Yuichi Tozuka

Improvement of physicochemical properties of N-4472 part I formulation design by using self-microemulsifying system.

The optimization of oral dosage form formulation has been developed for N-4472, N-[2-(3,5-di-tert-butyl-4-hydroxyphenethyl)-4,6-difluorophenyl]-N-[4-(N-benzylpiperidyl)] urea, which was a poorly water-soluble drug having a lipid-lowering effect. Formulations that contained various surfactants and water-soluble polymers were prepared and the solubility of N-4472 was evaluated in JP XIV first fluid (pH 1.2), JP XIV second fluid (pH 6.8), and distilled water. The highest solubility of N-4472 was achieved when L-ascorbic acid (VC), Gelucire 44/14, and HCO-60 were used as additives. It was confirmed that this formulation could create microemulsion droplets with a mean droplet size of approximately 20 nm and a sharp droplet distribution pattern in JP XIV first fluid, JP XIV second fluid, and distilled water. When JP XIV second fluid was used as a dissolution medium, however, an eventual decrease of solubility was observed, that is, the fluid became white and cloudy as time passed. It was found that the addition of sodium dodecyl sulfate (SDS) was effective to prevent the lowering of solubility, and that a weight ratio of 1.0/1.5/11.4/4.9/3.8 for N-4472/VC/Gelucire 44/14/HCO-60/SDS was optimum for the self-microemulsifying formulation. It was assumed that electrostatic repulsion of microemulsion droplets and an increase of the cloud point by the addition of SDS were responsible for the successful formation of a stable microemulsion.

Molecular Interaction among Probucol/PVP/SDS Multicomponent System Investigated by Solid-State NMR

PurposeEffects of polyvinylpyrrolidone (PVP) molecular weight on the solid-state intermolecular interactions among probucol/PVP/sodium dodecyl sulfate (SDS) ternary ground mixtures (GM) and the formation of nanoparticles were investigated by solid-state NMR spectroscopy.Materials and MethodsTernary GMs of probucol were prepared with PVP (K12, K17, K30 or K90) and SDS at a weight ratio of 1:3:1 and were ground for 15, 30 and 60xa0min. Solid-state interactions were evaluated using powder X-ray diffraction (PXRD) and solid-state cross polarization/magic angle spinning (CP/MAS) 13C NMR spectroscopy. A high resolution scanning electron microscopy (SEM) was employed to observe nanoparticles of probucol in the GM.ResultsThe solid-state 13C CP/MAS NMR results indicate that the low molecular weight PVP interacts with probucol and SDS more strongly than the high molecular weight PVP in the ternary GM. This finding was consistent with the result that smaller drug nanoparticles were obtained using low molecular weight of PVP. SEM images of probucol/PVP K12/SDS confirmed the presence of nanoparticles (15–25xa0nm) in the GM.ConclusionsGrinding-induced solid-state interactions among drug, PVP and SDS could be detected using solid state 13C NMR. The interactions in both probucol-PVP and PVP-SDS should occur simultaneously to generate nanometer-sized particles of probucol.

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.

Improvement of physicochemical properties of N-4472. Part II: characterization of N-4472 microemulsion and the enhanced oral absorption.

The optimized formulation of N-4472, N-[2-(3,5-di-tert-butyl-4-hydroxyphenethyl)-4,6-difluorophenyl]-N-[4-(N-benzylpiperidyl)] urea, which was a poorly water-soluble drug, was developed by utilizing the complexation between N-4472 and L-ascorbic acid (VC). It was found that the formulation with Gelucire((R)) 44/14, HCO-60((R)) and sodium dodecyl sulfate provided a self-microemulsifying system consisting of fine droplets in approximately 18 nm size with a narrow distribution. 1H-NMR spectroscopic study indicated that the N-4472/VC complex was molecularly incorporated into surfactant molecular assembly in the microemulsion droplets. It was found that the N-4472 microemulsion was stable at the pH range from 2.0 to 7.0, suggesting the stability in the gastrointestinal tract. When the microemulsion containing N-4472/VC complex was orally administrated in rats, high AUC value of N-4472 (2 to 4-fold) was observed in comparison with the aqueous solution containing N-4472/VC complex.

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.nMethods. 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.nResults. 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.nConclusion. 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.nMethods. 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.nResults. 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.nConclusions. 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.

Formation of fine drug particle by cogrinding with cyclodextrins: Part II. The influence of moisture condition during cogrinding process on fine particle formation

The purpose of this study was to investigate the effect of moisture condition during cogrinding process on fine drug particle formation. Cogrinding of cyclodextrins (CDs) and pranlukast (PRK) hemihydrate was performed in various moisture conditions at a mixing molar ratio of 2:1 (CDs:PRK) and the formation of PRK submicron particle was investigated. The moisture content in the cogrinding process significantly affected the fine particle formation. More than 90% of pranlukast loaded transformed to submicron particles when coground with alpha-CD, beta-CD or gamma-CD containing the specific amount of water for each CD system. Fine particle formation of PRK was considered as a particular phenomenon to cyclodextrins, since the submicron particles could not be formed when D-mannitol, lactose or microcrystalline cellulose (MCC) was used as a cogrinding additive. Moreover, the appearance and disappearance of fine particle formation was found to be reversible depending on the existence of water during the grinding process.

Supercritical carbon dioxide treatment as a method for polymorph preparation of deoxycholic acid.

A new polymorph of deoxycholic acid (DCA) was formed by using a supercritical carbon dioxide treatment. Deoxycholic acid crystals were stored in a pressure vessel purged with carbon dioxide at 12MPa, 60 degrees C for definite intervals. After storage for 1h in supercritical carbon dioxide (SC-CO2), new X-ray diffraction (XRD) peaks, not found in the bulk DCA crystal, were observed at 2theta = 7.4 degrees, 9.7 degrees and 14.0 degrees. The intensities of the new diffraction peaks increased with an increase in storage time, whereas the intensities of the diffraction peaks due to bulk DCA crystal decreased. On the DSC curves, the crystals obtained showed an exothermic peak at around 155 degrees C followed by the melting peak of bulk DCA crystal at 175 degrees C. By the temperature-controlled powder XRD measurement, the crystals obtained were found to be a metastable form of DCA. The polymorphs of DCA have not been reported; therefore, the SC-CO2 treatment would be a peculiar method to obtain a DCA polymorph.