The in-vitro pH-dissolution dependence and in-vivo bioavailability of frusemide-PVP solid dispersions

The dependence of the dissolution rate on the pH of the buffered medium, using constant surface area discs, has been examined for crystalline frusemide, a semi-crystalline frusemide-polyvinylpyrrolidone (PVP) solid dispersion and an X-ray amorphous frusemide-PVP dispersion. The marked changes observed in the pH-dissolution profiles indicate that differing dissolution mechanisms operate in the amorphous regions. This conclusion was further supported by the comparison of pH-dissolution and pH-equilibrium solubility profiles that suggested a supersaturation effect to be the relevant term in describing the dissolution enhancing effects of amorphous regions. A marked dissolution enhancement, relative to crystalline frusemide, was shown by the X-ray amorphous solid dispersion in weakly acidic solutions. A similar effect was observed in the dissolution characteristics of gelatin capsule formulations in simulated gastric and intestinal media. In a human bioavailability study, the X-ray amorphous frusemide-PVP solid dispersion exhibited a significant reduction in the time for maximum effect in comparison to crystalline frusemide and a semi-crystalline solid dispersion. This effect, demonstrated by the primary end organ response in seven healthy subjects, concurred with the in-vitro prediction of dissolution enhancement in weakly acidic media.