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Cyclodextrins are able to form host-guest complexes with hydrophobic molecules to result in the formation of inclusion complexes. The complex formation between norfloxacin form A and β-cyclodextrin was studied by exploring its structure affinity relationship in an aqueous solution and in the solid state. Kneading, freeze-drying, and physical mixture methods were employed to prepare solid complexes of norfloxacin and β-cyclodextrin. The solubility of norfloxacin significantly increased upon complexation with β-cyclodextrin as demonstrated by a solubility isotherm of the AL type along with the results of an intrinsic dissolution study. The complexes were also characterized in the solid stated by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier-transform infrared (FT-IR) spectroscopy, X-ray diffractometry, scanning electron microscopy (SEM), and solid-state nuclear magnetic resonance (ssNMR) spectrometry. The thermal analysis showed that the thermal stability of the drug is enhanced in the presence of β-cyclodextrin. Finally, the microbiological studies showed that the complexes have better potency when compared with pure drug. publishedVersion Fil: Chierentin, Lucas. Universidade Estadual Paulista Julio de Mesquita Filho. Faculdade de Ciências Farmacêuticas; Brazil. Fil: Garnero, Claudia. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; Argentina. Fil: Garnero, Claudia. Universidad Nacional de Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; Argentina. Fil: Garnero, Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; Argentina. Fil: Chattah, Ana Karina. Universidad Nacional de Córdoba. Facultad de Matemática, Astronomía y Física; Argentina. Fil: Chattah, Ana Karina. Universidad Nacional de Córdoba. Instituto de Física Enrique Gaviola; Argentina. Fil: Chattah, Ana Karina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Física Enrique Gaviola; Argentina. Fil: Delvadia, Poonam. Virginia Commonwealth University. Department of Pharmaceutics, School of Pharmacy; United States of America. Fil: Karnes, Thomas. Virginia Commonwealth University. Department of Pharmaceutics, School of Pharmacy; United States of America. Fil: Longhi, Marcela Raquel. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Ciencias Farmacéuticas; Argentina. Fil: Longhi, Marcela Raquel. Universidad Nacional de Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; Argentina. Fil: Longhi, Marcela Raquel. Consejo Nacional de Investigaciones Científicas y Técnicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; Argentina. Fil: Salgado, Hérida Regina Nunes. Universidade Estadual Paulista. Faculdade de Ciências Farmacêuticas; Brazil. Química orgánica

In this study, cyclodextrin inclusion complexes with rutin were prepared via co-precipitation method. Stability constant and solubility energy of beta-cyclodextrin complex were calculated as 262 M−1 and 1,737 kJ mol−1, respectively. Aqueous solubility of rutin was increased with inclusion complex of beta-cyclodextrin. The effect of temperature on both aqueous solubility of free rutin, and its inclusion complex was also studied. Characterization of cyclodextrin complexes were conducted with UV–Vis spectrophotometry, Fourier transform infrared spectroscopy, X-ray diffractometry, differential scanning calorimetry, thermal gravimetric analysis, nuclear magnetic resonance spectroscopy and scanning electron microscopy techniques. Characterization results supported formation of inclusion complexes. Dissolution profiles of rutin, physical mixture and inclusion complex of rutin were observed at 37 °C. Dissolution results proved the effect of cyclodextrin addition on solubility rate of rutin. After loading rutin and its complexes into silk fibroin based films, release tests were performed at 37 °C in neutral pH conditions for 24 h. Most of the rutin were released from silk fibroin films within the first 5 h and the rest of it was released slowly (sustained release). Electron microscope analyses showed that films had homogenous and dense morphologies. These results revealed that silk fibroin is useful for preparing bioactive films loaded with natural compounds and for modifying their release behaviour at physiological conditions.

The interaction of imidazolium-based ionic liquids with alpha- and beta-cyclodextrins was investigated by electrospray ionization mass spectrometry with variable collision induced dissociation energy and quantum chemical gas-phase calculations. The center-of-mass energy at which 50 % of a precursor ion decomposes (E-cm,E-1/2) was determined for the isolated [cyclodextrin + cation](+) or [cyclodextrin + anion](-) adduct ions of imidazolium-based ionic liquids with different alkyl chain lengths combined with a large set of anions, such as chloride, bromide, bis(trifluoromethylsulfonyl)imide, tetrafluoroborate, hexafluorophosphate, trifluoromethanesulfonate, methanesulfonate, dicyanamide, and hydrogensulfate. Moreover, both symmetric and asymmetric imidazolium cationic cores were evaluated. The relative interaction energies in the adduct ions were interpreted in terms of the influence of cation/anion structures and their inherent properties, such as hydrophobicity and hydrogen bond accepting ability, in the complexation process with the cyclodextrins. The trends observed in the mass spectral data together with quantum-chemical calculations suggest that in the gas phase, cations and anions will preferentially interact with the lower or upper rim of the cyclodextrin, respectively, as opposed to what has been reported in condensed phase where the formation of an inclusion complex between ionic liquid and cyclodextrin is assumed.

The design of enzyme mimics with therapeutic and industrial applications has interested both experimental and computational chemists for several decades. Recent advances in the computational methodology of restrained molecular dynamics, used in conjunction with data obtained from two-dimensional H-1 NMR spectroscopy, make it a promising method to study peptide and protein structure and function. Several issues, however, need to be addressed in order to assess the validity of this method for its explanatory and predictive value. Among the issues addressed in this study are: the accuracy and generizability of the GROMOS peptide molecular mechanics force field; the effect of inclusion of solvent on the simulations; and the effect of different types of restraining algorithms on the computational results. The decapeptide Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly, which corresponds to the sequence of ACTH(1-10), has been synthesized, cyclized, and studied by two-dimensional H-1 NMR spectroscopy. Restrained molecular dynamics (RMD) and time-averaged restrained molecular dynamics (TARMD) simulations were carried out on four different distance-geometry starting structures in order to determine and contrast the behavior of cyclic ACTH(1-10) in vacuum and in solution. For the RMD simulations, the structures did not fit the NOE data well, even at high values of the restraining potential. The TARMD simulation method, however, was able to give structures that fit the NOE data at high values of the restraining potential. In both cases, inclusion of explicit solvent molecules in the simulation had little effect on the quality of the fit, although it was found to dampen the motion of the cyclic peptide. For both simulation techniques, the number and size of the NOE violations increased as the restraining potential approached zero. This is due, presumably, to inadequacies in the force field. Additional TARMD vacuum-phase simulations, run with a larger memory length or with a larger sampling size (16 additional distance-geometry structures), yielded no significantly different results. The computed data were then analyzed to help explain the sparse NOE data and poor chymotryptic activity of the cyclic peptide. Cyclic ACTH(1-10), which contains the functional moieties of the catalytic triad of chymotrypsin, was evaluated as a potential mimic of chymotrypsin by measurement of the rate of hydrolysis of esters of L- and D-phenylalanine. The poor rate of hydrolysis is attributed to the flexibility of the decapeptide, the motion of the side chains, which result in the absence of long-range NOEs, the small size of the macrocycle relative to that of the substrate, and the inappropriate orientation of the Gly, His, and Ser residues. The results demonstrate the utility of this method in computer-aided molecular design of cyclic peptides and suggest structural modifications for future work based on a larger and more rigid peptide framework.

In the present work, inclusion complexes of α-terpineol (Terp) and β-cyclodextrin (BCD) were prepared by the coprecipitation method. Phase solubility studies were performed and thermodynamic parameters involved in the complex formation were calculated. The solubility of Terp increased linearly as the concentration of BCD was increased, confirming the 1:1 stoichiometry of the complex. The stability constants decreased along with increasing temperature. The negative value of the enthalpy and of the Gibbs free energy demonstrated that the process is exothermic and spontaneous. Since complexation gives more ordered systems, the negative value obtained for the entropy change evidenced the encapsulation of Terp. Terp was completely encapsulated in BCD at the preparation conditions and studied molar ratios, as confirmed in the freeze-dried samples by differential scanning calorimeter. The presence of Terp greatly modified the BCD water sorption curves, and the amount of adsorbed water was lower for the complexes. The limited water solubility of Terp could be overcome by the formation of BCD inclusion complexes, and the complexes were stable at different storage conditions (relative humidities 11-97% and 25 °C). The obtained phase solubility data are useful for food or pharmaceutical products formulation involving cyclodextrins and stability predictions. Fil: Mazzobre, Maria Florencia. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Industrias; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Dos Santos Ferreira, Cristina Isabel. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Industrias; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Buera, Maria del Pilar. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Industrias; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

15th International Cyclodextrin Symposium -- MAY 09-12, 2010 -- Vienna, AUSTRIA, WOS: 000294963800024, Fluconazole (FZ) is a triazole antifungal drug administered orally or intravenously. It is employed for the treatment of mycotic infections. However, the efficacy of FZ is limited with its poor aqueous solubility and low dissolution rate. One of the important pharmaceutical advantages of cyclodextrins is to improve pharmacological efficacy of drugs due to increasing their aqueous solubility. The aim of present study was to prepare an inclusion complex of FZ and beta-cyclodextrin (beta-CD) to improve the physicochemical and biopharmaceutical properties of FZ. The effects of beta-CD on the solubility of FZ were investigated according to the phase solubility technique. Complexes were prepared with 1: 1 M ratio by different methods namely, freeze-drying, spray-drying, co-evaporation and kneading. For the characterization of FZ/beta-CD complex, FZ amount, practical yield %, thermal, aqueous solubility, XRD, FT-IR and NMR (H-1 and C-13) analysis were performed. In vitro dissolution from hard cellulose capsules containing FZ/beta-CD complexes was compared to pure FZ and its commercial capsules and evaluated by f(1) (difference) and f(2) (similarity) factors. Paddle method defined in USP 31 together with high pressure liquid chromatographic method were used in in vitro dissolution experiments. It was found that solubility enhancement by FZ/beta-CD complexes depends on the type of the preparation method. High release of active agent from hard cellulose capsules prepared with beta-CD complexes compared to commercial capsules was attributed to the interactions between beta-CD and active agent, high energetic amorphous state and inclusion complex formation.

15th International Cyclodextrin Symposium -- MAY 09-12, 2010 -- Vienna, AUSTRIA, WOS: 000294963800025, Ketoconazole (KZ) is an imidazole antifungal agent which is administered topically and also orally. KZ is practically insoluble in water. Vaginal candidiasis is a common condition and up to 75% of all women have at least one episode of this infection during their lifetime. The aim of study was to prepare KZ/beta-cyclodextrin (beta-CD) complex to improve the physicochemical properties of KZ and to investigate the possibility of preparing vaginal suppositories with the complexes. A linear increase in KZ solubility as a function of beta-CD concentration was verified using the phase-solubility diagram. The resulting diagram was classified as AL-type, is generally related to the formation of a soluble complex. Complexes were prepared in a 1: 1 molar ratio by different methods, namely freeze-drying, spray-drying, co-evaporation and kneading. Characterization of the complexes prepared was performed by practical yield %, aqueous solubility, active agent amount analyses, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), powder X-ray diffractometry (PXRD) and H-1 and C-13 nuclear magnetic resonance (NMR) spectroscopy. Characterization studies provided additional evidences of complexation. The paddle method defined in USP31 was used in in vitro dissolution experiments on the prepared vaginal suppositories. It was found that solubility enhancement by preparing KZ/beta-CD complexes depends on the type of the preparation method. Dissolution of KZ from complexes was found to be faster than the active agent and the commercial suppositories. This result may be attributed to the interactions between beta-CD and active agent, high energetic amorphous state and decrease in the interfacial tension between insoluble active agent and dissolution media.