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.     

Structural Studies on Host + Guest Recognition Sensory Systems

Rhodamine B-ethylenediamine--cyclodextrins (RhB--CDen) and rhodamine B--cyclodextrins (RhB--CD) can form inclusive complexes with many guest molecules, a reaction which can be used as a nucleic acid probe. In this paper, the most stable conformations of RhB--CDen and RhB--CD have been determined by fluorescence experiments and analyzed by molecular modeling simulation. The interaction between RhB--CDen and two guest molecules, 1-borneol and cyclohexanol, has also been investigated. The results showed that RhB--CDen has a stronger interaction with 1-borneol than with cyclohexanol. Borneol could push the three aromatic-rings of rhodamine B out of the CD cavity, while the cyclohexanol could not. The interactive sites of host and guest are also presented.     

Inclusion of Ring A of Cholesterol Inside the β-Cyclodextrin Cavity: Evidence from Oxidation Reactions and Structural Studies

The disposition of cholesterol inside the -cyclodextrin cavity(-CD) was deduced from oxidation of cholesterol secondary alcoholgroups by Ca(OCl)₂ and H₂O₂ in thepyridine–acetic acid system. The amount of cholest-4-ene-3-one formedwas found to be proportional to the concentration of -cyclodextrin,resulting in 56.1% of ketone. The oxidation rate was enhanced by-cyclodextrin and its methyl, polymer and 1 : 1copper(II)–-cyclodextrin derivatives. Detailed investigationsinvolving UV-visible, ¹³C- and ¹H-NMR(T₁, 1D NOE and ROESY) spectroscopic studies were carried out.A binding constant value of 15,385 ± 1500 M^-2 wasobtained for the 2 : 1heptakis-2,6-di-O-methyl--cyclodextrin(DM-CD) : cholesterolcomplex in chloroform from UV studies. Proton and solid state¹³C-CP MAS spectra of the -CD–cholesterol mixtureshowed large magnitude shifts for the protons from the wider end of the-CD cavity as well as those of ring A and ring B of cholesterol. Both1D NOE and ROESY measurements indicated the proximity between ring A andring B protons of cholesterol and the wider end protons of -CD andDM-CD. Besides, analysis of _c,_i and tau;_m from T₁measurements showed not only a lowering of rotational motions but a value of 0.016–0.048 for some of the cholesterol protons, typical of aweak complex. Based on these studies, a probable structure for the 2 : 1complex involving two molecules of -CD/DM-CD was proposed withportions of ring A and ring B being present inside the wider end of the-CD/DM-CD cavity and ring D and the side chain attached atposition 17, projecting into the wider end of the secondCD/DM-CD molecule.     

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.     

Isomerization of (Het)arylbenzoins in Basic Media

The isomerization of the hetaryl analogs of unsymmetrical benzoins on heating in basic media is a convenient preparative method for the production of -hydroxyacyl derivatives of -excessive heterocycles. The motivating force here for the isomerization is the formation of a thermodynamically more stable product. It was established that isomerization is promoted by increase in the difference between the electron-donating characteristics of the (het)aryl residues     

Comparison of the Complexation of Cosmetical and Pharmaceutical Compounds with γ-Cyclodextrin, 2-Hydroxypropyl-β-cyclodextrin and Water-Soluble β-Cyclodextrin-co-epichlorhydrin Polymers

The ability of different cyclodextrins (CDs): CD, 2-hydroxypropyl CD to complex drugs like 3--hydroxy-11-oxoolean- 12-en-30-oic acid, 2-ethylhexyl-3-(4-methoxyphenyl)-2-propanoate and menthol was compared to that of water-soluble polymers: CD-co-epichlorhydrin polymer (pCD/EP) and CD-co-epichlorhydrin polymer partially modified with trimethylammonium groups (pCD/EPN⁺). 3--Hydroxy-11-oxoolean-12-en-30-oic acid was poorly solubilized by CD compared with other CD derivatives, however the determination of the complexation constants was possible for pCD/EP, K₁₁ = 740, K₁₂ = 4, for pCD/EPN⁺, K₁₁ = 681, for CD, K₁₁ = 16 and for hydroxypropyl CD, K₁₁ = 114, K₁₂ = 3.4. A significant increase of the solubility was observed for 2-ethylhexyl-3-(4-methoxyphenyl)-2-propanoate with all host molecules, it was 916 times its solubility in pure water with pCD/EPN⁺, 1116 and 1300 times with 2-hydroxypropyl CD and pCD/EP respectively. The association constants are K₁₁ = 7970, K₁₁ = 4700, K₁₁ = 1470, K₁₁ = 230 and K₁₂ = 200 with pCD/EP, pCD/EPN⁺, CD, 2-hydroxypropyl CD respectively. An increase of the solubility of menthol was observed with all CD derivatives, up to 36–37 times, except for CD. The complexation constants are similar equal to about 200.     

Nitrosation of mefenorex in the presence of cyclodextrins

- and -Cyclodextrin (CD) and heptakis-2,6-di-O-methyl--cyclodextrin (DIMEB) form soluble inclusion compounds with mefenorex (MEF); with -CD a partial inclusion occurs. No solid inclusion compound could be obtained with the four CDs. -, -CD and DIMEB, but not -CD, enhance the nitrosation rate of MEF if the nitrosation assay procedure (NAP test) is applied. During this reaction with - and -CD, solid inclusion compounds of the CDs and nitrosomefenorex (NMEF) precipitate.Part of the Ph.D. thesis of V. Wedelich, Freie Universität Berlin, 1985.     

Reactions of regioisomeric fluoroalkyl-containing β-aminovinyl ketones with hydrazines

Fluoroalkyl -alkyl--aminovinyl ketones react with hydrazine hydrate to give the respective razoles and with phenylhydrazine they form a mixture of pyrazoles and 5 hydroxy-²-pyrazolines. Alkyl(aryl) -fluoroalkyl--aminovinylketones do not react with the hydrazines mentioned above. With 2,4-dinitrophenylhydrazine, both types of fluoroalkyl-containing -aminovinyl ketones give only hydrazones of the corresponding methyl alkyl(aryl) ketones.     

Aqueous Solution Inclusion of the Nonionic Surfactant C 12 E 4 in β-Cyclodextrin: Implications of Micellization in Stoichiometry Determination and Model Calculations

The inclusion of -n-dodecyl--hydroxytetra(oxyethylene), C₁₂E₄, in -cyclodextrin (CD) has been studied in aqueous solution. Guest encapsulation is recognized by the upfield variations in the chemical shifts of the H3 and H5 inner protons of CD, and the chemical shift differences of the H5 protons are used for determining the complex stoichiometry (2CD : 1C₁₂E₄) by the continuous variation method. Self-association (micellization) of the surfactant molecules is considered, and the relative amount of surfactant involved in micellar systems at the stoichiometric point estimated. A two-layered integrated molecular orbital and molecular mechanics approach with the PM3 and UFF model chemistries for the guest and host, respectively, was used to perform full geometry optimizations and frequency calculations on the host-guest systems. Energies for the optimized structures were subsequently obtained by single point calculations at the Hartree–Fock level using the STO-3G basis set. These calculations showed that one C₁₂E₄ molecule encapsulated by a head-to-head CD dimer is a stable model system in consonance with the experimentally determined stoichiometry, and that the 1 : 1 complex is not stable with respect to dissociation. In the stable 2 : 1 model system, the guest molecule is appreciably tilted with respect to the CD dimer axis and presents a gradually bent alkylic chain in clear manifestation of conformational flexibility. Model calculations for CD inclusion complexes of other oligo(oxyethylene) molecules further indicate that the number and strength of HH intermolecular close contacts reflect the position and conformational flexibility of the guest hydrophobic chain inside CD.     

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.     

Triterpene Glycosides of Astragalus and Their Genins. LXI. Occurrence of Cycloartane 6-O-Monodesmosides

Cyclosiversigenin 6-O--L-rhamnopyranoside and 6-O--D-glucopyranoside were isolated fromAstragalus coluteocarpusBoiss. (Leguminosae) andAstragalus dissectusB. Fedtsch. et N. Ivanova, respectively. Cyclosiversigenin 5-O--L-rhamnopyranoside was shown to be an artifact forAstragalus coluteocarpus.Thus, the cyclosiversigenin 6-O--D-glucopyranoside that was isolated from certainAstragalusspecies is hypothesized also to be an artifact. Glycosylation of the 6 -hydroxyl group of cycloartanes by D-glucose and D-xylose, in contrast with other substituents, does not change the low-field position of the PMR signal of the 4-CH ₃ group (1.65 2.01 ppm) that is caused by the influence of deuteropyridine directly on the 6 -hydroxyl. Obviously one of the hydroxyls of the -D-glucopyranoside or -D-xylopyranoside residues has the same effect in this instance.     

β-Cyclodextrin Mediated Synthesis of Sterically Controlled Styrene-acrylonitrile Copolymer

Sterically controlled styrene-acrylonitrile (SAN)copolymers were prepared by inclusion polymerizationusing molar equivalents of -cyclodextrin(-CD) and its derivative. Comonomercompositions, reactivity ratios, monomer sequence andaverage styrene and acrylonitrile sequence lengthswere determined using ¹³C NMR spectroscopy. Themolecular weight of the polymers prepared increasedwith decreasing -CD concentration, but wasfound to be less than the control. With increase inthe styrene: -CD ratios the averageacrylonitrile sequence length and run number of thepolymers increased. The glass transition temperature(_g) also increased along with the meltingtemperature (_m) of the polymers at higherstyrene:-CD ratios.     

Characterization of Sesquiterpene Polygodial-Beta Cyclodextrin Inclusion Complex

Polygodial is a sesquiterpene drimane isolated from the genus Drimys, whichexhibits anti-asthmatic, anti-allergic, anti-inflammatory and antinociceptive effects.We have prepared a polygodial--cyclodextrin inclusion complex for furtherpharmacological studies. The inclusion complex was synthesized by co-precipitationand analyzed by Thermogravimetric Analysis, showing a decrease in the number ofwater molecules of hydration in relation to the native -cyclodextrin. DifferentialThermogravimetric Analysis indicated a peak corresponding to the evaporation ofpolygodial. With Differential Scanning Calorimetry, the melting peak to polygodial was not observed, however, there was an increase in the energy of vaporization of the water molecules in relation to native -cyclodextrin. Using a Scanning Electron Microscopy a clear difference in the morphology of crystals of the inclusion complex and native -cyclodextrin could be seen. The association constant between polygodial and -cyclodextrin, measured by UV spectroscopy was 1,006 M^-1 at 37 °C, pH 7.0 and ionic strength 0.2 M, following stoichiometry 1:1.     

Optimization of mobile phases for HPLC of cis-trans carotene isomers

Summary Various methanol-based, binary and ternary solvent systems were compared with respect to resolution of cis isomers of and -carotene by reversed-phase HPLC. A ternary system: acetonitrile-methanol-methylene chloride (751510), or a binary system: acetonitrilemethanol (9010 or 595) provided the best separation of -carotene and its four cis isomers, 9-cis, 13-cis, 15-cis and 13,15-di-cis--carotene. The elution order of 9-cis and 13-cis--carotene was dependent on the methanol concentration. Methanol-methylene chloride (991) resolved -carotene and its three cis isomers, 9-cis, 13-cis, and 15-cis--carotene. It also proved the best for simultaneous separation of cis isomers of and -carotene. Sample solvent can affect the separation efficiency of each isomer. The presence of cis isomers of and -carotene in fresh and cooked carrots was also determined.     

Thermal Stability and Decomposition Kinetics of the β-CD Cinnamic Aldehyde Inclusion Complex

The stability of the -CD cinnamic aldehyde inclusion complex wasinvestigated by TG and DSC. The weight loss takes place in three stages:dehydration occurs at 50–120 °C; the dissociationof -CDC₉H₈O occurs at 200–260 °C;and the decomposition of -CD begins at 280 °C. Thekinetics of the dissociation of cinnamic aldehyde from the -CD cavitywere studied by means of thermogravimetry both at constant temperatureand linear increasing temperature. The results show that the dissociationof -CDC9H8O is dominated by a one-dimensional diffusionprocess. The activation energy, E, is 160 kJmol-1. Thepre-exponential factor A is 5.8 × 1014 min-1.     

Effects of Modified β-Cyclodextrins on the Hydrolysis Reaction of p-Nitrophenyl α-Methoxyphenylacetate

Effects of -cyclodextrin (-CD) 1and its derivatives 2–7 on the deacylationreaction of p-nitrophenyl (R or S)--methoxyphenylacetatewere studied. The-CD derivatives used were6--D-glucosyl--CD 2, sulfated-CD (7–11 sulfate groups/CD ring) 3,dimethylated -CD 4, carboxymethylated-CD (3.5 carboxymethyl groups/CD ring) 5,2-tri(2-hydroxypropyl)--CD 6, and-CD appended on poly(allylamine) 7. Therate constant (k ^CD) of thesubstrate/-CD complexes and the formationconstants (K) of the complexes were determinedfrom the dependence of the pseudo-first order rateconstants of the deacylation reaction on theconcentration of -CDs. The order ofk ^CD for the R-enantiomer at pH8.0 is 45H₂O3 6 1 2 7, whilethat for the S-enantiomer is 4 5 6H₂O 1 2 3 7: H₂O denotes the rate in theabsence of -CDs. The order of K values is3 7 6 2 1 4 5. This work indicates that, though thesecondary hydroxyl groups of -CD play criticalroles in the deacylation reactions of the esterscomplexed with -CDs, the reactivity of theester/-CD complexes depends highly on thenature of the substituents at the secondary face of-CD. It also suggests that the substratesinserted from the secondary side as well as theprimary side of -CD of poly(allylamine)-bound-CD undergo the reaction by attack of aminogroups on the polymer chain.     

Triterpene Glycosides from Plants of the Astragalus Genus. Structure of Cyclounifolioside A from Astragalus unifoliolatus

The known compound oleanolic acid (1) and a new cycloartane glycoside cyclounifolioside A (2), which has the structure 6,16-di-O-acetyl-24R-cycloartan-6,16,24,25-pentaol 3-O--D-glucopyranoside, were isolated from Astragalus unifoliolatus Bunge. The structures of the isolated compounds were established using chemical transformations and two-dimensional spectra (TOCSY, ROESY, HMBC, HSQC, COSY).     

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.     

β-Cyclodextrin Mediated Synthesis of Syndiotactic-rich Polystyrene

Stereoregular polystyrene (PS) was prepared using various molarequivalents of -cyclodextrin (-CD) by polymerisingstyrene in the presence of -CD. Stereoregular (isotactic,atactic and syndiotactic) distributions of the preparedpolystyrene polymers were determined from terminal modelBernoullian statistics using ¹³C NMR data. Inclusioncomplexation of styrene by -cyclodextrin was detected byUV-Visible spectroscopy, which gave a binding constant value of31606 ± 3350 M^-1 for the 1 : 1 complex. With anincrease in the styrene : -CD ratios, the proportionof syndiotactic polymers increased. The glass transitiontemperature (T_g) of the polymer also increased along withmelting temperature (T_m) at higher styrene : -CDratios. In addition, the molecular weight of the polymers prepareddecreased with increase in the -CD concentration.     

Improvement of Solubility and Dissolution of 19-Norprogesterone via Inclusion Complexation

In an effort to modify the solubility and dissolution rate of the contraceptive steroid, 19-norprogesterone in order to improve its bioavailability, the cyclodextrin complexation approach was chosen. In solution, the complex formation with -cyclodextrin (-CD), hydroxyethyl -cyclodextrin (HE--CD) and hydroxypropyl -cyclodextrin (HP--CD) was confirmed by using solubility, UV, IR and ¹H-NMR spectrophotometric techniques. The phase solubility diagrams were categorized as A_L-type. The complexing affinity of the CDs investigated were ranked as follows: -CD > HP--CD > HE--CD. The complexation thermodynamic parameters were obtained from the temperature dependence of the dissociation constants. In the solid state, differential scanning calorimetery (DSC) and optical microscopy methods were utilized to characterize the complexes. Dissolution studies showed that such molecularly encapsulated forms offered a marked improvement in the dissolution rate compared to the parent drug.