title: Application of mixtures of polymeric carriers for dissolution enhancement of fenofibrate using hot-melt extrusion.
abstract: Hot-melt extrusion was applied to improve dissolution behavior of poorly soluble model drug fenofibrate. Blends of polymers were used as carrier: copovidone (COP), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol copolymer (PVCL-PVAc-PEG) and hypromellose 2910/5 (HPMC). The ratio of fenofibrate to COP remained constantly 1+3 (weighted parts) with varying amounts of PVCL-PVAc-PEG and HPMC. Solid state of fenofibrate was characterized by X-ray diffractometry and differential scanning calorimetry. Dissolution performance was compared to marketed formulations Lipidil and Lipidil-Ter. Stability studies were conducted at 25°C/60%rH. The dissolution rate from extrudates was significantly increased when compared to pure fenofibrate powder or physical mixture of the components. A supersaturation of 7.6-12.1 was reached with the pelletized extrudates. All extrudates were superior to marketed formulations. No recrystallization was observed after 26 weeks of storage for fenofibrate-COP extrudates 1+3 (weighted parts) with or without polymeric additives. Even so, both degree and duration of supersaturation decreased with increasing storage periods with the exception of fenofibrate-HPMC extrudates. Of particular interest is the finding that by adding polymers with differing release characteristics to the drug-carrier mixture, the dissolution performance of hot-melt extruded solid dosage forms can be readily adapted to meet specific requirements.
authors.affiliation: Merck Serono, Formulation and Process Development, Darmstadt, Germany.
authors.forename: Adela
authors.initials: A
authors.lastname: Kalivoda
authors.forename: Matthias
authors.initials: M
authors.lastname: Fischbach
authors.forename: Peter
authors.initials: P
authors.lastname: Kleinebudde
mesh_terms: D002152:Calorimetry, Differential Scanning; D003460:Crystallization; D004337:Drug Carriers / Q000737:chemistry*; D004339:Drug Compounding / Q000379:methods; D004355:Drug Stability; D004356:Drug Storage; D011345:Fenofibrate / Q000737:chemistry*; D065347:Hypromellose Derivatives; D008747:Methylcellulose / Q000031:analogs & derivatives / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D011145:Polyvinyls / Q000737:chemistry; D011759:Pyrrolidines / Q000737:chemistry; D012995:Solubility; D014753:Vinyl Compounds / Q000737:chemistry; D014961:X-Ray Diffraction
chemical_list: D004337:Drug Carriers; D011108:Polymers; D011145:Polyvinyls; D011759:Pyrrolidines; D014753:Vinyl Compounds; C402301:poly(vinylpyrrolidone-co-vinyl-acetate); C572167:polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; D065347:Hypromellose Derivatives; D011092:Polyethylene Glycols; D008747:Methylcellulose; D011345:Fenofibrate