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.
Doherty
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School of Pharmacy & Pharmaceutical Technology, Bradford University, West Yorks, England.
York
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D000328:Adult; D001682:Biological Availability; D002214:Capsules / Q000032:analysis; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D005665:Furosemide / Q000008:administration & dosage / Q000032:analysis* / Q000493:pharmacokinetics; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D011205:Povidone; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D014961:X-Ray Diffraction
D002214:Capsules; D005665:Furosemide; D011205:Povidone