title: Itraconazole/TPGS/Aerosil200 solid dispersions: characterization, physical stability and in vivo performance.
abstract: Solid dispersions were successfully prepared by co-spray-drying of TPGS-stabilized itraconazole nanosuspensions with Aerosil200, followed by heat treatment of the powders. The itraconazole/Aerosil200 weight ratios amounted to 50/50, 30/70, 40/60 and 20/80. The itraconazole content of the powders was close to the expected value, with relative errors between 0.3% and 7.8%. X-ray powder diffraction (XRPD), solid state NMR (SSNMR) and differential scanning calorimetry (DSC) evaluation on the powders revealed the formation of amorphous itraconazole and the absence of glassy itraconazole. Dissolution of the powders was enhanced compared to crystalline and glassy itraconazole (a 2-dimensional structured form of itraconazole). However, no clear trend could be observed between drug loading and dissolution performance of the solid dispersions. Upon storage, conversion to crystalline itraconazole was observed for the 50/50 powder based on XRPD, SSNMR and DSC measurements. Although the 40/60 powder remained X-ray amorphous upon storage, DSC did reveal that a small fraction (7.5+/-1.6% after 10 months of storage) of itraconazole crystallized upon storage. For the 30/70 and 20/80 dispersions, no crystallization could be seen. After 10 months of storage, important changes in the dissolution behavior of the powders were observed. A decrease in dissolution performance was seen for the 50/50 dispersion, which could be attributed to the crystallization of itraconazole. On the other hand, the 40/60, 30/70 and 20/80 dispersions showed an increase in dissolution rate (more than 60% after 10 min). Although not completely clear at this stage, adsorption of itraconazole onto the Aerosil200 surface during storage might be responsible for this behavior. Finally, in vivo experiments were performed in the rat. Oral bioavailability of the 30/70 dispersion was, although lower compared to the marketed Sporanox formulation, significantly enhanced compared to the crystalline drug.
authors.affiliation: Laboratory for Pharmacotechnology and Biopharmacy, K.U. Leuven, Gasthuisberg O&N2, Herestraat 49, Box 921, 3000 Leuven, Belgium.
authors.forename: Bernard
authors.initials: B
authors.lastname: Van Eerdenbrugh
authors.forename: Michiel
authors.initials: M
authors.lastname: Van Speybroeck
authors.forename: Raf
authors.initials: R
authors.lastname: Mols
authors.forename: Kristof
authors.initials: K
authors.lastname: Houthoofd
authors.forename: Johan A
authors.initials: JA
authors.lastname: Martens
authors.forename: Ludo
authors.initials: L
authors.lastname: Froyen
authors.forename: Jan
authors.initials: J
authors.lastname: Van Humbeeck
authors.forename: Patrick
authors.initials: P
authors.lastname: Augustijns
authors.forename: Guy
authors.initials: G
authors.lastname: Van den Mooter
mesh_terms: D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003460:Crystallization; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D004355:Drug Stability; D017964:Itraconazole / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry*; D008297:Male; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry; D011208:Powders; D051381:Rats; D017208:Rats, Wistar; D012822:Silicon Dioxide / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry*; D014810:Vitamin E / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry; D014961:X-Ray Diffraction
chemical_list: D004337:Drug Carriers; D011208:Powders; D014810:Vitamin E; D017964:Itraconazole; D011092:Polyethylene Glycols; D012822:Silicon Dioxide; C014225:tocophersolan