title: Reactive Melt Extrusion To Improve the Dissolution Performance and Physical Stability of Naproxen Amorphous Solid Dispersions.
abstract: The purpose of this study was to investigate the reaction between naproxen (NPX) and meglumine (MEG) at elevated temperature and to study the effect of this reaction on the physical stabilities and in vitro drug-release properties of melt-extruded naproxen amorphous solid dispersions (ASDs). Differential scanning calorimetry, hot-stage polarized light microscopy, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy analyses demonstrated that in situ salt formation with proton transfer between NPX and MEG occurred at elevated temperature during the melt extrusion process. The amorphous NPX-MEG salt was physically most stable when two components were present at a 1:1 molar ratio. Polymeric carriers, including povidone, copovidone, and SOLUPLUS, did not interfere with the reaction between NPX and MEG during melt extrusion. Compared to the traditional NPX ASDs consisting of NPX and polymer only, NPX-MEG ASDs were physically more stable and remained amorphous following four months storage at 40 °C and 75% RH (relative humidity). Based on nonsink dissolution testing and polarized light microscopy analyses, we concluded that the conventional NPX ASDs composed of NPX and polymers failed to improve the NPX dissolution rate due to the rapid recrystallization of NPX in contact with aqueous medium. The dissolution rate of NPX-MEG ASDs was two times greater than the corresponding physical mixtures and conventional NPX ASDs. This study demonstrated that the acid-base reaction between NPX and MEG during melt extrusion significantly improved the physical stability and the dissolution rate of NPX ASDs.
authors.affiliation: College of Pharmacy, The University of Texas at Austin , 2409 University Avenue, A1920, Austin, Texas 78712, United States.
authors.forename: Xu
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.affiliation: College of Pharmacy, The University of Texas at Austin , 2409 University Avenue, A1920, Austin, Texas 78712, United States.
authors.forename: Feng
authors.identifier: 0000-0002-5377-5841
authors.initials: F
authors.lastname: Zhang
mesh_terms: D002152:Calorimetry, Differential Scanning / Q000379:methods; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004337:Drug Carriers / Q000737:chemistry; D065546:Drug Liberation / Q000502:physiology; D004355:Drug Stability; D006358:Hot Temperature; D008536:Meglumine / Q000737:chemistry; D008859:Microscopy, Polarization / Q000379:methods; D009288:Naproxen / Q000737:chemistry*; D056951:Photoelectron Spectroscopy / Q000379:methods; D011108:Polymers / Q000737:chemistry; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared / Q000379:methods; D014961:X-Ray Diffraction / Q000379:methods
chemical_list: D004337:Drug Carriers; D011108:Polymers; D009288:Naproxen; D008536:Meglumine
keywords: amorphous solid dispersion; dissolution rate; ionic interaction; meglumine; naproxen; physical stability; reactive melt extrusion; salt formation