title: Nano-extrusion: a promising tool for continuous manufacturing of solid nano-formulations.
abstract: Since more than 40% of today's drugs have low stability, poor solubility and/or limited ability to cross certain biological barriers, new platform technologies are required to address these challenges. This paper describes a novel continuous process that converts a stabilized aqueous nano-suspension into a solid oral formulation in a single step (i.e., the NANEX process) in order to improve the solubility of a model drug (phenytoin). Phenytoin nano-suspensions were prepared via media milling using different stabilizers. A stable nano-suspension was obtained using Tween(®) 80 as a stabilizer. The matrix material (Soluplus(®)) was gravimetrically fed into the hot melt extruder. The suspension was introduced through a side feeding device and mixed with the molten polymer to immediately devolatilize the water in the nano-suspension. Phenytoin nano-crystals were dispersed and embedded in the molten polymer. Investigation of the nano-extrudates via transmission electron microscopy and atomic force microscopy showed that the nano-crystals were embedded de-aggregated in the extrudates. Furthermore, no changes in the crystallinity (due to the mechanical and thermal stress) occurred. The dissolution studies confirmed that the prepared nano-extrudates increased the solubility of nano-crystalline phenytoin, regardless of the polymer. Our work demonstrates that NANEX represents a promising new platform technology in the design of novel drug delivery systems to improve drug performance.
authors.affiliation: Research Center Pharmaceutical Engineering GmbH, Inffeldgasse 13, 8010 Graz, Austria.
authors.forename: Ramona
authors.initials: R
authors.lastname: Baumgartner
authors.affiliation: Research Center Pharmaceutical Engineering GmbH, Inffeldgasse 13, 8010 Graz, Austria; Institute for Process and Particle Engineering, Graz University of Technology, Inffeldgasse 13, 8010 Graz, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Eitzlmayr
authors.affiliation: Graz Center for Electron Microscopy (ZFE), Steyrergasse 17, 8010 Graz, Austria.
authors.forename: Nadejda
authors.initials: N
authors.lastname: Matsko
authors.affiliation: Institute of Pharmaceutical Sciences, Department of Pharmaceutical Technology, Karl-Franzens University Graz, Universitätsplatz 1, 8010 Graz, Austria.
authors.forename: Carolin
authors.initials: C
authors.lastname: Tetyczka
authors.affiliation: Research Center Pharmaceutical Engineering GmbH, Inffeldgasse 13, 8010 Graz, Austria; Institute for Process and Particle Engineering, Graz University of Technology, Inffeldgasse 13, 8010 Graz, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Khinast
authors.affiliation: Research Center Pharmaceutical Engineering GmbH, Inffeldgasse 13, 8010 Graz, Austria; Institute of Pharmaceutical Sciences, Department of Pharmaceutical Technology, Karl-Franzens University Graz, Universitätsplatz 1, 8010 Graz, Austria. Electronic address: eva.roblegg@uni-graz.at.
authors.forename: Eva
authors.initials: E
authors.lastname: Roblegg
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods; D003460:Crystallization; D016503:Drug Delivery Systems; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry; D018625:Microscopy, Atomic Force; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles; D036103:Nanotechnology / Q000379:methods*; D010316:Particle Size; D010672:Phenytoin / Q000008:administration & dosage / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D011136:Polysorbates / Q000737:chemistry; D011145:Polyvinyls / Q000737:chemistry; D012995:Solubility; D013535:Suspensions
chemical_list: D005079:Excipients; D011136:Polysorbates; D011145:Polyvinyls; D013535:Suspensions; C572167:polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; D011092:Polyethylene Glycols; D010672:Phenytoin
keywords: Hot melt extrusion; Nano-extrusion (NANEX); One-step continuous process; Phenytoin nano-suspension; Solid nano-formulation