Itziar Vélaz

Inclusion complexation of glisentide with α-, β- and γ-cyclodextrins

Abstract Complexation of glisentide with α -, β - and γ -cyclodextrin (CD) has been investigated in aqueous solution and in the solid state. Complex formation in solution has been analysed using solubility diagrams and NMR spectroscopy and the interaction in solid state has been studied by X-ray diffractometry, DSC and IR spectroscopy. The thermodynamic parameters, Δ H °, Δ S ° and Δ G °, of complexation with β - and γ -CD have been calculated from the temperature dependence of the stability constant. The process has been found to be exothermic and Δ S ° is slightly unfavourable. In addition, it has been found that the ionization state of glisentide plays an important role in complexation and the fact that the extent of complexation is greater with β - than with γ -CD has revealed the importance of the cavity size to get an adequate fitting between host and guest molecules. The inclusion of the ortho -substituted aromatic ring of glisentide has been evidenced by NMR spectroscopy. Finally, complexes have been prepared by coprecipitation and kneading methods and it has been found that the former is more suitable to achieve solid-state complexation.

Interactions of naproxen with vinylpyrrolidone and β-cyclodextrin: a fluorimetric study1

Abstract A spectrofluorimetric method to study the interactions of naproxen with 1-vinyl-2-pyrrolidone and β -cyclodextrin in aqueous solution has been proposed. As complexation causes appreciable spectral changes, this method enables the determination of the stability constants. Complexation with β -cyclodextrin results in an enhancement of the fluorescence of naproxen whereas 1-vinyl-2-pyrrolidone involves a quenching of fluorescence. It has been supposed 1:1 complex formation. Specifically, formation constants, enthalpy and entropy values have been obtained for the aforementioned complexes at different temperatures and pH values; their associated errors are given.

A fluorimetric study of pindolol and its complexes with cyclodextrins

Spectrofluorimetric characteristics of pindolol have been investigated with the aim of using this technique for analytical determinations. Other monosubstituted indole derivatives, 4-methoxy and 5-methoxyindole, have been also studied for comparative purposes. Corrected excitation and emission wavelengths in different solvents are reported and the effect of solvent on the Stokes shifts of these compounds has been analysed using the Lippert equation. In addition, the Stokes shift of pindolol has been determined in dioxan-water solvent mixtures and the presence of specific solvent effects is discussed. The fluorescence of pindolol is pH dependent, the quantum yields determined in water are lower than those in other solvents. With respect to the sensitivity, it has been found that the detection limits in aqueous solutions are improved in the presence of beta and methyl-beta-cyclodextrin. Finally, a fluorimetric analysis of the interaction between pindolol and different cyclodextrins has been carried out in order to determine the apparent stability constants of the complexes and the thermodynamic parameters associated to complexation.

Effect of PEG 4000 on the dissolution rate of naproxen

SummaryNaproxen is a nonsteroidal anti-inflammatory drug characterized by its low wettability and poor water solubility.Solid dispersions naproxen:PPEC 4000 have been prepared in order to improve the solubility and dissolution rate of the drug, since these factors can be the limiting steps for absorption and bioavailability of poorly soluble drugs. X-ray diffraction analysis, infrared spectroscopy and differential scanning calorimetry detected no physico-chemical interaction between the drug and the inert carrier PEG 4000. The phase diagram of the naproxen-PEG 4000 system produced by DSC and hot stage microscopy is reported.The intrinsic dissolution rate of naproxen is calculated. The dissolution kinetics of solid dispersions prepared by the solvent and melt methods are compared with those of free drug and physical mixture. The studies were carried out at 37°C and pH 1.2 according to the dispersed amount method.The dissolution profiles obtained indicate that a significant dissolution enhancement occurs with solid dispersions in comparison with the physical mixture. In addition, the physical mixture showed a dissolution rate higher than the free drug. Dissolution rate constants were determined by fitting the experimental data to the cube root function, to get straight line plots.

Influence of soluble and insoluble cyclodextrin polymers on drug release from hydroxypropyl methylcellulose tablets

Background: The influence of β-cyclodextrin (β-CD) polymers on drug release from hydroxypropyl methylcellulose (HPMC) matrices has not been reported in the literature. Aim: The influence of monomeric β-CD and both soluble and insoluble β‐CD polymers on drug release from tablets containing either 30% or 50% hydroxypropyl methylcellulose has been studied using diflunisal (DF) as model drug. Method: The DF-β-CD inclusion complex (1:1 M) was prepared by coevaporation and characterised using X-ray diffraction, differential thermal analysis, and IR spectroscopy. The dissolution assays were performed according to the USP paddle method. Results: The incorporation of β-CD in the complexed form increases drug release from hydroxypropyl methylcellulose tablets in comparison with the physical mixture because of the better solubilization of the drug. The soluble polymer promotes drug release to a higher extent than the physical mixture with monomeric β-CD, but the insoluble polymer, which is itself a hydrogel, gives rise to the most retarded release profile, probably by retention of the drug in its structure. The formulations containing physical mixtures with either β‐CD or the soluble polymer present an optimum adjustment to zero-order release kinetics, and the inclusion complex followed non-Fickian diffusion according to the Korsmeyer–Peppas model. Conclusion: The release profile of DF from a HPMC matrix can be modulated in different ways by the use of either monomeric or polymeric β-CD.

Characterization of Complexes Between Naftifine and Cyclodextrins in Solution and in the Solid State

Naftifine (NF) is an antifungal drug poorly soluble in basic aqueous solutions. Complexation with cyclodextrins (CDs) improves the physicochemical characteristics of many drugs. The aim of this work is to characterize the interactions between NF and α-CD, β-CD, hydroxypropylβ-CD, methylβ-CD, and γ-CD. The studies have been developed in pH 12 aqueous solutions at 25°C and in the solid state. The apparent stability constants of the complexes have been determined from phase-solubility diagrams. In the solid state, crystalline and amorphous complexes have been characterized using X-ray diffraction patterns, thermal analysis, and Fourier transform infrared spectroscopy. The solubility of NF improves with all the CDs studied, with the exception of α-CD. Different types of diagrams have been found depending on the CD used. The interaction between NF and hydroxypropylβ-CD is stronger than that with β-CD due to the specific properties of the substituents. The coevaporation method can be said the best method in preparing the solid complexes, except for NF–α-CD; again, there is no evidence of complexation. Furthermore, the presence of different types of CD structures upon complexation (i.e., cage or channel) has been discussed. Dissolution rate studies have been performed, and a positive influence of complexation in the solid state has been observed.

Dissolution kinetics for coprecipitates of diflunisal with PVP K30.

SummaryDiflunisal is a nonsteroidal anti-inflammatory drug that is poorly soluble in water. The present study describes the formulation of solid dispersions of the drug designed to increase its solubility. X-ray diffraction and DSC were used to examine the physico-chemical characteristics of solid dispersions of diflunisal and polyvinylpyrrolidone (PVP) prepared by the solvent method, using percentage proprtional compositions ranging from 20:80 to 50:50.X-ray diffraction analysis detected that diflunisal is present in solid dispersions in crystalline or amorphous state depending on the PVP content.The thermal behavior of diflunisal observed in the DSC curves of solid dispersion systems, was attributed to a solid-state interaction.The increased release of the PVP-drug dispersion as compared to the PVP-drug physical mixture was attributed to the formation of a complex resulting from the interaction of the drug and the polymer.

In Vitro Release from Reverse Poloxamine/α-Cyclodextrin Matrices: Modelling and Comparison of Dissolution Profiles

Gels obtained by complexation of octablock star polyethylene oxide/polypropylene oxide copolymers (Tetronic 90R4) with α-cyclodextrin (α-CD) were evaluated as matrices for drug release. Both molecules are biocompatible so they can be potentially applied to drug delivery systems. Two different types of matrices of Tetronic 90R4 and α-CD were evaluated: gels and tablets. These gels are capable to gelifying in situ and show sustained erosion kinetics in aqueous media. Tablets were prepared by freeze-drying and comprising the gels. Using these two different matrices, the release of two model molecules, L-tryptophan (Trp), and a protein, bovine serum albumin (BSA), was evaluated. The release profiles of these molecules from gels and tablets prove that they are suitable for sustained delivery. Mathematical models were applied to the release curves from tablets to elucidate the drug delivery mechanism. Good correlations were found for the fittings of the release curves to different equations. The results point that the release of Trp from different tablets is always governed by Fickian diffusion, whereas the release of BSA is governed by a combination of diffusion and tablet erosion.

Analysis of the complexation of gemfibrozil with γ- and hydroxypropyl-γ-cyclodextrins

The interactions of gemfibrozil with gamma- and HP-gamma-cyclodextrin (CD) have been studied in aqueous solution by fluorescence and NMR spectroscopy and by solubility measurements and in the solid state by X-ray diffraction, thermal analysis and FTIR spectroscopy. The influence of the technique employed in the analysis of complexation is discussed. The fluorescence of gemfibrozil increased in the presence of gamma- and hydroxypropyl-gamma-cyclodextrin (HP-gamma-CD), especially with the later, because the inclusion of the aromatic ring in the cavity, evidenced by 1H NMR, has a protective effect on the excited state of the drug. The fluorescence enhancement allowed the determination of the binding constants at pH 2.8. Complexation was a both entropy and enthalpy driven process. The solubility diagrams obtained with gamma-CD and HP-gamma-CD were B(s) and A(L) type, respectively. The apparent stability constants calculated from the solubility data at 25 degrees C were compared with those obtained from the fluorescence assays. It was found that drug solubilization with gamma-CD involves other contributions together with the inclusion phenomena. Solid complexes of gemfibrozil with gamma-CD (and not with HP-gamma-CD) have been obtained by kneading, coevaporation and coprecipitation methods. The solid complexes crystallised in the channel structure, in a process involving the carboxyl and aryl-ether groups.

RESEARCH ARTICLEIn Vitro Release from Reverse Poloxamine/α-Cyclodextrin Matrices: Modelling and Comparison of Dissolution Profiles

Gels obtained by complexation of octablock star polyethylene oxide/polypropylene oxide copolymers (Tetronic 90R4) with α-cyclodextrin (α-CD) were evaluated as matrices for drug release. Both molecules are biocompatible so they can be potentially applied to drug delivery systems. Two different types of matrices of Tetronic 90R4 and α-CD were evaluated: gels and tablets. These gels are capable to gelifying in situ and show sustained erosion kinetics in aqueous media. Tablets were prepared by freeze-drying and comprising the gels. Using these two different matrices, the release of two model molecules, L-tryptophan (Trp), and a protein, bovine serum albumin (BSA), was evaluated. The release profiles of these molecules from gels and tablets prove that they are suitable for sustained delivery. Mathematical models were applied to the release curves from tablets to elucidate the drug delivery mechanism. Good correlations were found for the fittings of the release curves to different equations. The results point that the release of Trp from different tablets is always governed by Fickian diffusion, whereas the release of BSA is governed by a combination of diffusion and tablet erosion.