Pharmaceutical Research

, Volume 33, Issue 10, pp 2481–2494 | Cite as

The use of Rheology Combined with Differential Scanning Calorimetry to Elucidate the Granulation Mechanism of an Immiscible Formulation During Continuous Twin-Screw Melt Granulation

  • Tinne Monteyne
  • Liza Heeze
  • Severine Therese F. C. Mortier
  • Klaus Oldörp
  • Ruth Cardinaels
  • Ingmar Nopens
  • Chris Vervaet
  • Jean-Paul Remon
  • Thomas De Beer
Research Paper



Twin screw hot melt granulation (TS HMG) is a valuable, but still unexplored alternative to continuous granulation of moisture sensitive drugs. However, knowledge of the material behavior during TS HMG is crucial to optimize the formulation, process and resulting granule properties. The aim of this study was to evaluate the agglomeration mechanism during TS HMG using a rheometer in combination with differential scanning calorimetry (DSC).


An immiscible drug-binder formulation (caffeine-Soluplus®) was granulated via TS HMG in combination with thermal and rheological analysis (conventional and Rheoscope), granule characterization and Near Infrared chemical imaging (NIR-CI).


A thin binder layer with restricted mobility was formed on the surface of the drug particles during granulation and is covered by a second layer with improved mobility when the Soluplus® concentration exceeded 15% (w/w). The formation of this second layer was facilitated at elevated granulation temperatures and resulted in smaller and more spherical granules.


The combination of thermal and rheological analysis and NIR-CI images was advantageous to develop in-depth understanding of the agglomeration mechanism during continuous TS HMG and provided insight in the granule properties as function of process temperature and binder concentration.


agglomeration mechanism caffeine anhydrous glass transition temperature granule properties soluplus® tan(δ) 



Active pharmaceutical ingredient


Attenuated Total Reflection


Caffeine anhydrous


Controlled deformation


Differential scanning calorimetry


Fourier Transform Infrared


Complex shear modulus


Storage modulus


Loss modulus


Granule size distribution


Hot melt granulation




Metoprolol tartrate


Near Infrared


Near Infrared chemical imaging


Polyethylene glycol


Polyvinyl acetate


Savitzky Golay




Standard Normal Variate


Glass transition temperature


Melting temperature


Twin screw hot melt granulation



Financial support for this research from the Agency for Innovation by Science and Technology (IWT - Ph.D. fellowship Tinne Monteyne) and Fund for Scientific Research Flanders (FWO Flanders - Postdoc fellowship Severine Therese F.C. Mortier) are gratefully acknowledged. BASF is acknowledged for sending large amounts of caffeine and Soluplus®. Thermo Fisher Scientific (Karlsruhe) is appreciatively acknowledged for giving me the opportunity to use their rheometers in parallel for a long period of time.


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Tinne Monteyne
    • 1
  • Liza Heeze
    • 1
  • Severine Therese F. C. Mortier
    • 1
    • 2
  • Klaus Oldörp
    • 3
  • Ruth Cardinaels
    • 5
  • Ingmar Nopens
    • 2
  • Chris Vervaet
    • 4
  • Jean-Paul Remon
    • 4
  • Thomas De Beer
    • 1
  1. 1.Laboratory of Pharmaceutical Process Analytical Technology Department of Pharmaceutical Analysis, Faculty of Pharmaceutical SciencesGhent UniversityGhentBelgium
  2. 2.BIOMATH, Department of Mathematical Modelling, Statistics and Bioinformatics, Faculty of Bioscience EngineeringGhent UniversityGhentBelgium
  3. 3.Center for Material Characterization of ProductsKarlsruheGermany
  4. 4.Laboratory of Pharmaceutical Technology, Department of Pharmaceutics, Faculty of Pharmaceutical SciencesGhent UniversityGhentBelgium
  5. 5.Polymer Technology, Department of Mechanical EngineeringEindhoven University of TechnologyEindhovenThe Netherlands

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