title: The use of rheology to elucidate the granulation mechanisms of a miscible and immiscible system during continuous twin-screw melt granulation.
abstract: Twin-screw hot melt granulation (TS HMG) is a valuable, but still unexplored alternative to granulate temperature and moisture sensitive drugs in a continuous way. Recently, the material behavior of an immiscible drug-binder blend during TS HMG was unraveled by using a rheometer and differential scanning calorimetry (DSC). Additionally, vibrational spectroscopic techniques proved the link between TS HMG and rheology since equal interactions at molecular level did occur in both processes. This allowed to use a rheometer to gain knowledge of the material behavior during hot melt processing of an immiscible drug-binder blend. However, miscibility of a drug-binder formulation and drug-binder interactions appear to influence the rheological properties and, hence conceivably also the granulation mechanism. The aim of this research was to examine if the TS HMG process of a miscible formulation system is comparable with the mechanism of an immiscible system and to evaluate whether rheology still serves as a useful tool to understand and optimize the hot melt granulation (HMG) process. The executed research (thermal analysis, rheological parameters and spectroscopic data) demonstrated the occurrence of a high and broad tan(δ) curve without a loss peak during the rheological temperature ramp which implies a higher material deformability without movement of the softened single polymer chains. Spectroscopic analysis revealed drug-polymer interactions which constrain the polymer to flow independently. As a result, the binder distribution step, which generally follows the immersion step, was hindered. This insight assisted the understanding of the granule properties. Inhomogeneous granules were produced due to large initial nuclei or adhesion of multiple smaller nuclei. Consequently, a higher granulation temperature was required in order to get the binder more homogeneously distributed within the granules.
authors.affiliation: Laboratory of Pharmaceutical Process Analytical Technology, Department of Pharmaceutical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium. Electronic address: Tinne.Monteyne@UGent.be.
authors.forename: Tinne
authors.initials: T
authors.lastname: Monteyne
authors.affiliation: Laboratory of Pharmaceutical Process Analytical Technology, Department of Pharmaceutical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium. Electronic address: Liza.Heeze@UGent.be.
authors.forename: Liza
authors.initials: L
authors.lastname: Heeze
authors.affiliation: Laboratory of Pharmaceutical Process Analytical Technology, Department of Pharmaceutical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium; BIOMATH, Department of Mathematical Modelling, Statistics and Bioinformatics, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium. Electronic address: Severine.Mortier@UGent.be.
authors.forename: Séverine Thérèse F C
authors.initials: ST
authors.lastname: Mortier
authors.affiliation: Center for Material Characterization of Products, Thermofisher, Dieselstrasse 4, 76227 Karlsruhe, Germany. Electronic address: Klaus.Oldoerp@Thermofisher.com.
authors.forename: Klaus
authors.initials: K
authors.lastname: Oldörp
authors.affiliation: BIOMATH, Department of Mathematical Modelling, Statistics and Bioinformatics, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium. Electronic address: Ingmar.Nopens@UGent.be.
authors.forename: Ingmar
authors.initials: I
authors.lastname: Nopens
authors.affiliation: Laboratory of Pharmaceutical Process Analytical Technology, Department of Pharmaceutical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium. Electronic address: JeanPaul.Remon@UGent.be.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Remon
authors.affiliation: Laboratory of Pharmaceutical Technology, Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium. Electronic address: Chris.Vervaet@UGent.be.
authors.forename: Chris
authors.initials: C
authors.lastname: Vervaet
authors.affiliation: Laboratory of Pharmaceutical Technology, Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium. Electronic address: Thomas.Debeer@Ugent.be.
authors.forename: Thomas
authors.initials: T
authors.lastname: De Beer
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011145:Polyvinyls / Q000737:chemistry*; D012212:Rheology / Q000379:methods*
chemical_list: D011145:Polyvinyls; C572167:polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; D011092:Polyethylene Glycols
keywords: Agglomeration mechanism; Drug–binder interactions; Miscibility; Spectroscopy; Tan(δ)