Akira Kusai

Inhibitory effects of water-soluble polymers on precipitation of RS-8359

Hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC) and polyvinylpyrrolidone (PVP) were used as water-soluble polymers. Incorporation of small amounts of each of these polymers into a phosphate buffer solution (pH 6.8) showed inhibitory effects on the precipitation of RS-8359 from supersaturated solutions. In the case of both HPMC and HPC, precipitation time lags of the compound were effectively prolonged as the polymer concentration increased. Further, all of the polymers decreased precipitation rates of the compound. The most effective concentration to decrease the precipitation rate existed and it was 0.01 mg/ml for each of HPMC and HPC, and 0.0001 mg/ml for PVP within this experimental range. The precipitates contained the polymers. Further, the incorporation of the polymers in the solutions increased the solubility of the compound. These evidences suggest the interaction of the polymers with the compound.

Comparison between polyvinylpyrrolidone and silica nanoparticles as carriers for indomethacin in a solid state dispersion.

States of interaction between indomethacin (IM) and polyvinylpyrrolidone (PVP) in an amorphous solid dispersion prepared by co-grinding were compared with those between IM and silica nanoparticles. Changes in the carbon chemical states of the solid dispersions were evaluated based on the chemical shift in the 13C-CP/MAS-NMR. Hydrogen bonds between the amide carbonyl of PVP particles and the carboxyl groups of IM molecules were formed by co-grinding. Despite the wide difference in carrier properties, the apparent equilibrium solubility (AES) of IM in the ground IM-PVP mixture was predicted by solid state NMR on the basis of the relationship previously established for IM with SiO(2). This indicates that AES is affected solely by the state of IM, irrespective of the carrier species, and despite carrier-dependent chemical interactions.

Factors influencing the diffusion-controlled release of papaverine from poly (l-lactic acid) matrix

Effects of drug content and medium pH on the release of papaverine (PAP) from biodegradable poly(l-lactic acid) [P(L)LA] matrix were investigated to reveal the predominant factors affecting the two-stage diffusion-controlled release mechanism. A drug-dissolved cylindrical matrix (rod; 10 mmx1 mm diameter) was prepared by heat compression method. In the case of a PAP content below 10%, pH was found to have a strong effect on the release rate, and drug content was found to have no effect on the release profile. The release profile consisted of two sequential diffusion stages due to P(L)LA transformation from amorphous to the semicrystalline state prior to release. In the first release stage PAP diffused through the swollen matrix. The release accelerated with increasing medium pH due to an increase in water content in the acidic P(L)LA rod. In the second release stage PAP diffused through the water-filled micropores developed as a result of the polymer crystallization. On the assumption that the drug partition between the polymer and the medium in the micropores affects the diffusion and the partition is controlled by pH, we derived a modified diffusion kinetic equation. The observation that the release decelerated with increasing medium pH can be explained by the derived equation as resulting from the increase in the drug partition to the polymer. In the case where the rods contained more than 15% of PAP, the drug precipitated out as crystals during release. Accordingly, these rods showed a slower release.

Measurement of agitation force in dissolution test and mechanical destructive force in disintegration test

The purpose of this study was to investigate the effect of the agitation force and mechanical destructive force on the drug dissolution of a tablet in the paddle rotation dissolution test and in the disintegration test. The agitation in the paddle method and the mechanical destructive force in the disintegration test were considered to be conclusive factors for drug dissolution. The dissolution rate of planar-constant-release tablets increased with increasing paddle rotation speed and increased with increasing distance from the center of the vessel bottom. Separately, the fluid resistance (agitation force) in the vessel was measured using a modified paddle method apparatus equipped with a fluid resistance sensor. The fluid resistance was 0.03 x 10(-3) N/(64 mm(2)) when the paddle rotation speed was 50 rpm at a position 4 mm away from the center. A considerable position-dependent change in agitation force intensity was seen with the fluid resistance sensor. The impulsive force (mechanical destructive force) in the disintegration test apparatus was measured using a modified basket-rack assembly with a strain gauge transducer. The fluid resistance was measured using the basket-rack assembly with a different sensor probe and amplifier. The impulsive force applied by the auxiliary disk was 0.31 N and the fluid resistance at the bottom of the basket-rack assembly was 1.66 x 10(-3) N/(64 mm(2)).

The effects of drug physico-chemical properties on release from copoly (lactic/glycolic acid) matrix

Abstract A study on the effect of physico-chemical properties of drugs on their release behavior from copoly ( l -lactic/glycolic acid); (PLGA) matrix was performed. PLGA and drugs of acidic, neutral or basic nature were mixed and molded by heat compression method into a cylindrical matrix. The release rate of drugs from the rod depended on their physico-chemical properties. Basic drugs were found to show high PLGA/aqueous medium partition coefficients ( K app ), implying a strong ionic interaction with the polymer. This interaction kept these drugs dissolved in the matrix during the release studies. The interaction shielded the polymer terminal carboxyl residues resulting in the slower matrix erosion, and made the matrix less swellable, thus diminishing drug diffusion through the matrix. Consequently, K app could be regarded as the determinant parameter to evaluate the release rate of basic drugs. In contrast, acidic and neutral drugs had only weak interaction with PLGA, so that the drugs quickly precipitated out as crystals in the matrix during the release studies. In this case, the drugs did not affect the matrix erosion, and hence the solubility of each drug in the hydrated matrix became the predominant parameter affecting drug diffusion.

Stabilization of amorphous indomethacin by co-grinding in a ternary mixture.

Mechanochemical amorphization of indomethacin (IM) was substantially enhanced by grinding with SiO(2), talc and a Mg(OH)(2)-SiO(2) mixture. The rates of the mechanochemical amorphization were in the order of Mg(OH)(2)-SiO(2) mixture>talc>SiO(2). Amorphous state stability of IM compounded with the carrier was examined by crystallization behavior under the condition of 30 degrees C and 11% relative humidity. Superiority of the binary mixture as a carrier was explained in terms of the mechanically induced strong acidic sites of the carrier.

Development of a method for the determination of caffeine anhydrate in various designed intact tables by near-infrared spectroscopy: A comparison between reflectance and transmittance technique

Using near-infrared (NIR) spectroscopy, an assay method which is not affected by such elements of tablet design as thickness, shape, embossing and scored line was developed. Tablets containing caffeine anhydrate were prepared by direct compression at various compression force levels using different shaped punches. NIR spectra were obtained from these intact tablets using the reflectance and transmittance techniques. A reference assay was performed by high-performance liquid chromatography (HPLC). Calibration models were generated by the partial least-squares (PLS) regression. Changes in the tablet thickness, shape, embossing and scored line caused NIR spectral changes in different ways, depending on the technique used. As a result, noticeable errors in drug content prediction occurred using calibration models generated according to the conventional method. On the other hand, when the various tablet design elements which caused the NIR spectral changes were included in the model, the prediction of the drug content in the tablets was scarcely affected by those elements when using either of the techniques. A comparison of these techniques resulted in higher predictability under the tablet design variations using the transmittance technique with preferable linearity and accuracy. This is probably attributed to the transmittance spectra which sensitively reflect the differences in tablet thickness or shape as a result of obtaining information inside the tablets.

Prediction of apparent equilibrium solubility of indomethacin compounded with silica by 13C solid state NMR.

The apparent equilibrium solubility (AES) of indomethacin increased by co-grinding with silica. Change in the long- and short range disorder of indomethacin by co-grinding was examined by X-ray powder diffraction and 13C solid state NMR, respectively, to elucidate the increased AES. Since the increase in AES was particularly marked after complete disappearance of X-ray diffraction peaks, we attributed the enhanced AES primarily to the short range disorder on the molecular basis. This was confirmed by a high correlation between the standardized full width at half maximum (SFWHM) of the specific peaks observed by 13C solid state NMR and log (AES). The correlation enables the prediction of AES as well.

Dissolution improvement of RS-8359 by the solid dispersion prepared by the solvent method

Study on dissolution improvement of a water-insoluble compound, RS-8359 ((±)-4-(4-cyanoanilino)-5,6-dihydro-7-hydroxy-7H-cyclopenta[d]pyrimidine) was carried out. A hydrochloric acid salt of RS-8359 had much higher solubility than its free form. However, the free form separated out of a neutral buffer solution instantaneously once the salt form was dissolved. We found that the dissolution properties were greatly improved by preparing a solid dispersion of the salt form with a water-soluble polymer mainly because the dissolved water-soluble polymer included in the solid dispersion retarded the precipitation rate of the free form. The crystallinity of the salt form in the solid dispersion did not affect the dissolution properties greatly. Furthermore, the importance of microenvironmental pH in the solid dispersion was suggested by a significant increase in the maximum concentration of RS-8359 in the dissolution process of the solid dispersion as compared with the case that the simple salt form was dissolved in the buffer solution that included the water-soluble polymer.

The skin permeation mechanism of ketotifen: evaluation of permeation pathways and barrier components in the stratum corneum.

To evaluate the pathways and barrier components in the stratum corneum (SC) for the permeation of ketotifen, the effect of delipidization on the permeation and partition was examined under several donor pHs. Assuming that ionized ketotifen (KTH+) and un-ionized ketotifen (KT) contribute independently in both permeation and partition, the intrinsic permeability coefficients and SC/water partition coefficients of both species were estimated. Delipidization enlarged the permeability of KTH+ 100 times. This suggested that the lipid phase functions as the barrier against KTH+. KT has an intrinsic permeability 100 times larger than that of KTH+. Delipidization did not result in a significant change in permeability of KT. This suggested that the permeability of KT through the lipid phase is comparable to that through the aqueous phase in delipidized SC; that is, the lipid phase functions as a highly permeable pathway for KT. On the other hand, the permeability coefficient of KTthrough delipidized SC was 1/34 of that through the pure aqueous layer, which had a thickness equivalent to SC. Since this suggests that the permeability of KT through the proteinaceous phase is much lower than that through the aqueous phase, the proteinaceous phase can be assumed to function as a barrier against the permeation of KT. From these results, it is concluded that the predominant permeation pathway for KT is through the lipid phase. The SC/water partition coefficient of KT was cut in half by delipidization, but the value was still more than 100. These results show that the proteinaceous phase functions not only as the barrier, but also as the depot for KT. The knowledge obtained here will be useful for formulation design and for the selection of enhancers in a transdermal therapeutic system of ketotifen.