title: An approach for chemical stability during melt extrusion of a drug substance with a high melting point.
abstract: Poorly water-soluble drug substances that exhibit high melting points are difficult to process by melt extrusion due to chemical instability at high temperatures required for processing. The purpose of this study was to extrude meloxicam (melting point 255°C) by optimizing processing parameters and formulation composition. Five extrusion studies were performed: 1) design space, 2) impact of moisture, 3) impact of melt residence time, 4) specific energy optimization, and 5) altered microenvironment pH. Powder X-ray diffraction and polarized light microscopy were used to confirm amorphous conversion. Liquid chromatography-mass spectrometry was used to characterize the extrusion degradation pathway. The formulation consisted of 10% meloxicam and 90% copovidone. When processed above 140°C, significant chemical degradation was observed. The minimum energy input to convert meloxicam was 1.8kWh/kg. Degradation of meloxicam during extrusion was identified as hydrolysis. Barrel configuration and screw design were designed to drive-off moisture and reduce melt residence time. With optimized parameters, the purity of the extrudate was 96.7%. To further enhance chemical stability, meglumine was added to provide a stabilizing basic microenvironment resulting in 100% purity. By process parameter optimization and formulation modification, we successfully extruded a meloxicam amorphous solid dispersion.
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The University of Texas at Austin, 2409 University Avenue, A1920, Austin, TX, 78712, USA.
authors.forename: Abbe
authors.initials: A
authors.lastname: Haser
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The University of Texas at Austin, 2409 University Avenue, A1920, Austin, TX, 78712, USA.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Huang
authors.affiliation: Foster Delivery Sciences,45 Ridge Road, Putnam, CT, 06260, USA.
authors.forename: Tony
authors.initials: T
authors.lastname: Listro
authors.affiliation: Foster Delivery Sciences,45 Ridge Road, Putnam, CT, 06260, USA.
authors.forename: David
authors.initials: D
authors.lastname: White
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The University of Texas at Austin, 2409 University Avenue, A1920, Austin, TX, 78712, USA. Electronic address: feng.zhang@austin.utexas.edu.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
mesh_terms: D002626:Chemistry, Pharmaceutical; D004355:Drug Stability; D006358:Hot Temperature; D012995:Solubility; D014961:X-Ray Diffraction
keywords: Amorphous solid dispersion; Chemical stability; Copovidone; Meloxicam; Melt extrusion