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The AAPS Journal

, Volume 19, Issue 3, pp 827–836 | Cite as

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

  • Cordula StillhartEmail author
  • Neil J. Parrott
  • Marc Lindenberg
  • Pascal Chalus
  • Darren Bentley
  • Anikó Szepes
Research 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.

KEY WORDS

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

Notes

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.

Supplementary material

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References

  1. 1.
    FDA. Guidance for Industry Q8(R2) Pharmaceutical Development. FDA (CDER). 2009.Google Scholar
  2. 2.
    Polli JE, Cook JA, Davit BM, Dickinson PA, Argenti D, Barbour N, et al. Summary workshop report: facilitating oral product development and reducing regulatory burden through novel approaches to assess bioavailability/bioequivalence. AAPS J. 2012;14(3):627–38. doi: 10.1208/s12248-012-9376-z.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Kesisoglou F, Rossenu S, Farrell C, Van Den Heuvel M, Prohn M, Fitzpatrick S, et al. Development of in vitro-in vivo correlation for extended-release niacin after administration of hypromellose-based matrix formulations to healthy volunteers. J Pharm Sci. 2014;103(11):3713–23. doi: 10.1002/jps.24179.CrossRefPubMedGoogle Scholar
  4. 4.
    Eaga C, Mantri S, Malayandi R, Kondamudi PK, Chakraborty S, Raju SVN, et al. Establishing postprandial bio-equivalency and IVIVC for generic metformin sustained release small sized tablets. J Pharm Investig. 2014;44(3):197–204. doi: 10.1007/s40005-013-0115-y.CrossRefGoogle Scholar
  5. 5.
    Ilic M, Duris J, Kovacevic I, Ibric S, Parojcic J. In vitro-in silico-in vivo drug absorption model development based on mechanistic gastrointestinal simulation and artificial neural networks: nifedipine osmotic release tablets case study. Eur J Pharm Sci. 2014;62:212–8. doi: 10.1016/j.ejps.2014.05.030.CrossRefPubMedGoogle Scholar
  6. 6.
    Parejiya PB, Barot BS, Patel HK, Chorawala MR, Shelat PK, Shukla A. In vivo performance evaluation and establishment of IVIVC for osmotic pump based extended release formulation of milnacipran HCl. Biopharm Drug Dispos. 2013;34(4):227–35. doi: 10.1002/bdd.1840.CrossRefPubMedGoogle Scholar
  7. 7.
    Selen A, Cruañes M, Müllertz A, Dickinson P, Cook J, Polli J, et al. Meeting report: applied biopharmaceutics and quality by design for dissolution/release specification setting: product quality for patient benefit. AAPS J. 2010;12(3):465–72. doi: 10.1208/s12248-010-9206-0.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Zhang X, Lionberger RA, Davit BM, Yu LX. Utility of physiologically based absorption modeling in implementing Quality by Design in drug development. AAPS J. 2011;13(1):59–71. doi: 10.1208/s12248-010-9250-9.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Kesisoglou F, Mitra A. Application of absorption modeling in rational design of drug product under Quality-by-Design paradigm. AAPS J. 2015;17(5):1224–36. doi: 10.1208/s12248-015-9781-1.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Mathias NR, Crison J. The use of modeling tools to drive efficient oral product design. AAPS J. 2012;14(3):591–600. doi: 10.1208/s12248-012-9372-3.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Zhang H, Xia B, Sheng J, Heimbach T, Lin T-H, He H, et al. Application of physiologically based absorption modeling to formulation development of a low solubility, low permeability weak base: mechanistic investigation of food effect. AAPS PharmSciTech. 2014;15(2):400–6. doi: 10.1208/s12249-014-0075-1.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Flanagan T, Van Peer A, Lindahl A. Use of physiologically relevant biopharmaceutics tools within the pharmaceutical industry and in regulatory sciences: where are we now and what are the gaps? Eur J Pharm Sci. 2016;91:84–90. doi: 10.1016/j.ejps.2016.06.006.CrossRefPubMedGoogle Scholar
  13. 13.
    Johnson KC, Swindell AC. Guidance in the setting of drug particle size specifications to minimize variability in absorption. Pharm Res. 1996;13(12):1795–8. doi: 10.1023/a:1016068705255.CrossRefPubMedGoogle Scholar
  14. 14.
    Galia E, Nicolaides E, Hörter D, Löbenberg R, Reppas C, Dressman JB. Evaluation of various dissolution media for predicting in vivo performance of class I and II drugs. Pharm Res. 1998;15(5):698–705. doi: 10.1023/a:1011910801212.CrossRefPubMedGoogle Scholar
  15. 15.
    Parrott N, Lave T. Applications of physiologically based absorption models in drug discovery and development. Mol Pharm. 2008;5(5):760–75. doi: 10.1021/mp8000155.CrossRefPubMedGoogle Scholar
  16. 16.
    Wagner JG. Pharmacokinetic absorption plots from oral data alone or oral/intravenous data and an exact Loo–Riegelman equation. J Pharm Sci. 1983;72(7):838–42. doi: 10.1002/jps.2600720738.CrossRefPubMedGoogle Scholar
  17. 17.
    Langenbucher F. Handling of computational in vitro/in vivo correlation problems by Microsoft Excel: III. Convolution and deconvolution. Eur J Pharm Biopharm. 2003;56(3):429–37. doi: 10.1016/S0939-6411(03)00140-1.CrossRefPubMedGoogle Scholar
  18. 18.
    Kostewicz ES, Aarons L, Bergstrand M, Bolger MB, Galetin A, Hatley O, et al. PBPK models for the prediction of in vivo performance of oral dosage forms. Eur J Pharm Sci. 2014;57:300–21. doi: 10.1016/j.ejps.2013.09.008.CrossRefPubMedGoogle Scholar
  19. 19.
    Potharaju S. Effect of compression force on agglomeration of micronized active pharmaceutical ingredients: techniques to prevent API agglomeration during compression. Tennessee: University of Tennessee Health Science Center; 2012.Google Scholar
  20. 20.
    Leuenberger H. The application of percolation theory in powder technology. Adv Powder Technol. 1999;10(4):323–52. doi: 10.1163/156855299X00190.CrossRefGoogle Scholar
  21. 21.
    Mohamed FA, Roberts M, Seton L, Ford JL, Levina M, Rajabi-Siahboomi AR. The effect of HPMC particle size on the drug release rate and the percolation threshold in extended-release mini-tablets. Drug Dev Ind Pharm. 2015;41(1):70–8. doi: 10.3109/03639045.2013.845843.CrossRefPubMedGoogle Scholar
  22. 22.
    Miranda A, Millan M, Caraballo I. Investigation of the influence of particle size on the excipient percolation thresholds of HPMC hydrophilic matrix tablets. J Pharm Sci. 2007;96(10):2746–56. doi: 10.1002/jps.20912.CrossRefPubMedGoogle Scholar
  23. 23.
    Boersen N, Carvajal MT, Morris KR, Peck GE, Pinal R. The influence of API concentration on the roller compaction process: modeling and prediction of the post compacted ribbon, granule and tablet properties using multivariate data analysis. Drug Dev Ind Pharm. 2015;41(9):1470–8. doi: 10.3109/03639045.2014.958754.CrossRefPubMedGoogle Scholar
  24. 24.
    Hirschorn JO, Kornblum SS. Dissolution of poorly water-soluble drugs II: excipient dilution and force of compression effects on tablets of a quinazolinone compound. J Pharm Sci. 1971;60(3):445–8. doi: 10.1002/jps.2600600321.CrossRefPubMedGoogle Scholar
  25. 25.
    Honório da Silva T, Pinto EC, Rocha HVA, Esteves VSAD, dos Santos TC, Castro HCR, et al. In vitro–in vivo correlation of Efavirenz tablets using GastroPlus®. AAPS PharmSciTech. 2013;14(3):1244–54. doi: 10.1208/s12249-013-0016-4.
  26. 26.
    Kesisoglou F, Xia B, Agrawal NGB. Comparison of deconvolution-based and absorption modeling IVIVC for extended release formulations of a BCS III drug development candidate. AAPS J. 2015;17(6):1492–500. doi: 10.1208/s12248-015-9816-7.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Margolskee A, Darwich AS, Galetin A, Rostami-Hodjegan A, Aarons L. Deconvolution and IVIVC: exploring the role of rate-limiting conditions. AAPS J. 2016;18(2):321–32. doi: 10.1208/s12248-015-9849-y.CrossRefPubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2017

Authors and Affiliations

  • Cordula Stillhart
    • 1
    Email author
  • Neil J. Parrott
    • 2
  • Marc Lindenberg
    • 3
  • Pascal Chalus
    • 3
  • Darren Bentley
    • 4
  • Anikó Szepes
    • 1
  1. 1.Formulation Research & DevelopmentF. Hoffmann-La Roche Ltd.BaselSwitzerland
  2. 2.Pharmaceutical Research & Early Development, Roche Innovation Center BaselF. Hoffmann-La Roche Ltd.BaselSwitzerland
  3. 3.Analytical DevelopmentF. Hoffmann-La Roche Ltd.BaselSwitzerland
  4. 4.Clinical PharmacologyF. Hoffmann-La Roche Ltd.BaselSwitzerland

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