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Downstream processing from hot-melt extrusion towards tablets : a quality by design approach

Wouter Grymonpré (UGent) , Nils Bostijn (UGent) , Simon Van Herck (UGent) , Glenn Verstraete (UGent) , Valérie Vanhoorne (UGent) , Lutz Nuhn (UGent) , Pieter Rombouts (UGent) , Thomas De Beer (UGent) , Jean Paul Remon (UGent) and Chris Vervaet (UGent)
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Abstract
Since the concept of continuous processing is gaining momentum in pharmaceutical manufacturing, a thorough understanding on how process and formulation parameters can impact the critical quality attributes (CQA) of the end product is more than ever required. This study was designed to screen the influence of process parameters and drug load during HME on both extrudate properties and tableting behaviour of an amorphous solid dispersion formulation using a quality-by-design (QbD) approach. A full factorial experimental design with 19 experiments was used to evaluate the effect of several process variables (barrel temperature: 160-200 degrees C, screw speed: 50-200 rpm, throughput: 0.2-0.5 kg/h) and drug load (0-20%) as formulation parameter on the hot-melt extrusion (HME) process, extrudate and tablet quality of Soluplus (R)-Celecoxib amorphous solid dispersions. A prominent impact of the formulation parameter on the CQA of the extrudates (i.e. solid state properties, moisture content, particle size distribution) and tablets (ie. tabletability, compactibility, fragmentary behaviour, elastic recovery) was discovered. The resistance of the polymer matrix to thermo-mechanical stress during HME was confirmed throughout the experimental design space. In addition, the suitability of Raman spectroscopy as verification method for the active pharmaceutical ingredient (API) concentration in solid dispersions was evaluated. Incorporation of the Raman spectroscopy data in a PLS model enabled API quantification in the extrudate powders with none of the DOE-experiments resulting in extrudates with a CEL content deviating > 3% of the label claim. This research paper emphasized that HME is a robust process throughout the experimental design space for obtaining amorphous glassy solutions and for tabletting of such formulations since only minimal impact of the process parameters was detected on the extrudate and tablet properties. However, the quality of extrudates and tablets can be optimized by adjusting specific formulations parameters (e.g. drug load).
Keywords
Hot-melt extrusion (HME), Tableting, Quality by design, Solid dispersion, Tablet quality, Raman spectroscopy, Principle component analysis (PCA), AMORPHOUS SOLID DISPERSIONS, COMPACTION PROPERTIES, MECHANICAL ENERGY, PRESS SIMULATOR, SOLUBLE DRUGS, DEGRADATION, FORMULATION, SPECTROSCOPY, POWDER

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MLA
Grymonpré, Wouter et al. “Downstream Processing from Hot-melt Extrusion Towards Tablets : a Quality by Design Approach.” INTERNATIONAL JOURNAL OF PHARMACEUTICS 531.1 (2017): 235–245. Print.
APA
Grymonpré, W., Bostijn, N., Van Herck, S., Verstraete, G., Vanhoorne, V., Nuhn, L., Rombouts, P., et al. (2017). Downstream processing from hot-melt extrusion towards tablets : a quality by design approach. INTERNATIONAL JOURNAL OF PHARMACEUTICS, 531(1), 235–245.
Chicago author-date
Grymonpré, Wouter, Nils Bostijn, Simon Van Herck, Glenn Verstraete, Valérie Vanhoorne, Lutz Nuhn, Pieter Rombouts, Thomas De Beer, Jean Paul Remon, and Chris Vervaet. 2017. “Downstream Processing from Hot-melt Extrusion Towards Tablets : a Quality by Design Approach.” International Journal of Pharmaceutics 531 (1): 235–245.
Chicago author-date (all authors)
Grymonpré, Wouter, Nils Bostijn, Simon Van Herck, Glenn Verstraete, Valérie Vanhoorne, Lutz Nuhn, Pieter Rombouts, Thomas De Beer, Jean Paul Remon, and Chris Vervaet. 2017. “Downstream Processing from Hot-melt Extrusion Towards Tablets : a Quality by Design Approach.” International Journal of Pharmaceutics 531 (1): 235–245.
Vancouver
1.
Grymonpré W, Bostijn N, Van Herck S, Verstraete G, Vanhoorne V, Nuhn L, et al. Downstream processing from hot-melt extrusion towards tablets : a quality by design approach. INTERNATIONAL JOURNAL OF PHARMACEUTICS. 2017;531(1):235–45.
IEEE
[1]
W. Grymonpré et al., “Downstream processing from hot-melt extrusion towards tablets : a quality by design approach,” INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 531, no. 1, pp. 235–245, 2017.
@article{8550662,
  abstract     = {Since the concept of continuous processing is gaining momentum in pharmaceutical manufacturing, a thorough understanding on how process and formulation parameters can impact the critical quality attributes (CQA) of the end product is more than ever required. This study was designed to screen the influence of process parameters and drug load during HME on both extrudate properties and tableting behaviour of an amorphous solid dispersion formulation using a quality-by-design (QbD) approach. A full factorial experimental design with 19 experiments was used to evaluate the effect of several process variables (barrel temperature: 160-200 degrees C, screw speed: 50-200 rpm, throughput: 0.2-0.5 kg/h) and drug load (0-20%) as formulation parameter on the hot-melt extrusion (HME) process, extrudate and tablet quality of Soluplus (R)-Celecoxib amorphous solid dispersions. A prominent impact of the formulation parameter on the CQA of the extrudates (i.e. solid state properties, moisture content, particle size distribution) and tablets (ie. tabletability, compactibility, fragmentary behaviour, elastic recovery) was discovered. The resistance of the polymer matrix to thermo-mechanical stress during HME was confirmed throughout the experimental design space. In addition, the suitability of Raman spectroscopy as verification method for the active pharmaceutical ingredient (API) concentration in solid dispersions was evaluated. Incorporation of the Raman spectroscopy data in a PLS model enabled API quantification in the extrudate powders with none of the DOE-experiments resulting in extrudates with a CEL content deviating > 3% of the label claim. This research paper emphasized that HME is a robust process throughout the experimental design space for obtaining amorphous glassy solutions and for tabletting of such formulations since only minimal impact of the process parameters was detected on the extrudate and tablet properties. However, the quality of extrudates and tablets can be optimized by adjusting specific formulations parameters (e.g. drug load).},
  author       = {Grymonpré, Wouter and Bostijn, Nils and Van Herck, Simon and Verstraete, Glenn and Vanhoorne, Valérie and Nuhn, Lutz and Rombouts, Pieter and De Beer, Thomas and Remon, Jean Paul and Vervaet, Chris},
  issn         = {0378-5173},
  journal      = {INTERNATIONAL JOURNAL OF PHARMACEUTICS},
  keywords     = {Hot-melt extrusion (HME),Tableting,Quality by design,Solid dispersion,Tablet quality,Raman spectroscopy,Principle component analysis (PCA),AMORPHOUS SOLID DISPERSIONS,COMPACTION PROPERTIES,MECHANICAL ENERGY,PRESS SIMULATOR,SOLUBLE DRUGS,DEGRADATION,FORMULATION,SPECTROSCOPY,POWDER},
  language     = {eng},
  number       = {1},
  pages        = {235--245},
  title        = {Downstream processing from hot-melt extrusion towards tablets : a quality by design approach},
  url          = {http://dx.doi.org/10.1016/j.ijpharm.2017.08.077},
  volume       = {531},
  year         = {2017},
}

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