Applications of supercritical fluids to enhance the dissolution behaviors of Furosemide by generation of microparticles and solid dispersions

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• 作者：Nicola De Zordi^a ; ^{ndezordi@units.it} ; Mariarosa Moneghini^a ; Ireneo Kikic^b ; Mario Grassi^b ; Antonio Esau Del Rio Castillo^a ; Dario Solinas^b ; Michael B. Bolger^c
• 关键词：Micronization ; Solid dispersions ; Furosemide ; Crospovidone ; Supercritical antisolvent technology ; Mathematical modeling
• 刊名：European Journal of Pharmaceutics and Biopharmaceutics
• 出版年：2012
• 期刊代码：16_09396411
• 类别：pha
• 出版时间：May, 2012
• 卷：81
• 期：1
• 页码：131-141
• 文件大小：1648 K

摘要

The 鈥榗lassical鈥?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 CO₂ antisolvent process, preliminary studies of Furosemide microparticles generation were conducted using Peng Robinson鈥檚 Equation of State. These preliminary studies indicated using acetone as a solvent with pressures of 100 and 200 bar and a temperature of 313 K would yield optimum results. These operative conditions were then adopted for the SDs. Micronization by means of SAS at 200 bar 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 100 bar and using traditional solvent evaporation. Moreover, changes in polymorphic form were observed in the 200 bar 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 100 bar still remaining stable after 6 months. 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.