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Characterising Drug Release from Immediate-Release Formulations of a Poorly Soluble Compound, Basmisanil, Through Absorption Modelling and Dissolution Testing

The AAPS Journal volume 19, pages 827–836 (2017)Cite this article

Abstract

The study aimed to characterise the mechanism of release and absorption of Basmisanil, a biopharmaceutics classification system (BCS) class 2 compound, from immediate-release formulations via mechanistic absorption modelling, dissolution testing, and Raman imaging. An oral absorption model was developed in GastroPlus® and verified with single-dose pharmacokinetic data in humans. The properties and drug release behaviour of different oral Basmisanil formulations were characterised via biorelevant dissolution and Raman imaging studies. Finally, an in vitro-in vivo correlation (IVIVC) model was developed using conventional and mechanistic deconvolution methods for comparison. The GastroPlus model accurately simulated oral Basmisanil exposure from tablets and granules formulations containing micronized drug. Absorption of oral doses below 200 mg was mostly dissolution rate-limited and thus particularly sensitive to formulation properties. Indeed, reduced exposure was observed for a 120-mg film-coated tablet and the slower dissolution rate measured in biorelevant media was attributed to differences in drug load. This hypothesis was confirmed when Raman imaging showed that the percolation threshold was exceeded in this formulation. This biorelevant dissolution method clearly differentiated between the formulations and was used to develop a robust IVIVC model. The study demonstrates the applicability and impact of mechanistic absorption modelling and biopharmaceutical in vitro tools for rational drug development.

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Acknowledgements

The authors would like to thank Dr. Anni Pabst-Ravot (F. Hoffmann-La Roche Ltd., Basel, Switzerland) for analytical support. Dr. Carsten Brüsewitz (F. Hoffmann-La Roche Ltd., Basel, Switzerland) is gratefully acknowledged for providing the clinical study material for pharmacokinetic studies.

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Authors and Affiliations

  1. Formulation Research & Development, F. Hoffmann-La Roche Ltd., Basel, Switzerland

    Cordula Stillhart & Anikó Szepes

  2. Pharmaceutical Research & Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland

    Neil J. Parrott

  3. Analytical Development, F. Hoffmann-La Roche Ltd., Basel, Switzerland

    Marc Lindenberg & Pascal Chalus

  4. Clinical Pharmacology, F. Hoffmann-La Roche Ltd., Basel, Switzerland

    Darren Bentley

Authors
  1. Cordula Stillhart
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  2. Neil J. Parrott
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  3. Marc Lindenberg
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  4. Pascal Chalus
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  6. Anikó Szepes
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Correspondence to Cordula Stillhart.

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Stillhart, C., Parrott, N.J., Lindenberg, M. et al. Characterising Drug Release from Immediate-Release Formulations of a Poorly Soluble Compound, Basmisanil, Through Absorption Modelling and Dissolution Testing. AAPS J 19, 827–836 (2017). https://doi.org/10.1208/s12248-017-0060-1

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  • DOI: https://doi.org/10.1208/s12248-017-0060-1

KEY WORDS

  • absorption modelling
  • GastroPlus
  • immediate-release formulation
  • in vitro-in vivo correlation
  • poorly water-soluble compound