Estimation of partitioning parameters of nonionic surfactants using calculated descriptors of molecular size, polarity, and hydrogen bonding.

A study was carried out to verify the capacity of the Abraham's solute descriptors (R2, an excess molar refraction; pi 2H, the dipolarity/polarizability; sigma alpha 2H and sigma beta 2H, the summation hydrogen-bond acidity and basicity; and Vx, the characteristic volume of McGowan) to predict the alkane-water partition coefficient (log Palk) of nonionic surfactants. Log P values were taken from the literature and examined for linear solvation energy-related (LSER) equations with calculated physicochemical descriptors. A stepwise multiple linear regression (MLR) analysis allowed us to derive LSER models which, unlike those previously published for a standard set of solutes, revealed that R2 and sigma beta 2H are the major contributors to log Palk. A minor contribution of Vx was also detected, whereas surprisingly sigma alpha 2H required a positive coefficient. The less relevant size effect seems to indicate that for nonionic surfactants the energy needed for creating a water cavity is largely compensated for by the favorable interactions of ethoxy groups in the polar chain with water, whereas the log P-increasing effect of hydrogen-bond donor groups could be explained by considering the occurrence of folded, more lipophilic conformers, favored by the formation of intramolecular hydrogen bonds in the apolar phase. This hypothesis was substantiated by the calculation of the molecular lipophilicity potential on the water-accessible surface of extended and folded conformers of two representative surfactants, selected by high-temperature molecular dynamics. Besides MLR, a principal component analysis on a larger set of descriptors, comprising three solubility parameters (delta D, based on dispersion forces; delta H, including the contribution of hydrogen bonding; delta O, overall solubility parameter) afforded the so-called principal properties, which were able to characterize nonionic surfactants and to satisfactorily assess their lipophilicity-related properties.

Physicochemical characterization and in vivo properties of Zolpidem in solid dispersions with polyethylene glycol 4000 and 6000.

Solid dispersions and physical mixtures of Zolpidem in polyethylene glycol 4000 (PEG 4000) and 6000 (PEG 6000) were prepared with the aim to increase its aqueous solubility. These PEG based formulations of the drug were characterized in solid state by FT-IR spectroscopy, X-ray powder diffraction, and differential scanning calorimetry. By these physical determinations no drug-polymer interactions were evidenced. Both solubility and dissolution rate of the drug in these formulations were increased. Each individual dissolution profile of PEG based formulation fitted Baker-Lonsdale and first order kinetic models. Finally, significant differences in ataxic induction time were observed between Zolpidem orally administered as suspension of drug alone and as solid dispersion or physical mixture. These formulations, indeed, showed almost two- to three-fold longer ataxic induction times suggesting that, in the presence of PEG, the intestinal membrane permeability is probably the rate-limiting factor of the absorption process.

Dissolution properties and anticonvulsant activity of phenytoin-polyethylene glycol 6000 and -polyvinylpyrrolidone K-30 solid dispersions.

Solid dispersions of phenytoin in polyethylene glycol 6000 and polyvinylpyrrolidone K-30 with different drug-to-carrier ratios were prepared by the solvent method with the aim of increasing dissolution rate and bioavailability of the drug. These new formulations were characterized in the solid state by FT-IR spectroscopy, X-ray powder diffraction, and differential scanning calorimetry. Drug solubility and dissolution rate are improved by these formulations, particularly with SDPEG 1/20 and SDPVP 1/20 systems. Storage was found to influence the stability of the solid dispersions. By maximal electroshock test, it was found that the intraperitoneal administration in mice of the SDPEG 1/20 and SDPVP 1/20 systems exhibited anticonvulsant activity similar to diphenylhydantoin sodium salt.

Effects of different cyclodextrins on the morphology, loading and release properties of poly (DL-lactide-co-glycolide)-microparticles containing the hypnotic agent etizolam.

The aim of this study was to gain insight into the feasibility of using microparticles (MPs) constituted by the biodegradable poly (DL-lactide-co-glycolide) (PLGA) and a number of cyclodextrins (CDs) as an orally sustained delivery system of the hypnotic agent etizolam (ETZ). A further aim of the work was to investigate the effects of different CDs on the morphology, loading, and release properties of the MPs prepared. For these purposes, ETZ alone, and ETZ/CD-PLGA loaded MPs were prepared by the W/O/W emulsion-solvent evaporation method. It was found that the release of ETZ in vitro was more prolonged over three days with a kinetic constant proportional to t(1/2). It was also demonstrated that the CDs in these MPs are able to modulate several properties such as morphology, drug loading, and release properties. In fact, marked differences in shape, surface, and encapsulation efficiencies were noted depending on the presence, hydrophilicity, and charge of the CD employed. The obtained results induce us to consider the present ETZ-containing formulations as new valuable tools for the treatment of different insomnia categories.

Valproic acid-hydrophilic cyclodextrin complexes and valproic acid-solid dispersions: evaluation of their potential pharmaceutical use.

The purpose of this study was to evaluate the potential use of two novel solid formulations of valproic acid (VPA) prepared by complexation with hydrophilic cyclodextrins (CDs) as hydroxypropyl-beta- and sulfobutylether-beta-cyclodextrin and by solid dispersion (SD) in hydrophilic carriers as polyethylene glycol 6000 (PEG 6000) and polyvinylpyrrolidone K-30 (PVP K-30). The corresponding cyclodextrin-based complexes were prepared by the freeze-drying method while the solid dispersions were obtained by the solvent method. Valproic acid solubility improved by CDs complexation and solid dispersion techniques. Comparison of dissolution profiles with that of VPA sodium salt (NaVP) was made by using release parameters such as dissolution efficiency, percent of drug dissolved after 60 min, and difference and similarity factors. Based on difference and similarity factors, it can be concluded that all the VPA formulations possess dissolution profiles essentially equivalent to those of NaVP at pH 6. However, this conclusion is not confirmed by using the analysis of variance (ANOVA) approach, indicating some significant differences between some SD-based formulations and NaVP at that pH value. Preliminary pharmacological studies in the pentylenetetrazole test in rats showed some important differences among the SD-based formulations, NaVP, and VPA as oil/water emulsion. Some implications and limitations of the investigated formulations are discussed.