title: Elucidation and visualization of solid-state transformation and mixing in a pharmaceutical mini hot melt extrusion process using in-line Raman spectroscopy.
abstract: Mixing of raw materials (drug+polymer) in the investigated mini pharma melt extruder is achieved by using co-rotating conical twin screws and an internal recirculation channel. In-line Raman spectroscopy was implemented in the barrels, allowing monitoring of the melt during processing. The aim of this study was twofold: to investigate (I) the influence of key process parameters (screw speed - barrel temperature) upon the product solid-state transformation during processing of a sustained release formulation in recirculation mode; (II) the influence of process parameters (screw speed - barrel temperature - recirculation time) upon mixing of a crystalline drug (tracer) in an amorphous polymer carrier by means of residence time distribution (RTD) measurements. The results indicated a faster mixing endpoint with increasing screw speed. Processing a high drug load formulation above the drug melting temperature resulted in the production of amorphous drug whereas processing below the drug melting point produced solid dispersions with partially amorphous/crystalline drug. Furthermore, increasing the screw speed resulted in lower drug crystallinity of the solid dispersion. RTD measurements elucidated the improved mixing capacity when using the recirculation channel. In-line Raman spectroscopy has shown to be an adequate PAT-tool for product solid-state monitoring and elucidation of the mixing behavior during processing in a mini extruder.
authors.affiliation: Laboratory of Process Analytical Technology, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium. Electronic address: jeroen.vanrenterghem@ugent.be.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Van Renterghem
authors.affiliation: BIOMATH, Ghent University, Coupure Links 653, 9000 Ghent, Belgium.
authors.forename: Ashish
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Laboratory of Pharmaceutical Technology, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
authors.forename: Chris
authors.initials: C
authors.lastname: Vervaet
authors.affiliation: Laboratory of Pharmaceutical Technology, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
authors.forename: Jean Paul
authors.initials: JP
authors.lastname: Remon
authors.affiliation: BIOMATH, Ghent University, Coupure Links 653, 9000 Ghent, Belgium.
authors.forename: Ingmar
authors.initials: I
authors.lastname: Nopens
authors.affiliation: Dept of Analytical Chemistry and Pharmaceutical Technology, VUB, Laarbeeklaan 103, 1090 Brussels, Belgium.
authors.forename: Yvan
authors.initials: Y
authors.lastname: Vander Heyden
authors.affiliation: Laboratory of Process Analytical Technology, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: De Beer
mesh_terms: D000179:Acrylates / Q000737:chemistry; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical / Q000295:instrumentation / Q000379:methods*; D004339:Drug Compounding; D004867:Equipment Design; D006358:Hot Temperature; D020366:Methylmethacrylate / Q000737:chemistry; D008790:Metoprolol / Q000737:chemistry*; D011109:Polymethacrylic Acids / Q000737:chemistry; D013059:Spectrum Analysis, Raman; D013678:Technology, Pharmaceutical / Q000295:instrumentation / Q000379:methods*
chemical_list: D000179:Acrylates; C496966:Eudragit RSPO; D011109:Polymethacrylic Acids; D020366:Methylmethacrylate; C040833:ethyl acrylate; D008790:Metoprolol
keywords: Hot-melt extrusion; Mixing; Raman spectroscopy; Recirculation time; Residence time distribution; Solid-state transformation; Transport