title: Applications of supercritical fluids to enhance the dissolution behaviors of Furosemide by generation of microparticles and solid dispersions.
abstract: The 'classical' loop diuretic drug Furosemide has been used as a model compound to investigate the possibility of enhancing the dissolution rate of poorly water-soluble drugs using supercritical anti-solvent techniques (SASs). In the present study we report upon the in vitro bioavailability improvement of Furosemide through particle size reduction as well as formation of solid dispersions (SDs) using the hydrophilic polymer Crospovidone. Supercritical carbon dioxide was used as the processing medium for these experiments. In order to successfully design a CO(2) antisolvent process, preliminary studies of Furosemide microparticles generation were conducted using Peng Robinson's Equation of State. These preliminary studies indicated using acetone as a solvent with pressures of 100 and 200bar and a temperature of 313K would yield optimum results. These operative conditions were then adopted for the SDs. Micronization by means of SAS at 200bar resulted in a significant reduction of crystallites, particle size, as well as improved dissolution rate in comparison with untreated drug. Furosemide recrystallized by SAS at 100bar and using traditional solvent evaporation. Moreover, changes in polymorphic form were observed in the 200bar samples. The physicochemical characterization of Furosemide:crospovidone SDs (1:1 and 1:2 w/w, respectively) generated by SAS revealed the presence of the drug amorphously dispersed in the 1:2 w/w sample at 100bar still remaining stable after 6months. This sample exhibits the best in vitro dissolution performance in the simulated gastric fluid (pH 1.2), in comparison with the same SD obtained by traditional method. No interactions between drug and polymer were observed. These results, together with the presence of the selected carrier, confirm that the use of Supercritical fluids antisolvent technology is a valid mean to increase the dissolution rate of poorly soluble drugs. Theoretical in vivo-in vitro relation was predicted by means of a pharmacokinetics mathematical model.
authors.affiliation: Dept. Chemical and Pharmaceutical Sciences, University of Trieste, V. Giorgieri 1, Trieste, Italy. ndezordi@units.it
authors.forename: Nicola
authors.initials: N
authors.lastname: De Zordi
authors.forename: Mariarosa
authors.initials: M
authors.lastname: Moneghini
authors.forename: Ireneo
authors.initials: I
authors.lastname: Kikic
authors.forename: Mario
authors.initials: M
authors.lastname: Grassi
authors.forename: Antonio Esau
authors.initials: AE
authors.lastname: Del Rio Castillo
authors.forename: Dario
authors.initials: D
authors.lastname: Solinas
authors.forename: Michael B
authors.initials: MB
authors.lastname: Bolger
mesh_terms: D001682:Biological Availability; D002245:Carbon Dioxide / Q000737:chemistry; D003460:Crystallization; D004232:Diuretics / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D004355:Drug Stability; D005665:Furosemide / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D005750:Gastric Juice / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D008863:Microspheres; D008962:Models, Theoretical; D010316:Particle Size; D011205:Povidone / Q000737:chemistry; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D013678:Technology, Pharmaceutical / Q000379:methods; D013997:Time Factors
chemical_list: D004232:Diuretics; D012997:Solvents; D002245:Carbon Dioxide; D005665:Furosemide; D011205:Povidone