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

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Abstract

Purpose

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).

Methods

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).

Results

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.

Conclusion

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.

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Abbreviations

API:

Active pharmaceutical ingredient

ATR:

Attenuated Total Reflection

CAF:

Caffeine anhydrous

CD:

Controlled deformation

DSC:

Differential scanning calorimetry

FTIR:

Fourier Transform Infrared

G*:

Complex shear modulus

G’:

Storage modulus

G”:

Loss modulus

GSD:

Granule size distribution

HMG:

Hot melt granulation

MCT:

Mercury-Cadmium-Telluride

MPT:

Metoprolol tartrate

NIR:

Near Infrared

NIR-CI:

Near Infrared chemical imaging

PEG:

Polyethylene glycol

PVA:

Polyvinyl acetate

SG:

Savitzky Golay

SLP:

Soluplus®

SNV:

Standard Normal Variate

Tg :

Glass transition temperature

Tm :

Melting temperature

TS HMG:

Twin screw hot melt granulation

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ACKNOWLEDGMENTS AND DISCLOSURES

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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Authors and Affiliations

  1. Laboratory of Pharmaceutical Process Analytical Technology Department of Pharmaceutical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000, Ghent, Belgium

    Tinne Monteyne, Liza Heeze, Severine Therese F. C. Mortier & Thomas De Beer

  2. BIOMATH, Department of Mathematical Modelling, Statistics and Bioinformatics, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653,, 9000, Ghent, Belgium

    Severine Therese F. C. Mortier & Ingmar Nopens

  3. Center for Material Characterization of Products, Thermo sher Dieselstrasse 4,, 76227, Karlsruhe, Germany

    Klaus Oldörp

  4. Laboratory of Pharmaceutical Technology, Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460,, 9000, Ghent, Belgium

    Chris Vervaet & Jean-Paul Remon

  5. Polymer Technology, Department of Mechanical Engineering, Eindhoven University of Technology, Gemini-Zuid 4.142, 5600, Eindhoven, The Netherlands

    Ruth Cardinaels

Authors
  1. Tinne Monteyne
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Correspondence to Tinne Monteyne.

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Monteyne, T., Heeze, L., Mortier, S.T.F.C. et al. The use of Rheology Combined with Differential Scanning Calorimetry to Elucidate the Granulation Mechanism of an Immiscible Formulation During Continuous Twin-Screw Melt Granulation. Pharm Res 33, 2481–2494 (2016). https://doi.org/10.1007/s11095-016-1973-6

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  • DOI: https://doi.org/10.1007/s11095-016-1973-6

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