title: Dissolution and precipitation behavior of ternary solid dispersions of ezetimibe in biorelevant media.
abstract: The effects of different formulations and processes on inducing and maintaining the supersaturation of ternary solid dispersions of ezetimibe (EZ) in two biorelevant media fasted-state simulated intestinal fluid (FaSSIF) and fasted-state simulated gastric fluid (FaSSGF) at different temperatures (25 °C and 37 °C) were investigated in this work. Ternary solid dispersions of EZ were prepared by adding polymer PVP-K30 and surfactant poloxamer 188 using melt-quenching and spray-drying methods. The resulting solid dispersions were characterized using scanning electron microscopy, differential scanning calorimetry (DSC), modulated DSC, powder X-ray diffraction and Fourier transformation infrared spectroscopy. The dissolution of all the ternary solid dispersions was tested in vitro under non-sink conditions. All the prepared solid dispersions were amorphous in nature. In FaSSIF at 25 °C, the melt-quenched (MQ) solid dispersions of EZ were more soluble than the spray-dried (SD) solid dispersions and supersaturation was maintained. However, at 37 °C, rapid and variable precipitation behavior was observed for all the MQ and SD formulations. In FaSSGF, the melting method resulted in better solubility than the spray-drying method at both temperatures. Ternary solid dispersions show potential for improving solubility and supersaturation. However, powder dissolution experiments of these solid dispersions of EZ at 25 °C may not predict the supersaturation behavior at physiologically relevant temperatures.
authors.affiliation: a Department of Health Sciences, Division of Medical Sciences , Luleå University of Technology , Lulea , Sweden.
authors.forename: Amani
authors.initials: A
authors.lastname: Alhayali
authors.affiliation: b Departments of Pharmacology and Clinical Neuroscience , Umea University , Umeå , Sweden.
authors.forename: Staffan
authors.initials: S
authors.lastname: Tavellin
authors.affiliation: a Department of Health Sciences, Division of Medical Sciences , Luleå University of Technology , Lulea , Sweden.
authors.forename: Sitaram
authors.initials: S
authors.lastname: Velaga
mesh_terms: D000924:Anticholesteremic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D001826:Body Fluids / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D011232:Chemical Precipitation; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D000069438:Ezetimibe / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared / Q000379:methods; D014961:X-Ray Diffraction
chemical_list: D000924:Anticholesteremic Agents; D000069438:Ezetimibe
keywords: Poorly soluble drugs; biorelevant media; dissolution; supersaturation; ternary solid dispersions