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Evaluation of injection moulding as a pharmaceutical technology to produce matrix tablets

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Abstract
The aim of this study was to develop sustained-release matrix tablets by means of injection moulding and to evaluate the influence of process temperature, matrix composition (EC and HPMC concentration) and viscosity grade of ethylcellulose (EC) and hydroxypropylmethylcellulose (HPMC) on processability and drug release. The drug release data were analyzed to get insight in the release kinetics and mechanism. Formulations containing metoprolol tartrate (30%, model drug), EC with dibutyl sebacate (matrix former and plasticizer) and hydrophilic polymer HPMC were extruded and subsequently injection moulded into tablets (375 mg, 10 mm diameter, convex-shaped) at temperatures ranging from 110 to 140 °C. Tablets containing 30% metoprolol and 70% ethylcellulose (EC 4 mPa s) showed an incomplete drug release within 24 h (<50%). Increasing production temperatures resulted in a lower drug release rate. Substituting part of the EC fraction by HPMC (HPMC/EC-ratio: 20/50 and 35/35) resulted in faster and constant drug release rates. Formulations containing 50% HPMC had a complete and first-order drug release profile with drug release controlled via the combination of diffusion and swelling/erosion. Faster drug release rates were observed for higher viscosity grades of EC (Mw > 20 mPa s) and HPMC (4000 and 10,000 mPa s). Tablet porosity was low (<4%). Differential scanning calorimetry (DSC) and X-ray powder diffraction studies (X-RD) showed that solid dispersions were formed during processing. Using thermogravimetrical analysis (TGA) and gel-permeation chromatography no degradation of drug and matrix polymer was observed. The surface morphology was investigated with the aid of scanning electron microscopy (SEM) showing an influence of the process temperature. Raman spectroscopy demonstrated that the drug is distributed in the entire matrix, however, some drug clusters were identified.
Keywords
Injection moulding, Melt extrusion, Drug delivery, Matrix system, Sustained release, Tablet, Ethylcellulose, Hydroxypropylmethylcellulose, Metoprolol tartrate

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Chicago
Quinten, Thomas, Thomas De Beer, Chris Vervaet, and Jean Paul Remon. 2009. “Evaluation of Injection Moulding as a Pharmaceutical Technology to Produce Matrix Tablets.” Ed. Peter Kleinebudde. European Journal of Pharmaceutics and Biopharmaceutics 71 (1): 145–154.
APA
Quinten, T., De Beer, T., Vervaet, C., & Remon, J. P. (2009). Evaluation of injection moulding as a pharmaceutical technology to produce matrix tablets. (P. Kleinebudde, Ed.)European Journal of Pharmaceutics and Biopharmaceutics, 71(1), 145–154.
Vancouver
1.
Quinten T, De Beer T, Vervaet C, Remon JP. Evaluation of injection moulding as a pharmaceutical technology to produce matrix tablets. Kleinebudde P, editor. European Journal of Pharmaceutics and Biopharmaceutics. Amsterdam: Elsevier; 2009;71(1):145–54.
MLA
Quinten, Thomas, Thomas De Beer, Chris Vervaet, et al. “Evaluation of Injection Moulding as a Pharmaceutical Technology to Produce Matrix Tablets.” Ed. Peter Kleinebudde. European Journal of Pharmaceutics and Biopharmaceutics 71.1 (2009): 145–154. Print.
@article{513939,
  abstract     = {The aim of this study was to develop sustained-release matrix tablets by means of injection moulding and to evaluate the influence of process temperature, matrix composition (EC and HPMC concentration) and viscosity grade of ethylcellulose (EC) and hydroxypropylmethylcellulose (HPMC) on processability and drug release. The drug release data were analyzed to get insight in the release kinetics and mechanism. Formulations containing metoprolol tartrate (30\%, model drug), EC with dibutyl sebacate (matrix former and plasticizer) and hydrophilic polymer HPMC were extruded and subsequently injection moulded into tablets (375 mg, 10 mm diameter, convex-shaped) at temperatures ranging from 110 to 140 {\textdegree}C. Tablets containing 30\% metoprolol and 70\% ethylcellulose (EC 4 mPa s) showed an incomplete drug release within 24 h ({\textlangle}50\%). Increasing production temperatures resulted in a lower drug release rate. Substituting part of the EC fraction by HPMC (HPMC/EC-ratio: 20/50 and 35/35) resulted in faster and constant drug release rates. Formulations containing 50\% HPMC had a complete and first-order drug release profile with drug release controlled via the combination of diffusion and swelling/erosion. Faster drug release rates were observed for higher viscosity grades of EC (Mw {\textrangle} 20 mPa s) and HPMC (4000 and 10,000 mPa s). Tablet porosity was low ({\textlangle}4\%). Differential scanning calorimetry (DSC) and X-ray powder diffraction studies (X-RD) showed that solid dispersions were formed during processing. Using thermogravimetrical analysis (TGA) and gel-permeation chromatography no degradation of drug and matrix polymer was observed. The surface morphology was investigated with the aid of scanning electron microscopy (SEM) showing an influence of the process temperature. Raman spectroscopy demonstrated that the drug is distributed in the entire matrix, however, some drug clusters were identified.},
  author       = {Quinten, Thomas and De Beer, Thomas and Vervaet, Chris and Remon, Jean Paul},
  editor       = {Kleinebudde, Peter},
  issn         = {0939-6411},
  journal      = {European Journal of Pharmaceutics and Biopharmaceutics},
  keyword      = {Injection moulding,Melt extrusion,Drug delivery,Matrix system,Sustained release,Tablet,Ethylcellulose,Hydroxypropylmethylcellulose,Metoprolol tartrate},
  language     = {eng},
  number       = {1},
  pages        = {145--154},
  publisher    = {Elsevier},
  title        = {Evaluation of injection moulding as a pharmaceutical technology to produce matrix tablets},
  url          = {http://dx.doi.org/10.1016/j.ejpb.2008.02.025},
  volume       = {71},
  year         = {2009},
}

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