Fusao Usui

Stability of amorphous indomethacin compounded with silica

The stability of indomethacin (IM) compounded with SiO(2) either by co-grinding or by melt-quenching was examined by recrystallization kinetics under the conditions 30 degrees C and 11% relative humidity. A decrease of the recrystallization rate with and without an appreciable induction period was observed in both compounds. Higher stability of amorphous IM compounded with SiO(2) was attained by prolonged co-grinding than by melt-quenching. This was explained by the stronger chemical interaction at the interface between IM and SiO(2) by co-grinding, as revealed by (29)Si and (13)C solid state NMR. Incomplete co-grinding with the rest of the crystalline state, however, made the amorphous state appreciably unstable, since the remaining crystallites serve as seeds for recrystallization.

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.

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.

Solid phase transition of CS-891 enantiotropes during grinding.

The physical properties of N-[1-(4-methoxyphenyl)-1-methylethyl]-3-oxo-4-aza-5a-androst-1-ene-17beta-carboxamide (CS-891), a novel and orally effective testosterone 5-reductase inhibitor, were investigated by differential scanning calorimetry, powder X-ray diffraction at elevated temperature and single crystal X-ray crystallography. CS-891 was revealed to exist as two enantiotropic forms, a low-temperature stable form (Form A) and a high-temperature stable form (Form B) which reversibly transforms to Form A at around 58 degrees C. The effect of grinding temperature on the transition of CS-891 between the amorphous and the crystalline state during grinding of the eantiotropes was examined. Form A transformed into an amorphous form during the grinding process while the product temperature was kept below the transition temperature. On the other hand, when the product temperature during grinding reached above the transition temperature, Form A transformed into an amorphous form and some of the amorphous form converted back to Form B. Form B crystallized from the amorphous form was physically stable even at below the transition temperature. The amorphous form in equilibrium with Form B exhibited remarkable physical stability in comparison with the amorphous form obtained by continued grinding below the transition temperature.