title: Linking granulation performance with residence time and granulation liquid distributions in twin-screw granulation: An experimental investigation.
abstract: Twin-screw granulation is a promising wet granulation technique for the continuous manufacturing of pharmaceutical solid dosage forms. A twin screw granulator displays a short residence time. Thus, the solid-liquid mixing must be achieved quickly by appropriate arrangement of transport and kneading elements in the granulator screw allowing the production of granules with a size distribution appropriate for tableting. The distribution of residence time and granulation liquid is governed by the field conditions (such as location and length of mixing zones) in the twin-screw granulator, thus contain interesting information on granulation time, mixing and resulting sub-processes such as wetting, aggregation and breakage. In this study, the impact of process (feed rate, screw speed and liquid-to-solid ratio) and equipment parameters (number of kneading discs and stagger angle) on the residence time (distribution), the granulation liquid-powder mixing and the resulting granule size distributions during twin-screw granulation were investigated. Residence time and axial mixing data was extracted from tracer maps and the solid-liquid mixing was quantified from moisture maps, obtained by monitoring the granules at the granulator outlet using near infra-red chemical imaging (NIR-CI). The granule size distribution was measured using the sieving method. An increasing screw speed dominantly reduced the mean residence time. Interaction of material throughput with the screw speed and with the number of kneading discs led to most variation in the studied responses including residence time and mixing capacity. At a high screw speed, granulation yield improved due to high axial mixing. However, increasing material throughput quickly lowers the yield due to insufficient mixing of liquid and powder. Moreover, increasing liquid-to-solid ratio resulted in more oversized granules, and the fraction of oversized granules further increased at higher throughput. Although an increasing number of kneading discs was found to be critical for achieving a uniform distribution of the granulation liquid, the granulation performance was hampered due to insufficient solid-liquid mixing capacity of the current kneading discs which is essential for wet granulation. Thus, a balance between material throughput and screw speed should be strived for in order to achieve a specific granulation time and solid-liquid mixing for high granulation yield. Additionally, more efforts are needed both in modification of the screw configuration as well as the geometry of the mixing elements to improve the mixing capacity of the twin-screw granulator. The results from the current experimental study improved the understanding regarding the interplay between granulation time and the axial and solid-liquid mixing responsible for the granulation performance in twin-screw wet granulation.
authors.affiliation: BIOMATH, Dept. of Mathematical Modelling, Statistics and Bioinformatics, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Gent, Belgium; Laboratory of Pharmaceutical Process Analytical Technology, Dept. of Pharmaceutical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium. Electronic address: ashish.kumar@ugent.be.
authors.forename: Ashish
authors.initials: A
authors.lastname: Kumar
authors.affiliation: School of Pharmacy, University of Eastern Finland, Kuopio, Finland. Electronic address: maijaa@student.uef.fi.
authors.forename: Maija
authors.initials: M
authors.lastname: Alakarjula
authors.affiliation: Laboratory of Pharmaceutical Technology, Dept. of Pharmaceutics, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium. Electronic address: valerie.vanhoorne@ugent.be.
authors.forename: Valérie
authors.initials: V
authors.lastname: Vanhoorne
authors.affiliation: Optical Measurement Technologies, VTT Technical Research Centre, Kuopio, Finland. Electronic address: maunu.toiviainen@vtt.fi.
authors.forename: Maunu
authors.initials: M
authors.lastname: Toiviainen
authors.affiliation: Laboratory of Pharmaceutical Process Analytical Technology, Dept. of Pharmaceutical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium. Electronic address: fien.deleersnyder@ugent.be.
authors.forename: Fien
authors.initials: F
authors.lastname: De Leersnyder
authors.affiliation: Laboratory of Pharmaceutical Technology, Dept. of Pharmaceutics, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium. Electronic address: jurgen.vercruysse@ugent.be.
authors.forename: Jurgen
authors.initials: J
authors.lastname: Vercruysse
authors.affiliation: Optical Measurement Technologies, VTT Technical Research Centre, Kuopio, Finland. Electronic address: mikko.juuti@vtt.fi.
authors.forename: Mikko
authors.initials: M
authors.lastname: Juuti
authors.affiliation: School of Pharmacy, University of Eastern Finland, Kuopio, Finland. Electronic address: jarkko.ketolainen@uef.fi.
authors.forename: Jarkko
authors.initials: J
authors.lastname: Ketolainen
authors.affiliation: Laboratory of Pharmaceutical Technology, Dept. of Pharmaceutics, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium. Electronic address: chris.vervaet@ugent.be.
authors.forename: Chris
authors.initials: C
authors.lastname: Vervaet
authors.affiliation: Laboratory of Pharmaceutical Technology, Dept. of Pharmaceutics, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium. Electronic address: jeanpaul.remon@UGent.be.
authors.forename: Jean Paul
authors.initials: JP
authors.lastname: Remon
authors.affiliation: CAPEC-PROCESS Research Center, Department of Chemical and Biochemical Engineering, Technical University of Denmark, DK-2800 Kongens Lyngby, Denmark. Electronic address: kvg@kt.dtu.dk.
authors.forename: Krist V
authors.initials: KV
authors.lastname: Gernaey
authors.affiliation: Laboratory of Pharmaceutical Process Analytical Technology, Dept. of Pharmaceutical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium. Electronic address: thomas.debeer@ugent.be.
authors.forename: Thomas
authors.initials: T
authors.lastname: De Beer
authors.affiliation: BIOMATH, Dept. of Mathematical Modelling, Statistics and Bioinformatics, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Gent, Belgium. Electronic address: ingmar.nopens@ugent.be.
authors.forename: Ingmar
authors.initials: I
authors.lastname: Nopens
mesh_terms: D000465:Algorithms; D004339:Drug Compounding / Q000295:instrumentation / Q000379:methods*; D004345:Drug Industry / Q000295:instrumentation / Q000379:methods*; D005583:Fourier Analysis; D007785:Lactose / Q000737:chemistry; D008962:Models, Theoretical; D019265:Spectroscopy, Near-Infrared / Q000295:instrumentation / Q000379:methods; D013678:Technology, Pharmaceutical / Q000295:instrumentation / Q000379:methods*
chemical_list: D007785:Lactose
keywords: Axial mixing; NIR chemical imaging; Residence time distribution; Solid–liquid mixing