Toshio Oguchi

Physicochemical properties of amorphous clarithromycin obtained by grinding and spray drying

In order to characterize the amorphous clarithromycin (CAM) obtained by grinding and spray drying, physicochemical properties (crystallinity, thermal behavior, stability and solubility parameters) were evaluated. From powder X-ray diffraction, it was estimated that the crystalline state of CAM was changed into an amorphous state by grinding and spray drying. In differential scanning calorimetry measurements, both broad and sharp peaks for crystallization were observed in ground samples, whereas spray dried samples showed one broad peak due to crystallization. As to the stability test under high humidity, structural difference was confirmed between ground CAMs and spray dried CAM. The heat of dissolution of ground CAMs was greater than that of intact CAM. In the solubility parameter measurement, the increase of the special term, deltas, indicated that the energy change was due to the polarity of the surface energy of the powder particles by grinding.

Improved dissolution of ofloxacin via solid dispersion

Abstract The objective of this study was to improve the dissolution rate of a sparingly water soluble drug, ofloxacin, by solid dispersion systems with urea and mannitol. Differential scanning calorimetry (DSC), powder x-ray diffraction (PXRD) analysis and infrared spectroscopy (IR) were performed to evaluate the physicochemical properties of the prepared solid dispersions. The dissolution rate of ofloxacin was markedly increased in solid dispersion of urea and mannitol. Solubility studies revealed a marked increase in the solubility of ofloxacin with an increase in urea concentration. Mannitol concentration had no effect on the solubility of ofloxacin. The PXRD study revealed that the crystallinity of ofloxacin was decreased as the ratio of drug to carrier was decreased. The results from DSC and IR indicated that there was no interaction between drug and carriers.

Evaluation of Amorphous Ursodeoxycholic Acid by Thermal Methods

AbstractPurpose. The purpose of this study was to characterize the amorphous state of ursodeoxycholic acid (UDCA) samples by using isothermal microcalorimetry, X-ray diffraction, infrared (IR) spectroscopy and solid state carbon 13 nuclear magnetic resonance (13C-NMR) spectroscopy, and to demonstrate the application of the thermal methods (microcalorimetry and differential scanning calorimetry (DSC)) for studying the amorphous state and clarifying the dissolution mechanism of UDCA. Methods. Amorphous UDCA was prepared by grinding and rapid cooling of the melts. The heat of solution of UDCA was measured by an isothermal heat-conduction twin microcalorimeter at 25.0°C. Some physicochemical properties of amorphous UDCA were also studied. Results. The intensities of X-ray diffraction peaks of crystalline UDCA decreased with an increase in grinding time. The heat levels of solution of crystalline UDCA and UDCA ground for 1 min were endothermic, and became exothermic with an increase in grinding time. A good correlation was obtained between the heat of solution and the heat of crystallization determined from the peak area in DSC. Although no significant difference was observed in X-ray diffraction patterns of amorphous UDCA prepared by the two methods, significant differences were recognized in DSC, IR and 13C-NMR, and the heat of solution indicated different values among the two samples. The stability of amorphous UDCA samples stored under 74.5% relative humidity at 40°C was found to depend upon the preparation methods. Conclusions. Different states of amorphous UDCA were obtained depending on the preparation method. The application of thermal methods to evaluate the amorphous state was demonstrated. The mechanism of dissolution of UDCA was discussed from the results of the heat of solution examination.

Micronization and Polymorphic Conversion of Tolbutamide and Barbital by Rapid Expansion of Supercritical Solutions

ABSTRACT Rapid expansion of supercritical solutions (RESS) was applied to tolbutamide and barbital. The solubility in supercritical CO2 was determined to estimate the extraction efficiency roughly by a simple method and accurately by a direct spectrophotometric technique. The latter revealed that the solubility of tolbutamide was a function of applied pressure and temperature and was proportional to the pressure. No significant difference in solubility between polymorphic Forms I and II of tolbutamide was detected. Tolbutamide and barbital particles produced by the RESS were characterized by size distribution measurement, polymorph identification and morphological evaluation. Significant size reduction to micron or sub-micron level with narrow size distribution was achieved, while conventional mechanical grinding had only slight effect. The particle size was greatly affected by both extraction and expansion conditions. The lower the extraction temperature was, the smaller was the mean particle size. Higher extraction pressure resulted in smaller mean particle size when compared at the same extraction temperature. The mean particle size was reduced by lowering the spray nozzle temperature, by lowering the expansion chamber temperature, by increasing the CO2 amount per spray, and by increasing the exhaust gas flow rate. The RESS processing realized the polymorphic conversion as well. As for tolbutamide, three polymorphs (Forms I, II, and IV) out of four could be produced by changing the extraction conditions, and in the case of barbital, one polymorph (Form II) out of three was produced consistently.

Differences in Crystallization Behavior Between Quenched and Ground Amorphous Ursodeoxycholic Acid

AbstractPurpose. To study the crystallization of ground and quenched ursodeoxycholic acid (UDCA) and to characterize their amorphous states. Methods. Amorphous UDCA was prepared by grinding and also by rapid cooling of the melt. These samples were characterized by powder X-ray diffraction (XRD), near IR spectra and dynamic water sorption. The heat associated with crystallization was measured in an isothermal microcalorimeter at 25°C at various relative humidities (RH) (50%−100%) and, in the presence of the vapour from a mixed solvent of ethanol and water (ethanol conc. 10%−100%). The specific surface area was calculated from krypton adsorption. Contact angles were measured by using a Wilhelmy plate to calculate the surface energy of the samples. Results. Ground and quenched samples yielded amorphous XRD patterns. Differential scanning calorimetry thermographs of the milled sample revealed that crystallization occurred at around 80°C, whereas the quenched sample did not crystallize. Exposure to humid air did not result in crystallization of either amorphous sample during the microcalorimetric experiments. In the presence of ethanol vapour, the ground sample did, but the quenched sample did not, crystallize. The amount of water sorption into the quenched sample was larger than that of the ground sample at low RH. The surface energy of the quenched material was different to that of the ground. Peak shifts were observed in the NIR spectra at around 1450, 2100 nm, allowing differentiation between the ground and quenched samples. Conclusions. It can be concluded that different molecular states of amorphous UDCA were obtained depending on the preparation method. The crystallisation of amorphous UDCA was related to the molecular state of disorder.

Enhanced Dissolution of Ursodeoxycholic Acid from the Solid Dispersion

AbstractSolid dispersions of a very slightly water-solubte drug, ursodeoxycholic acid (UDCA), were prepared using urea, mannitol, and PEG 6000 as a carrier, and the solubility of UDCA was determined in water-ethanol (1:1) mixed solvent as a function of UDCA-carrier ratio. The solubility of UDCA was slightly improved when urea or PEG 6000 was used as a carrier. The powder x-ray diffraction measurements revealed that UDCA did not exist in the crystalline state in the solid dispersions. Differential scanning calorimetry (DSC) studies showed that UDCA was able to dissolve in the melt of urea, mannitol, and PEG 6000. The effect of carriers of solid dispersions on the UDCA dissolution rate was examined. The dissolution rate of UDCA was markedly increased from the solid dispersions of urea, PEG 6000, and mannitol, respectively.

Formation of Fine Drug Particles by Cogrinding with Cyclodextrins. I. The Use of β-Cyclodextrin Anhydrate and Hydrate

AbstractPurpose. To improve the micromeritical properties of pranlukast (PRK) hydrate, a cogrinding process with cyclodextrin was used, and the formation of fine drug particles was investigated. Methods. PRK crystals were ground with either β-cyclodextrin (β-CD) anhydrate or β-CD hydrate crystals at a mixing molar ratio of 2:1 (β-CD:PRK) to prepare the ground mixtures (GMs). Powder X-ray diffraction measurement and particle size analysis were performed. Results. The two GMs differed from one another in appearance, wettability, and fine particle production. Quantitative determination demonstrated that when the β-CD hydrate/PRK GM was dispersed in water, 96% of PRK loaded in GM became fine particles smaller than 0.8 μm. In contrast, only 1.4% of PRK in GM transformed to fine particles in the case of β-CD anhydrate/PRK GM. The PRK fine particles were considered to be dispersed as small crystals. The stability of PRK particles in the aqueous solution was improved by the addition of a water-soluble polymer. Conclusion. Cogrinding with a β-CD of higher water content can be an effective method to prepare fine drug particles at the submicron level.

Pharmaceutics: Characterization of Amorphous Ursodeoxycholic Acid Prepared by Spray-drying

The objectives of this study were to characterize the amorphous state of ursodeoxycholic acid (UDCA) samples prepared by spray‐drying, and to demonstrate the applicability of thermal and water‐vapour‐adsorption techniques for studying the material.

Formation and stability of drug nanoparticles obtained from drug/PVP/SDS ternary ground mixture

The purpose of this study was to investigate the stability and the formation mechanism of drug nanoparticles obtained from a ternary system consisting of poorly water-soluble drug, polyvinylpyrrolidone (PVP), and sodium dodecyl sulfate (SDS). The physical state of drug nanoparticles was investigated by powder X-ray diffraction and zeta potential measurements. Poorly water-soluble drug, PVP K17 and SDS were mixed at a weight ratio of 1:3:1 and ground for 30 min by vibrational rod mill. Most of the poorly water-soluble drugs used in this study provided the nano- particle formation in the submicron region after the ternary ground mixtures (GMs) were dispersed into distilled water. Stability and mechanism of drug nanoparticle formation were investigated by focusing on phenytoin, probucol and griseofulvin. The drug nanoparticle formation was also observed when the ternary GMs were dispersed in the dissolution media. The mean particle size of the dispersed particles was still less than 250 nm after storage at 25°C for one month, indicating the long-term stability of drug nanoparticles. The quantitative determination of drug content demonstrated that more than 93% of the drug was recovered as fine particles smaller than 0.8 ^m from the ternary GMs, whereas the nanoparticles were hardly gained from binary GMs, drug with PVP K17 or SDS. Powder X-ray diffraction analysis for the dispersed particles accumulated by ultracentrifugation indicated that the dispersed particles existed as fine crystals. The zeta potential measurement revealed that the obtained nanoparticles were stable in aqueous media because the particle agglomeration was effectively inhibited by the adsorption of both PVP and SDS onto the particle surface.

Adsorption and entrapment of salicylamide molecules into the mesoporous structure of folded sheets mesoporous material (FSM-16)

AbstractPurpose. The aim of this study was to estimate the molecular state of salicylamide on the surface of mesoporous silicas and to investigate the dissolution behavior of salicylamide from the solid dispersion. Methods. Folded sheets mesoporous material (FSM-16) were used as a porous material. The molecular state of salicylamide was estimated by powder X-ray diffractometry, infrared spectroscopy, and fluorescence spectroscopy. Results. The molecular state of salicylamide can be changed by simple blending with FSM-16. When a physical mixture of 25% salicylamide and 75% FSM-16 was heated at 120°C for 3 h, amorphization of salicylamide was observed from the powder X-ray diffraction pattern. The fluorescence emission peak of salicylamide at 433.5 nm shifted to a longer wavelength of 447.5 nm after heating. Changes in fluorescence decay curve suggested that salicylamide molecules were dispersed into the hexagonal FSM-16 channels during the heating process. Enhanced dissolution in the initial stage of salicylamide from the sealed heated sample was observed in comparison with salicylamide crystals. Conclusions. Heat treatment of a physical mixture of salicylamide with FSM-16 gave a solid dispersion in which the salicylamide molecules changed to an amorphous state by adsorption onto the FSM-16 channels. Amorphization of salicylamide contributed to the improvement of dissolution.