Yoshinobu Nakai

Dissolution rate and bioavailability of griseofulvin from a ground mixture with microcrystalline cellulose

A ground mixture of griseofulvin and microcrystalline cellulose was prepared by grinding them in a vibrational ball mill. The dissolution rate and bioavailability of griseofulvin from the ground mixture were shown to be significantly greater than those from a micronized griseofulvin powder.

Freeze-drying of drug-additive binary systems III. Crystallization of α-cyclodextrin inclusion complex in freezing process

Abstract The crystallization of α-cyclodextrin (α-CD) inclusion complexes during the process of freeze-drying has been studied. Benzoic acid, salicylic acid, m -hydroxybenzoic acid, p -hydroxybenzoic acid and methyl p -hydroxybenzoate were used as guest molecules. Various amounts of guest compound were dissolved in aqueous α-CD solution. By annealing the binary solutions at −13 to −18°C, the inclusion complex crystallized readily at a molar ratio of 2:1 (α-CD: guest). All inclusion crystals obtained via freeze-drying were of a channel-type structure, while in the coprecipitation method p -hydroxybenzoic acid and methyl p -hydroxybenzoate formed a layer-type inclusion crystal with α-CD. Further, an aqueous binary solution of α-CD and aspirin (2:1 molar ratio) was slowly frozen at −14°C, and then lyophilized. The infrared spectra and the powder X-ray diffractograms indicated that the channel-type inclusion compound of aspirin with α-CD was formed by freeze-drying, although the coprecipitation method did not provide the inclusion compound crystal. It was assumed that the mechanism of solid-phase formation differed between the freezing and coprecipitation processes and that the channel-type structure of α-CD inclusion crystal was preferentially formed during the freezing process.

Interaction of tri-O-methyl-?-cyclodextrin with drugs

The effect of tri-0-methyl-β-cyclodextrin( methyl-β-CD ) on the partition coefficients of drugs, such as p-nitrophenol, salicylic acid, benzoic acid, and aspirin, was studied at 25 °C. The partition coefficients of these drugs were increased linearly with methyl-β-CD concentration. The increase of partition coefficients was interpreted by the 1:1 complex formation between methyl-β-CD and the drug in CHCl3 phase.

Thermal behavior of ground mixtures of heptakis (2,6-di-O-methyl)-β-cyclodextrin and benzoic acid

Characterization of an inclusion complex prepared from amorphous ground mixtures of heptakis (2,6-di-O-methyl)-β-cyclodextrin (DMβCD) and benzoic acid was carried out by a sealed heating method. The formation of the crystalline inclusion complex and the variation in physicochemical properties of the ground mixture were investigated as a function of heating temperature. On the basis of X-ray diffractometry and Fourier transform infrared spectroscopy, the crystallization of the ground mixture was confirmed to take place at about 135°C. The crystallization temperature was shifted to lower temperatures and the bound molar ratio of benzoic acid to DMβCD increased as the mixing molar ratio of benzoic acid to DMβCD was raised.

Dissolution studies in organic solvents for evaluating hydrogen-bond matrix of cellulose in the ground mixture

Abstract Benzoic acid crystals were ground with microcrystalline cellulose. In order to evaluate the hydrogen-bond matrix of cellulose in the ground mixture, dissolution experiments were carried out using organic solvents as dissolution media. With prolongation of grinding, benzoic acid was gradually amorphized and the dissolution of benzoic acid from the ground sample was significantly suppressed in cyclohexane. This result was considered to be due to the dispersion of benzoic acid molecules in the hydrogen-bond matrix of cellulose through the grinding process. From experiments using a series of organic solvents, it was found that the amount of benzoic acid dissolved was correlated to the polarity of solvents. On the other hand, moisture in the solvent and primary hydroxyl groups in solvent molecules were considered to be effective factors for enhancing the dissolution of benzoic acid from the ground mixture.

Fluorometric Study of the Molecular States of 2,5-Diphenyloxazole in Ground Mixtures with γ-Cyclodextrin

Molecular states of 2,5-diphenyloxazole (PPO) were investigated in ground mixtures with -γ-cyclodextrin (γ-CD). Crystalline PPO gradually became amorphous upon grinding in the presence of γ-CD. Solid-state fluorescence spectra of the ground mixtures showed that the fluorescence emission peak due to PPO crystals was reduced in intensity with an increasing duration of grinding. A new fluorescence peak attributed to PPO excimer appeared at a longer wavelength. Results of the time-resolved fluorescence study indicated that the cogrinding caused an increase in the portion of PPO excimer in the γ-CD ground mixture. On the other hand, only a small portion of excimer was formed in ground mixtures with (β-CD, which has a smaller cavity than γ-CD. These results suggest that cogrinding of PPO with γ-CD caused two PPO molecules to be included in the γ-CD cavity, contributing to excimer formation.

Acceleration of the addition reaction of succinic anhydride and p-nitroaniline in synthetic aluminium silicate

Intact and heat-treated synthetic aluminum silicates (SAS) were used to investigate the change in crystalline properties and the solid-state reaction of succinic anhydride and p-nitroaniline mixed with SAS. Heat-treated SAS was obtained by heating at 850°C for 3 h. Pore volume and specific surface area of SAS heated at 120°C (SAS120) were much greater than those of SAS heated at 850°C (SAS850). From the powder X-ray diffraction measurement, it was found that the mixing of organic compounds with SAS caused changes in their crystalline state. The ability of SAS120 for changing organic components from crystal to amorphous state was greater than that of SAS850. Extreme acceleration of the addition reaction between succinic anhydride and p-nitroaniline was observed when mixed with SAS. The acceleration of the reaction can be explained in terms of the adsorption of organic molecules in the pores of SAS and the surface acidity of SAS.

Diffusion and reaction of p-nitroaniline and succinic anhydride in controlled pore glass

A multi-layered tablet which consisted of controlled pore glass (CPG) and organic compounds was prepared. Addition reactions between succinic anhydride and p-nitroaniline, which were induced separately in the CPG layers of the multi-layered tablet, have been studied. The reaction product, succinyl-p-nitroanilide, was mainly distributed near the p-nitroaniline layer. This can be explained in terms of a higher diffusion rate of succinic anhydride, resulting in its higher vapor pressure. The diffusion rate constant of succinic anhydride in the CPG120 system was evaluated as 6.00×10-7 cm2/s by fitting the diffusion equation to experimental results.

Interaction between Polyethylene Films and Bromhexine HCl in Solid Dosage Forms. I. Effects of Moisture Contents in the Solid Dosage Forms on the Sorption of the Drug

The decrease of bromhexine HCl contents in granules and tablets was determined when the preparations were stored in polyethylene film package. Effects of temperature, contact area with film, excipients and moisture contents in the preparation on the remaining amount of bromhexin HCl were studied in order to investigate the interaction mechanism between bromhexine HCl and polyethylene film. It was observed that the decrease of bromhexine HCl was due to the sorption to the polyethylene film. The results indicated that the moisture contents of the dosage forms determined the rate of sorption predominantly, and that removal of adsorbed water from dosage forms was effective to prevent bromhexine HCl content decrease.