In vitro Release Study of Tretinoin from Tretinoin/Cyclodextrin Derivative Complexes

The effects of -cyclodextrin, hydroxypropyl -cyclodextrin and dimethyl -cyclodextrin complexes on the in vitro release of tretinoin gels were investigated. The experiments were carried out in a Franz cell using a silicone membrane as a barrier for the diffusion of the vehicle. Two types of vehicle were compared: a hydroalcoholic gel in which both tretinoin and the inclusion complexes are soluble, and an aqueous gel in which only the complexes are soluble but tretinoin is dispersed. As expected, the release rate of free tretinoin in the hydroalcoholic gel is much faster than in the aqueous gel. However, with the aqueous gel, the cyclodextrin complexation enhances the diffusion rate of the active drug through the membrane, especially with the hydroxypropyl cyclodextrin inclusion compound. The release of tretinoin is related not only to the stability constant of the inclusion, but also to the binding properties of the inclusion compounds to the vehicle.     

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.     

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.     

The terfenadine/β-cyclodextrin inclusion complex

Terfenatine (TFN) is a very hydrophobic antiallergic drug. It exists in three polymorphic and two solvated forms and is practically insoluble in water. These properties make a pharmaceutical formulation with acceptable biopharmaceutical characteristics difficult to prepare. Inclusion complexation with -cyclodextrin (CD) may eliminate such problems. The properties of the TFN/CD system have been studied in liquid, gaseous and solid phases by¹H and¹³C NMR spectroscopy, powder X-ray diffractometry, differential scanning calorimetry and fast atom bombardment mass spectrometry. The solubility phase diagram was also recorded. In solution and in the gaseous phase the 11 complex prevails, whereas a 12 TFN/CD complex has been isolated by precipitation from homogeneous solution.     

Reaction of β-Cyclodextrin with N-2,3-Epoxypropylphthalimide. Preparation, Characterisation and Study of a New Substituted Cycloheptaamylose. Effects on the Water Solubility of Drugs

The reaction of -cyclodextrinwith N-2,3-epoxypropylphthalimide yielded a set of newamorphous host compounds with high solubility whichwas transmitted to the corresponding host-guestcomplexes. The structure was determined by comparing the 1H- and 13C-NMR spectra with those of theparent compound, the degree of substitution by integration of the corresponding NMR signals, and C, H,and N elemental analysis.     

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.     

Photochemical addition of diethyl ether to β,β,β',β'-tetrakis(trifluoromethyl)divinyl ether

The 1:1 adducts of diethyl and ,,','-tetrakis(trifluoromethyl)divinyl ether (1),i.e., 3,5-(ee)-bis[2,2,2-trifluoro-1-(trifluoromethyl)ethyl]-2,6-dimethyl-1,4-dioxane (2) (3 isomers) and 4-ethoxy-1,1,1-trifluoro-2-trifluoromethyl-3-[3,3,3-trifluoro-2(trifluoromethyl)propenyloxy]pentane (3), have been obtained by UV-irradiation of a solution of divinyl ether1 in diethyl ether. The X-ray structural investigation of the all-(e)-isomer of dioxane (2) has been carried out.Deceased.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 85–88, January, 1994.     

Elucidation of a common structure of selective fibrinogen receptor antagonists

In this paper, we investigate the common structural and electrostatic parameters of a series of specific inhibitors of the IIb3 integrin. Molecular dynamics simulations with an explicit aqueous environment led to an original theoretical pattern. Our results may suggest that the studied non-peptide IIb3 antagonists developed upon the Arg-Gly-Asp ubiquitous recognition sequence, in fact, should mimic the C-terminus part of the fibrinogen chain. This assumption could, therefore, explain their specificity with respect to other Arg-Gly-Asp-dependent integrins.     

Experimental and Theoretical Studies on the Inclusion Complexation of β-Cyclodextrin with Phenothiazine Derivatives

Inclusion complexation of -cyclodextrin (-CD) with N-phenylphenothiazine ( 1), N-benzylphenothiazine ( 2) and N-phenethylphenothiazine ( 3) has been studied by means of UV-vis spectroscopy and molecular dynamics simulations. The association constants (K_a) were determined to be 126, 312 and 211 dm³/mol for inclusion of -CD with 1, 2 and 3, respectively. It shows that the K_a values are affected by the substituents of the guest compounds. The structures of the complexes and the conformation of the guest compounds bound by -CD in the complex have been discussed.     

Charge-transfer complexes betweenp-toluidine and iodine in solution: A kinetic study

The kinetics of charge-transfer interaction betweenp-toluidine and iodine in methylene chloride was investigated in depth. Thethermal process of formation of theinner complex was found to proceed to an equilibrium. Thephotochemical process follows a different reaction coordinate, going through the formation of an exciplex between the excitedouter complex and the amine ground state. In both cases the same ionic complex (Am ₂I⁺I ₃ ^– , whereAm stands forp-toluidine) was detected as the final product.

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Kinetische Untersuchung der Charge-Transfer-Komplexe zwischenp-Toluidin und Jod

Zusammenfassung Die Kinetik der Charge-Transfer-Wechselwirkung zwischenp-Toluidin und Jod in Methylenchlorid wurde ausführlich untersucht. Derthermische Prozeß, der zur Bildung desinner-Komplexes führt, geht bis zu einem Gleichgewicht. Derphotochemische Prozeß folgt einer unterschiedlichen Reaktionskoordinate und verläuft über die Bildung eines Exziplexes zwischen dem angeregtenouter-Komplex und dem Amin im Grundzustand. In beiden Fällen wurde derselbe ionische Komplex (Am ₂I⁺I ₃ ^– , wobeiAm fürp-Toluidin steht) als Endprodukt festgestellt.

     

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.     

Spectroscopic and quantum chemical investigation of enol-enol tautomerism of 2-acetyltetronic acid

Vibratonal spectra of 2-acetyltetronic acid (ATA) (3-acetyloxolane-2,4-dione) were investigated in different aggregate states.Ab initio quantum chemical calculations (3-21G basis set) of 2-formyltetronic acid as analogue of ATA and semi empirical calculation of ATA were carried out. The tautomeric forms of ATA can be arranged in the following series with respect to thermodynamic stability (in decresing order):1a,1b,2a,2b.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1043–1048, June, 1995.     

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

The known compound cyclocantogenin (1) and a new cycloartane glycoside cyclounifolioside C (2), which has the structure 24R-cycloartan-3,6,16,24,25-pentaol 3-O--D-glucopyranoside, were isolated from roots of Astragalus unifoliolatus Bunge. The structures of the isolated compounds are established using hydrolysis and spectral data.     

Molecular Modeling Studies of the β-Cyclodextrin in Monomer and Dimer Form as Hosts for the Complexation of Cholesterol

Molecular modeling studies on the inclusion complex formation ofcholesterol with -cyclodextrin in monomer anddimer form were performed. Monte Carlo docking simulations, moleculardynamics, and non-equilibrium molecular dynamicssimulations were applied to assess the energeticdriving force for the formation of these inclusioncomplexes. Both Monte Carlo docking and moleculardynamics simulations supported the more favorableinclusion complex formation of -cyclodextrindimer. Non-equilibrium molecular dynamics simulationsprovided a direct assessment of the binding force for theinclusion complexes, of which that of dimer form is much greater.     

Unexchangeable Interlayer Anions; Synthesis and Characterization of Zn/Al- and Mg/Al-Layered Double Hydroxides with Interlayer Alizarin red S

The formation of complexes between -cyclodextrin and 1-alkanols hasbeen studied calorimetrically at 298 K in water and in concentrated aqueoussolutions of ethanol or urea. When a complex is formed, calorimetry enables thecalculation of both the enthalpy and the association constant, from which thefree energy and the entropy of the process can be obtained. The effects ofethanol and urea on the hydration cospheres of the interacting substances havebeen investigated through the study of the binary solutions of the involvedsolutes in water and in the mixed solvents. The findings obtained are, then,related to the consequent changes in the association parameters.The forces involved in the association process are discussed in the light of the signsand values of the thermodynamic parameters obtained. The most important featurescoming out from this study are: (i) association in water is an entropy-driven process;(ii) in concentrated aqueous solutions of cosolvent, the enthalpic term contributessignificantly to the Gibbs energy, while the entropic contribution is smaller; (iii) forevery solvent medium employed, the invariance of the entropic contribution withincreasing alkyl chain length of the alkanol is an indication that the relaxation ofwater molecules from the cavity of the macrocycle mainly determines the associationprocess.     

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.     

Alfaxalone: Effect of Temperature on Complexation with 2-Hydroxypropyl-β-cyclodextrin

Phase solubility analysis is used to investigate the complex formation of alfaxalone with various cyclodextrins(2-hydroxypropyl--cyclodextrine [HPBCD],-cyclodextrin [BCD] and2-hydroxypropyl--cyclodextrin [HPGCD]).The complexationwith HPBCD was studied in more detail by looking at the effect of temperature on the stability constants using phase solubility analysis. HPLC-analysis was used to measure the dissolved amount of alfaxalone.The solubility of alfaxalone increases linearly with increasing concentration of cyclodextrin, suggesting the formation of a 1 : 1 complex. For the parent BCD the complex starts precipitating out of solution when the solubilizer concentration exceeds 0.25% making the unsubstituted BCD less useful for the preparation of solutions of alfaxalone. Substituted cyclodextrins do not form insoluble complexes with alfaxalone. The complexation constant for BCD and HPBCD are comparable in magnitude, but for HPGCD, the constant is substantially lower.The effect of temperature on thecomplexation constant was also studied at elevated temperature. Increasing the temperature results in an increased S₀ (solubility without HPBCD) and a decrease in the value of the complexation constant. The net effect results in minor changes of the solubility of alfaxalone as a function of temperature. Based on regression analysis, the change in enthalpy for complex formation between alfaxalone and HPBCD is calculated as -4610 cal/mol.The results indicate that substitutedcyclodextrins are useful in the preparation of solutions of alfaxalone. Since 1 : 1 complexes are formed there is no theoretical danger for precipitation on dilution, e.g., after injection.     

Reactions with β-cyanoethylhydrazine,III. A new approach for the synthesis of substituted 3,5-diaminopyrazole and 1,2,4-triazoles

The reactivity of -cyanoethylhydrazine toward enaminonitrile and aroyl isothiocyanates is reported. A variety of 3,5-diaminopyrazole and ³-1,2,4-triazolin-5-thione derivatives could be prepared.

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Reaktionen mit -Canyethylhydrazin, 3. Mitt.: Ein neuer Weg zur Synthese von substituierten 3,5-Diaminopyrazolen und 1,2,4-Triazolen

Zusammenfassung Es wird über die Reaktivität von -Cyanethylhydrazin gegenüber Enaminonitril und Aroylisothiocyanaten berichtet. Es konnte eine Reihe von 3,5-Diaminopyrazol-und ³-1,2,4-Triazolin-Derivaten hergestellt werden.

     

Semiempirical calculations on cyclodextrins

In order to obtain information on the different reactivities of the hydroxyl groups of the glucopyranose units or the inclusion complex formation mechanism, the charge distributions and the geometrical constraints must be determined. Geometry optimizations, employing the AM1 semiempirical method, have been performed for -D-glucopyranose, –,–, and -cyclodextrins. The data obtained were compared with X-ray diffraction data of the cyclodextrins.Dedicated to Professor József Szejtli.     

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.