title: Itraconazole formulation studies of the melt-extrusion process with mixture design.
abstract: Itraconazole is a poorly water soluble compound. One method to increase the aqueous solubility of itraconazole is through formation of a solid dispersion. The purpose of this study is to develop a 40% w/w itraconazole formulation through solid dispersion formation, using hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and hydroxypropylmethyl-cellulose (HPMC) as mixture components. The solid dispersion was obtained by melt-extrusion using a twin-screw corotating melt extruder. A D-optimal mixture design was applied for the development of the optimal itraconazole formulation. The itraconazole fraction varied between 20% w/w and 50% w/w in the mixture design and the HPMC and HP-beta-CD fractions varied between 10% w/w and 60% w/w. The itraconazole formulation was optimized by producing clear extrudates, minimizing the torque, and maximizing the glass transition temperature and the apparent itraconazole solubility in 0.1 N HCl. Regression models were developed for the torque, glass transition temperature, and apparent solubility of itraconazole. High itraconazole fraction in the mixture promoted a better melt processing (minimizes torque). High HPMC fraction (>33% w/w) resulted in clear extrudates, indicating a solid dispersion and resulted in high glass transition temperature of the melt. High HP-beta-CD fraction resulted in increased apparent itraconazole solubility in 0.1 N HCl. The optimal itraconazole formulation consisted of 45% w/w HPMC and 15% HP-beta-CD w/w.
authors.affiliation: Farmaceutische Instituut, Vrije Universiteit Brussel, Brussels, Belgium. bisoen.rambali@rivm.nl
authors.forename: B
authors.initials: B
authors.lastname: Rambali
authors.forename: G
authors.initials: G
authors.lastname: Verreck
authors.forename: L
authors.initials: L
authors.lastname: Baert
authors.forename: D L
authors.initials: DL
authors.lastname: Massart
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000935:Antifungal Agents / Q000008:administration & dosage / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D003460:Crystallization; D003505:Cyclodextrins / Q000737:chemistry; D065347:Hypromellose Derivatives; D017964:Itraconazole / Q000008:administration & dosage / Q000737:chemistry*; D008747:Methylcellulose / Q000031:analogs & derivatives / Q000737:chemistry; D012044:Regression Analysis; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods; D014783:Viscosity; D047392:beta-Cyclodextrins
chemical_list: D000935:Antifungal Agents; D003505:Cyclodextrins; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D017964:Itraconazole; D065347:Hypromellose Derivatives; D008747:Methylcellulose