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Pellet manufacturing by extrusion-spheronization using process analytical technology

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Abstract

The aim of this study was to investigate the phase transitions occurring in nitrofurantoin and theophylline formulations during pelletization by extrusion-spheronization. An at-line process analytical technology (PAT) approach was used to increase the understanding of the solid-state behavior of the active pharmaceutical ingredients (APIs) during pelletization. Raman spectroscopy, near-infrared (NIR) spectroscopy, and X-ray powder diffraction (XRPD) were used in the characterization of polymorphic changes during the process. Samples were collected at the end of each processing stage (blending, granulation, extrusion, spheronization, and drying). Batches were dried at 3 temperature levels (60°C, 100°C, and 135°C). Water induced a hydrate formation in both model formulations during processing. NIR spectroscopy gave valuable real-time data about the state of water in the system, but it was not able to detect the hydrate formation in the theophylline and nitrofurantoin formulations during the granulation, extrusion, and spheronization stages because of the saturation of the water signal. Raman and XRPD measurement results confirmed the expected pseudopolymorphic changes of the APIs in the wet process stages. The relatively low level of Raman signal with the theophylline formulation complicated the interpretation. The drying temperature had a significant effect on dehydration. For a channel hydrate (theophylline), dehydration occurred at lower drying temperatures. In the case of isolated site hydrate (nitrofurantoin), dehydration was observed at higher temperatures. To reach an understanding of the process and to find the critical process parameters, the use of complementary analytical techniques are absolutely necessary when signals from APIs and different excipients overlap each other.

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Authors and Affiliations

  1. Division of Pharmaceutical Technology, Faculty of Pharmacy, University of Helsinki, PO Box 56, FIN-00014, Helsinki, Finland

    Niklas Sandler, Jyrki Heinämäki, Meike Römer & Jouko Yliruusi

  2. Viikki Drug Discovery and Development Technology Centre (DDTC), Faculty of Pharmacy, University of Helsinki, Helsinki, Finland

    Jukka Rantanen, Martti Marola & Jouko Yliruusi

  3. Division of Biopharmacy and Pharmacokinetics, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland

    Martti Marola

Authors
  1. Niklas Sandler
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  2. Jukka Rantanen
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  3. Jyrki Heinämäki
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  4. Meike Römer
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  5. Martti Marola
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  6. Jouko Yliruusi
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Correspondence to Niklas Sandler.

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Published: September 30, 2005

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Sandler, N., Rantanen, J., Heinämäki, J. et al. Pellet manufacturing by extrusion-spheronization using process analytical technology. AAPS PharmSciTech 6, 26 (2005). https://doi.org/10.1208/pt060226

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  • DOI: https://doi.org/10.1208/pt060226

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