermische Zersetzung vorgeschlagen. Es ist offensichtlich, daß der Mechanismus, nach der die thermische Zersetzung eines gegebenen Komplexes verläuft, von der Struktur des relevanten Thioharnstoffliganden und nicht von der Natur des Halidliganden oder vom Vorliegen einer geometrischen Isomerie abhängt.

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/ - NiL₄Cl₂, L= , -, -, -, ---, -, - . . , .

     

Sodium Dithionite Reduction of 2S,5R-(-)-menthone and R-(+)-pulegone in the Presence of β-Cyclodextrin and Hydroxypropyl-β-cyclodextrin

Menthone on reduction with sodium dithionite,showed a good amount of mentholformation in the water/DMF system, withincreasing -cyclodextrin (-CD)concentration from 47.0% for 0.1 equivalent of-CD to 93.5% for 1 equivalentof -CD. Increasing hydroxypropyl--cyclodextrin(HP-CD) gave higher menthol/neomenthol (M/N) ratiosfrom 2.8 to 3.5. In the case of pulegone,increasing -CD showed an increase in the formationof menthols in thewater/DMF system from 13.3% for 0.1 equivalent of-CD to 78.1% for 1equivalent of -CD with greater proportions ofneomenthol and neoisomenthol.However, HP-CD which showed only marginalenhancement in the formationof menthol from menthone (32.1–41%), exhibiteda greater proportion of mentholformation in the case of pulegone (55.1%).However, the phase-transfer capabilityof HP-CD was not found to be significant.     

Circular dichroism spectra of the inclusion complexes of phlorizin in cyclodextrins

Two aromatic rings of a phlorizin molecule form inclusion complexes with -CD and -CD. Induced circular dichroism spectra of these complexes have been measured to estimate the orientation of the two aromatic rings in the hydrophobic space of CDs. Apparent complex formation constants have been also estimated for each complex. It is concluded that phlorizin forms a stronger inclusion complex with -CD than with -CD.     

Supramolecular Polymers Formed by Modified Cyclodextrins

6-Hydrocinnamoyl -cyclodextrin(6-HyCiO--CD), 6-hydrocinnamoyl -cyclodextrin(6-HyCiO--CD), 6-cinnamoyl -cyclodextrin(6-CiO--CD), and 6-cinnamoyl -cyclodextrin (6-HyCiO--CD) have been prepared.6-HyCiO--CD formed an intramolecular complex in an aqueous solution. 6-HyCiO--CD formed weak intermolecular complexes.6-CiO--CD formed intermolecular complexes to give supramolecular oligomers. 6-CiO--CD formed insoluble supramolecular complexes in the solid state. The structures of these complexes are discussed.     

Inclusion of Nonopiate Analgesic Drugs in Cyclodextrins. I. X-Ray Structure of a 1 : 1 β-Cyclodextrin-p-bromoacetanilide Complex

The preparation and X-ray crystal structure of a 1 : 1 complex between -cyclodextrin (-CD) and the analgesic p-bromoacetanilide are reported. Thermogravimetric and UV spectrophotometric analyses of single crystals grown from an aqueous solution containing host and guest in 1 : 1 molar ratio yielded the composition -CD p-bromoacetanilide $ 13.5H2O. Crystals of the complex are triclinic, space group P1, with a = 15.197(3), b = 15.613(2), c = 15.743(4) Å, = 87.16(2), = 98.29(2), = 103.39(1)° and Z = 2 crystallographically independent complex units per unit cell. The -CD molecules form head-to-head dimers which pack in the channel-mode. Each dimer contains two guest molecules whose acetylamino substituents are located at the dimer interface while the bromine atoms protrude from the -CD primary faces. The acetyl residues of both guest molecules were found to be disordered but the X-ray data permitted     

Chiral Recognition of Phenylacetic Acid Derivatives by Aminated Cyclodextrins

Chiral recognition of mandelic acid ( 1), acetylmandelic acid ( 2), 1-methoxyphenylacetic acid ( 3), phenylsuccinic acid ( 4), 2-phenylpropanoic acid ( 5) and ibuprofen ( 6) in their anionic forms by protonated 6A-amino-6A-deoxy--cyclodextrin (mono-NH3+--CD) and 6A,6D-diamino-6A,6D-dideo xy--cyclodextrin (di-NH3+--CD) has been studied by means of capillary zone electrophoresis (CZE) and 1H NMR spectroscopy. Both methods show the preferable guests for mono-NH3+--CD to be the (R)-enantiomers of 1, 3 and 5 and the (S)-enantiomers of 2, 4 and 6. Cooperative work of Coulomb interactions and inclusion is essential for chiral recognition of these anionic guests.     

An Investigation of Inclusion Complexes of Cyclodextrins with Phenylurea Herbicides by Photochemically-Induced Fluorescence. Analytical Applications

The effect of -cyclodextrin (-CD) and hydroxypropyl--cyclodextrin (HP--CD) upon the photochemically-induced fluorescence (PIF) properties of four phenylurea herbicides, including linuron, diuron, isoproturon and neburon has been studied. Photochemical conversion of these nonfluorescent herbicides into strongly fluorescent photoproducts was shown to occur in -CD and HP--CD aqueous media. The influence of pH, UV irradiation time and photoproduct stability on the fluorescence intensity was also investigated. In addition, the stoichiometry and formation constants of the complexes formed between herbicides and -cyclodextrin (-CD) or 2-hydroxypropyl--cyclodextrin (HP--CD) were determined. The formation constant values, ranging from 184 ± 40 to 1498 ± 245 M^-1, were calculated by applying the iterative nonlinear regression (NLR) approach to the PIF data. Linear calibrations graphs were established in the interval 1–12 g/mL, for diuron, linuron and neburon. The IUPAC limits of detection ranged between 580 and 700 ng/mL, according to the compound. Application to the analysis of phenylurea herbicides in spiked river water was also described.     

Complexation of Na-, Ca-, and Cu-montmorillonites with some parent and methylated cyclodextrins

The uptake of -, -, -, hexakis-2,6-di-O-methyl--(DM--), heptakis-2,6-di-O-methyl--(DM--) and heptakis-2,3,6-tri-O-methyl-- (TM--) cyclodextrins (CD's) by Na-, Ca-, and Cu-montmorillonites has been studied at 25°C. Each of -, DM--, DM--, and TM--CD's forms a complex with all of these montmorillonites in which the guest molecules are arranged as a monolayer with their open faces parallel to the silicate sheet of montmorillonite. On the other hand, -CD is intercalated only by the Na form and -CD cannot be taken up by any of the clays used. The interlayer spacing of the -CD complex varies from 18.0 to 21.5 Å with replacement of the interlayer cation, but those of the methylated -and -CD complexes remain unchanged, beingca. 21 and 18 Å, respectively. The different behaviour of the parent and methylated CD's is explained in terms of the structural and physicochemical characteristics of the individual CD's and interlayer cations.     

Enantiomer separations with chromatographic supports based on β-cyclodextrin polymers immobilized on porous silica. Role of the polymer structure in separating ability

Summary Two -cyclodextrin (-CD)-containing polymers have been prepared either by condensation of -CD molecules with a bifunctional reagent or by grafting a -CD derivative on to a linear polymer (polyvinylimidazole). HPLC stationary phases were obtained by adsorption of the -CD polymers on to silica. The ability of these chromatographic supports to resolve racemic mixtures of organic compounds such as amino acid derivatives, phenylhydantoins, barbiturates, and hydroxycoumarin derivatives has been investigated. Results were found to depend on the chemical structure of the -CD polymers     

Stereoselective Hydrogenation of Thymol over Rh/alumina in the Presence of β:-cyclodextrin and its Derivatives

Stereoselective hydrogenation of thymol over Rh/alumina in the presence of various equivalents of -cyclodextrin (-CD) and itsderivatives in the solid state was studied. Hydrogenation of thymol in the absence of -CD gave 76.8% epimeric alcohols with a menthol/neomenthol (M/N) ratio of 5.6 and an alcohol/ketone ratio of 4.5, whereas the presence of 0.1 equivalent (to thymol) of -CD gave rise to 94.6% of epimeric alcohols with a M/N ratio of 6.3 and an alcohol/ketone ratio of 45.4. The effect of -cyclodextrin and its derivatives on the modification of the yield and the proportion of epimeric alcohols formed were found to be the salient features of this investigation. Inclusion complexation of thymol by -CD studied by UV-Visible spectroscopyindicated a 2:1 stoichiometry ofthymol: -CD complex with a binding constant value of 480 ±40 M^-2.     

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.