title: Investigation of a suitable in vitro dissolution test for itraconazole-based solid dispersions.
abstract: The difficulty to find a relevant in vitro dissolution test to evaluate poorly soluble drugs is a well-known issue. One way to enhance their aqueous solubility is to formulate them as amorphous solid dispersions. In this study, three formulations containing itraconazole (ITZ), a model drug, were tested in seven different conditions (different USP apparatuses and different media). Two of the formulations were amorphous solid dispersions namely Sporanox®, the marketed product, and extrudates composed of Soluplus® and ITZ produced by hot melt extrusion; and the last one was pure crystalline ITZ capsules. After each test, a ranking of the formulations was established. Surprisingly, the two amorphous solid dispersions exhibited very different behavior depending primarily on the dissolution media. Indeed, the extrudates showed a better release profile than Sporanox® in non-sink and in biphasic conditions, whilst Sporanox® showed a higher release profile than the extrudates in sink and fasted simulated gastric conditions. The disintegration, dynamic light scattering and nuclear magnetic resonance results highlighted the presence of interaction between the surfactants and Soluplus®, which slowed down the erosion of the polymer matrix. Indeed, the negative charge of sodium dodecyl sulfate (SDS) and bile salts interacted with the surface of the extrudates that formed a barrier through which the water hardly diffused. Moreover, Soluplus® and SDS formed mixed micelles in solution in which ITZ interacts with SDS, but no longer with Soluplus®. Regarding the biphasic dissolution test, the interactions between the octanol dissolved in the aqueous media disrupted the polymer--ITZ system leading to a reduced release of ITZ from Sporanox®, whilst it had no influence on the extrudates. All together these results pointed out the difficulty of finding a suitable in vitro dissolution test due to interactions between the excipients that complicates the prediction of the behavior of these solid dispersions in vivo.
authors: Laboratory of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege, 4000, Liege, Belgium. Electronic address: jthiry@ulg.ac.be.
authors: Justine
authors: J
authors: Thiry
authors: Center for Education and Research on Macromolecules, University of Liege, Chemistry Department, B6a, Sart-Tilman, Liege, Belgium.
authors: Guy
authors: G
authors: Broze
authors: Laboratory of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege, 4000, Liege, Belgium.
authors: Aude
authors: A
authors: Pestieau
authors: Center of Nuclear Magnetic Resonance (CREMAN), Department of Chemistry, University of Liege, 4000, Liege, Belgium.
authors: Andrew S
authors: AS
authors: Tatton
authors: Center of Nuclear Magnetic Resonance (CREMAN), Department of Chemistry, University of Liege, 4000, Liege, Belgium.
authors: France
authors: F
authors: Baumans
authors: Center of Nuclear Magnetic Resonance (CREMAN), Department of Chemistry, University of Liege, 4000, Liege, Belgium.
authors: Christian
authors: C
authors: Damblon
authors: Laboratory of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege, 4000, Liege, Belgium.
authors: Fabrice
authors: F
authors: Krier
authors: Laboratory of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, Center for Interdisciplinary Research on Medicines (CIRM), University of Liege, 4000, Liege, Belgium.
authors: Brigitte
authors: B
authors: Evrard
mesh_terms: D001647:Bile Acids and Salts / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods; D000067493:Dynamic Light Scattering / Q000379:methods; D005079:Excipients / Q000737:chemistry; D017964:Itraconazole / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D011108:Polymers / Q000737:chemistry; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry; D012995:Solubility; D013501:Surface-Active Agents / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D001647:Bile Acids and Salts; D005079:Excipients; D011108:Polymers; D013501:Surface-Active Agents; D014867:Water; D017964:Itraconazole; D012967:Sodium Dodecyl Sulfate
keywords: Excipient-medium interactions; In vitro dissolution test; Itraconazole; Solid dispersions; Soluplus®; Sporanox®