Nanoparticle formation from probucol/PVP/sodium alkyl sulfate co-ground mixture.

Nanoparticles of a poorly water-soluble drug, probucol, have been obtained by co-grinding with PVP and SDS. The purpose of this study was to investigate the effect of the alkyl chain length of sodium alkyl sulfates (CnS, n=6, 8, 12, 16 and 18) on probucol nanoparticle formation. From the results of particle size determination and quantitative measurement of nanoparticle fraction of probucol by HPLC, it was found that the alkyl chain length of the sodium alkyl sulfate affected the probucol nanoparticle formation. The efficiency, based on the quantitative determination of nanoparticles, was in the order: C18S>C16S>C12S>C8S>C6S. Probucol nanoparticles of less than 800 nm were effectively produced (more than 95%) with the increase of the amount of surfactants. (13)C solid-state NMR of co-ground mixtures showed a new peak originating from the probucol interaction with PVP together with the existence of probucol crystal peaks. Excess amounts of surfactants were expected to play an important role for stabilizing the probucol nanoparticles in the suspension via the electrostatic repulsive effect.

Micronization and polymorphic conversion of tolbutamide and barbital by rapid expansion of supercritical solutions.

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.

Drug nanoparticle formation from drug/HPMC/SDS ternary ground mixtures.

Drug nanoparticle formation from a ternary ground mixture consisting of a poorly water-soluble drug, hydroxypropylmethylcellulose (HPMC), and sodium dodecyl sulfate (SDS) was investigated. Flurbiprofen, which did not show nanoparticle formation by co-grinding with polyvinylpyrrolidone (PVP) and SDS, was used as a model drug. Flurbiprofen, HPMC and SDS were mixed at the weight ratio of 1:3:1 and ground for 30 min in a vibrational rod mill. The drug nanoparticle formation was observed after the ternary ground mixture (GM) was dispersed into distilled water. Molecular interactions both between flurbiprofen and HPMC and between polymer and surfactant were found to be important factors for the nanoparticle formation. The GM was stable for 2 months at the storage condition of 40 degrees C and RH 22%. Mean particle size of the dispersed particles was still less than 350 nm after storage at 25 degrees C for 1 month. It was found that the drug/HPMC/SDS ternary grinding method was applicable not only for flurbiprofen but also for other hydrophobic drugs, such as tolbutamide, probucol, phenytoin and griseofulvin. The drug nanoparticles were also obtained using other cellulose derivatives, indicating that these pharmaceutical excipients were alternative to PVP for the grinding-induced drug nanoparticle formation.

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.

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.

Effects of dehydration temperatures on moisture absorption and dissolution behavior of theophylline.

Anhydrous theophylline was prepared by heating theophylline monohydrate at temperatures between 60 degrees C and 140 degrees C. The effects of dehydration temperatures on the moisture absorption and dissolution behavior of anhydrous theophylline were investigated in this study. The hydration rate of anhydrous theophylline at 95% relative humidity and 25 degrees C decreased with increasing dehydration temperatures. From the fitting analysis of solid-state reaction models, the hydration reaction was found to be governed by the phase boundary reaction model for samples prepared at lower dehydration temperatures (<100 degrees C) but the reaction obeyed the growth of nuclei reaction model when samples were dehydrated at higher temperatures. The dissolution rates of various anhydrous theophylline samples were measured by the rotating disk method. The calculated solubility of anhydrous theophylline prepared by heating was about 2.5 times higher than that of theophylline monohydrate. The phase transformation rate from the anhydrous form to the monohydrate during dissolution tests decreased with higher dehydration temperatures. It was found that the anhydrous theophylline prepared at different dehydration temperatures transformed to the monohydrate by way of different growth of hydrate nuclei mechanism.

Water vapor adsorption properties of amorphous cefditoren pivoxil evaluated by adsorption isotherms and microcalorimetry.

Water vapor adsorption of ground cefditoren pivoxil was studied. The amount of water adsorbed increased with a decrease in the crystallinity of cefditoren pivoxil. It was found from the microcalorimetric measurements that the differential heat of water vapor adsorption at 1.5% adsorbed water increased with decreasing crystallinity of cefditoren pivoxil, suggesting that hygroscopicity of cefditoren pivoxil was enhanced by grinding. These results indicated that hydrophilic adsorption sites in cefditoren pivoxil increased through the grinding process. The results of infrared (IR) spectra examination suggested that the increment of hydrophilic adsorption sites through the grinding process resulted from the change of the environment of the carbonyl groups in two esters and amide.

Fluorometric Studies of Pyrene Adsorption on Porous Crystalline Cellulose.

Pyrene crystals were physically mixed with either porous crystalline cellulose (PCC) or octa decyl siryl silica-80Tm (ODS). Solid-state fluorescence spectra of pyrene were analyzed to estimate the interaction between pyrene and porous materials. Pyrene monomer emission was observed at 398 nm immediately after being mixed with PCC, while pyrene crystals showed only excimer emission at 475 nm, indicating that the pyrene molecules adsorbed onto the PCC surface in a short period. For the PCC system containing 1.0% pyrene, long-term storage caused an increase in the intensity of excimer-like emission peak at 477 nm accompanied by a decrease in the intensity of monomer emission peak at 398 nm. For the ODS system containing 1.0% pyrene, spectrometric changes were similar to those for the PCC system. In the process of interaction formation between pyrene and an additive, a two-step mechanism was proposed, i.e., the adsorption of pyrene molecules onto the surface of porous additives, and the formation of a ground state dimer of pyrene. The formation of dimeric pyrene could be associated with the surface polarity of additives. Copyright 1998 Academic Press.

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. Amorphous UDCA was prepared by spray-drying a solution of the compound in a mixture of ethanol and dichloromethane. The amorphous material was characterized by powder X-ray diffraction, infrared (IR) spectroscopy, isothermal microcalorimetry, differential scanning calorimetry (DSC) and water-vapour adsorption. When the inlet-air temperature of the spray drier was increased beyond 140 degrees C, the intensity of X-ray diffraction peaks from crystalline UDCA decreased and the IR bands in the hydroxyl-stretching and carboxyl-stretching regions changed. Dissolution of intact and spray-dried samples of UDCA prepared at 60 and 100 degrees C was an endothermic process but the dissolution became exothermic with increasing inlet-air temperature. UDCA samples differing in crystallinity were obtained, depending on the inlet-air temperature. A good correlation was obtained between the heat of solution and the heat of crystallization determined from DSC peak area. A good correlation was also obtained between the heat of solution and the crystallinity determined by Ruland's method from X-ray diffraction patterns. The amount of water vapour adsorbed on UDCA samples increased with increasing inlet-air temperature, indicating hydrogen bonding between water molecules and the hydroxyl groups or the carboxyl groups of amorphous UDCA. These results indicate that measurement of adsorption of water vapour and thermal analysis can both be used to evaluate the crystallinity of solid substances.