Effect of Cyclodextrins on the Chemical Stability of ST1435, a Contraceptive Steroid Progestin, in Aqueous Solution

The influence of cyclodextrins (CDs) on the chemical stability of the contraceptive steroid progestin, ST1435, in aqueous solution has been studied using reversed phase high performance liquid chromatography. The effects of CD structure, temperature, and CD concentration on the rate of degradation were investigated. It was found that the drug degraded to different extents following a pseudo-first order reaction mechanism. The presence of the host molecules affected the degradation rate as a result of complexation which might result in protection of the labile moiety of the drug molecule against degradation. Hydroxypropyl--cyclodextrin (HP--CD) and hydroxyethyl--cyclodextrin (HE--CD) retarded the degradation in contrast to -cyclodextrin (-CD) which accelerated the steroid degradation. The stabilizing action of HP--CD is larger than that of HE--CD. The degradation rate increased upon increasing temperature and the Arrhenius equation is valid. Lineweaver-Burk equation analysis indicated that the steroid included inside the CD cavity degraded three times more slowly than did the free ST1435 in solution. This equation further supported the formation of a 1 : 1 inclusion complex between ST1435 and HP--CD with a stability constant of 934.5 M-1 at 65°C.     

Influence of cyclodextrins on nitrosation of drugs

The World Health Organization issued a nitrosation procedure (NAP Test) which allows to carry out nitrosation under standard conditions. It has proved that the in vitro reaction rates of the fast nitrosatable drugs piperazine, cimetidine and ethambutol are not influenced by -, - and -cyclodextrin. On the contrary, -, -cyclodextrin and heptakis-2,6-di-O-methyl--cyclodextrin enhance the nitrosation of the slower nitrosatable 1-ephedrine and fencamfamine significantly. This possible reaction must be considered if nitrosatable drugs are formulated with cyclodextrins to be administered to human beings.     

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.     

The Chlorhexidine: beta;-Cyclodextrin Inclusion Compound: Preparation, Characterization and Microbiological Evaluation

The 1 : 2 chlorhexidine : -cyclodextrin(Cx : CD) complex was prepared and characterised using X-ray crystallography, infrared spectroscopy, thermal analysis and nuclearmagnetic resonance. The minimum inhibitory concentration (MIC₅₀) of the chlorhexidine : -cyclodextrin inclusion compoundagainst Streptococcus mutans, Eubacterium Lentum, Fusobacterium nucleatum, Bacteroides fragilis andActinomices actinomycetemcomitans was determined. TheCx : CD inclusion compound inhibited the bacterial growth at a low concentration.     

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.     

Complexation of Oleuropein and trans-Cinnamic Acid with Cyclodextrins

The complexation of oleuropein and trans-cinnamic acid with -, -, and -cyclodextrin has been studied in aqueous model systems by light scaterring. The influence of various parameters (pH, concentration, reaction time, nature of cyclodextrin) has been thoroughly examined. The formation of binary (1:1) inclusion complexes and the higher inclusion ability of -CD for both compounds has been indicated. Trans-cinnamic acid was extracted from olive olive oil following its complexation with -CD at satisfactory recovery levels.     

Structural Features of the β-CD Complexes with Naringin and its Dihydrochalcone and Aglycon Derivatives by 1H NMR

The -CD inclusion complexes of naringin 1, naringin dihydrochalcone 2 and the aglycon of naringin dihydrochalcone 3 have been investigated by ¹H NMR spectroscopy. Continuous variation plots show the stoichiometry of all complexes to be 1 : 1. Thestructure of complexes was determined from 2D ROESY and 1D ROE experiments. For 1 and 2 the inclusion involves the aromatic rings leaving the disaccharide unit -L-Rha-(1-2)--D-Glc outside the -CD cavity. For naringin 1 the inclusion occurs preferentially from the wider rim of the -CD truncated cone with the terminal phenolic ring deeply inserted into the -CD cavity while for naringin dihydrochalcon 2 it occurs from the side of the -CD narrower rim. The -CD/aglycon 3 complex exists as an equilibrium of the two inclusion modes.     

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.     

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.     

Synthesis and Characterization of Silica Gels Functionalized with Monochlorotriazinyl β-Cyclodextrin and their Sorption Capacities towards Organic Compounds

Different supports, containing a new derivative of-cyclodextrin – monochlorotriazinyl-cyclodextrin (-CDMCT) – used forthe reduction of pollutants in waste water, have beenprepared. They are based on silica gel, initially eithercoated with polyethyleneimine (PEI) or grafted with3-aminopropyltrimethoxysilane, functionalized in asecond step with -CDMCT. In order to obtainsorbents with high -cyclodextrin content andmaximum accessibility of the -CD cavity, thefuntionalization was studied while varying experimentalconditions. Thermogravimetry, Raman spectroscopy,specific surface area and pore size distribution were usedfor the characterization of supports. Sorption experimentsshow that these sorbents have sorption capacities towardssome organic pollutants. The mechanism of sorption is bothphysical adsorption in the polymer network (for supportsobtained by coating) and/or the formation of an inclusioncomplex between -CDMCT and guest molecules.     

Effects of Some Hydrotropic Agents on the Formation of Indomethacin/β-Cyclodextrin Inclusion Compounds

The influence of the water structure promoters, mannitol and sucrose, on the indomethacin/-cyclodextrin inclusion process at different pH values was evaluated using the phase solubility method and circular dichroism spectroscopy. The effect of mannitol and sucrose on the total solubilizing activity of -cyclodextrin as well as on the stabilization of the complex was moderate, and depended strongly on the pH value of the medium. The most pronounced effect on the association constant of the indomethacin inclusion compound was observed in KCl/HCl buffer of pH 1.6, because mannitol and sucrose, in the absence of -cyclodextrin, approximately double the indomethacin solubility so that the constant value decreases. On the other hand, a very strong complex formation between indomethacin and -cyclodextrin was observed in acid medium (KCl/HCl buffer, pH = 1.6), a fact not much discussed in the literature. The apparent association constant of the inclusion compound formed in the absence of mannitol or sucrose was found to be of the same order of magnitude as for the complex formed at pH 6.8. Changes in the optical activity of the indomethacin/-cyclodextrin inclusion complex were registered in the presence of sucrose, which interacts more strongly than mannitol with water molecules, and could probably adhere to the surface of the inclusion complex, thus changing its configuration and environment.     

Conformational Heterogeneity of a Tripeptide in the Solid State and in Solution: Characterization of a γ-Turn Containing Incipient Hairpin in Solution

A terminally blocked tripeptide Boc--Ala-Aib--Ala-OMe 1 with noncoded amino acids forms a novel type of hairpin structure containing a -turn instead of a conventional -turn in the central loop region in solution. This new type structural motif was characterized by NMR and restraint molecular dynamics simulation study. In the solid state peptide 1 adopts an extended backbone conformation and self-assembles to form supramolecular -sheet.     

Dual Behaviour of Maltosyl-β-Cyclodextrins: Investigation of Formation of Inclusion and Glucose-type Complexes

To clarify the complexation behaviour of the less studied maltosyl--cyclodextrin, its interactions with some characteristic guests such as phenolphthalein and p-nitrophenol have been studied. The results show that similar types of inclusion complexes are formed as in the case of the unsubstituted -cyclodextrin. In addition to the formation of inclusion complexes, maltosyl--cyclodextrins interact with other complexing reagents, like borate, vanadate or molybdate and the maltosyl substituent forms sugar-type complexes. The properties of these complexes are similar to those of glucose.     

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.     

Enhanced dissolution and oral bioavailability of α-tocopheryl esters by dimethyl-β-cyclodextrin complexation

Inclusion complexation of heptakis (2,6-di-O-methyl)--cyclodextrin (DM--CyD) with -tocopheryl acetate and -tocopheryl nicotinate in aqueous solution was studied by the solubility method. The aqueous solubilities of the esters were about 10⁵ times increased by DM--CyD complexation. The phase-solubility diagram of the tocopheryl ester-DM--CyD systems showed a typicalA _p type, and the stability constants (K) of high-order complexes were estimated by analyzing the upward curvature of the diagrams. The solid complex of -tocopheryl nicotinate with DM--CyD in a molar ratio of 12 was prepared by the kneading method. The dissolution rate of the solid complex was much greater than that of the drug itself, and the rapidly dissolving form of -tocopheryl nicotinate, as an example, showed a markedly increased bioavailability (about 70-fold) after oral administration to fasted dogs.     

Interaction of fluoroalkyl-containing β-diketones with amines

The composition of products of the interaction of asymmetric fluoroalkyl-containing -diketones with amines was studied. Mixtures of regioisomeric -aminovinylketones and products of cleavage and secondary condensation are formed, depending on the temperature, the solvent, the nature of the fluorinated and nonfluorinated substituents in the -diketone, and the basicity of the amine. The major product is a -aminovinylketone in which the NH₂ group is removed from the fluoroalkyl substituent. No -aminovinylimines, products of condensation involving two electrophilic centers, were observed.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 2278–2284, September, 1996.     

Reduction of photohemolytic activity of benoxaprofen byβ-cyclodextrin complexations

Inclusion complexations of benoxaprofen (BXP) with-cyclodextrin (-CyD) and heptakis (2,6-di-O-methyl)--CyD (DM--CyD) were studied by the solubility method and CD and¹H-NMR spectroscopy. Both -CyDs decelerated the photodecarboxylation of BXP, and suppressed the BXP-photosensitized hemolysis, where the inhibitory effect of DM--CyD was larger than that of -CyD. This order was well correlated with the magnitude of the stability constants of BXP--CyD complexes. The peroxidation of lipid components in erythrocyte ghosts induced by BXP was also suppressed particularly by DM--CyD. The protective effect of -CyDs on the BXP-induced photohemolysis seems to be due to the suppression in the photochemical reactions of BXP yielding toxic transient species, together with the inhibition in attacks of the transient species to the membrane, through inclusion complexation.     

Reaction of Pregnenolone and 3α,5-Cyclo-5α-pregnan-6β-ol-20-one with Trifluoroperacetic Acid

The reaction of pregnenolone and 3,5-cyclo-5-pregnan-6-ol-20-one with trifluoroperacetic acid produces the trifluoroacetates, hydrolysis of which gives the 3,5alpha;,6-triol.     

The Association of Triton X Surfactants with β-Cyclodextrin. An Isothermal Titration Calorimetry Study

The association with -cyclodextrinof a series of Triton X surfactants with differentethylene oxide (EO) chain lengths was studied byisothermal titration calorimetry at 298.15 K. Theresults agree with a 1:1 association model.Association constants and changes in Gibbs freeenergies, enthalpies and entropies were derived forthe association process. Association of thesesurfactants with -cyclodextrin have favorableenthalpy changes and unfavorable entropy changes. Theshorter the EO chain of the surfactant, the greaterthe association constant with -cyclodextrin.     

Selective reduction of the acyl group in cyclic α-acyl-β-dicarbonyl compounds with sodium cyanoborohydride. Efficient synthesis of cyclic α-alkyl-β-dicarbonyl compounds

Efficient synthesis of cyclic -alkyl--dicarbonyl compounds of the cyclopentane, cyclohexane, tetronic acid, and -pyrone series from the corresponding cyclic -acyl--dicarbonyl compounds under the action of NaBH₃(CN) in a THF--HCl system is described.