Advertisement

AAPS PharmSciTech

, Volume 19, Issue 4, pp 1592–1605 | Cite as

Development and Performance of a Highly Sensitive Model Formulation Based on Torasemide to Enhance Hot-Melt Extrusion Process Understanding and Process Development

  • Rachel C. Evans
  • Samuel O. Kyeremateng
  • Lutz Asmus
  • Matthias Degenhardt
  • Joerg Rosenberg
  • Karl G. WagnerEmail author
Research Article

Abstract

The aim of this work was to investigate the use of torasemide as a highly sensitive indicator substance and to develop a formulation thereof for establishing quantitative relationships between hot-melt extrusion process conditions and critical quality attributes (CQAs). Using solid-state characterization techniques and a 10 mm lab-scale co-rotating twin-screw extruder, we studied torasemide in a Soluplus® (SOL)-polyethylene glycol 1500 (PEG 1500) matrix, and developed and characterized a formulation which was used as a process indicator to study thermal- and hydrolysis-induced degradation, as well as residual crystallinity. We found that torasemide first dissolved into the matrix and then degraded. Based on this mechanism, extrudates with measurable levels of degradation and residual crystallinity were produced, depending strongly on the main barrel and die temperature and residence time applied. In addition, we found that 10% w/w PEG 1500 as plasticizer resulted in the widest operating space with the widest range of measurable residual crystallinity and degradant levels. Torasemide as an indicator substance behaves like a challenging-to-process API, only with higher sensitivity and more pronounced effects, e.g., degradation and residual crystallinity. Application of a model formulation containing torasemide will enhance the understanding of the dynamic environment inside an extruder and elucidate the cumulative thermal and hydrolysis effects of the extrusion process. The use of such a formulation will also facilitate rational process development and scaling by establishing clear links between process conditions and CQAs.

KEY WORDS

hot-melt extrusion amorphous solid dispersion process development and understanding torasemide critical quality attribute 

Notes

Acknowledgements

The authors wish to thank Karlheinz Rauwolf, Teresa Dagenbach, David Gessner, and Stefan Weber of AbbVie for their support in conducting the experiments and Mirko Pauli, Mario Hirth, Thomas Kessler, Christian Schley, and Ariana Low of AbbVie and Esther Bochmann of the University of Bonn for helpful and productive discussions.

Compliance with Ethical Standards

Disclosures

Rachel C. Evans, Samuel O. Kyeremateng, Lutz Asmus, Matthias Degenhardt, and Joerg Rosenberg are employees of AbbVie and may own AbbVie stock options. Karl G. Wagner is an employee of the University of Bonn. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.

Supplementary material

12249_2018_970_MOESM1_ESM.docx (48 kb)
ESM 1 (DOCX 47 kb)

References

  1. 1.
    Melt BJ. Extrusion: from process to drug delivery technology. Eur J Pharm Biopharm. 2002;54(2):107–17.CrossRefGoogle Scholar
  2. 2.
    Crowley MM, Zhang F, Repka MA, Thumma S, Upadhye SB, Kumar Battu S, et al. Pharmaceutical applications of hot-melt extrusion: part I. Drug Dev Ind Pharm. 2007;33(9):909–26.CrossRefPubMedGoogle Scholar
  3. 3.
    Stanković M, Frijlink HW, Hinrichs WLJ. Polymeric formulations for drug release prepared by hot melt extrusion: application and characterization. Drug Discov Today. 2015;20(7):812–23.CrossRefPubMedGoogle Scholar
  4. 4.
    Theil F, Anantharaman S, Kyeremateng SO, van Lishaut H, Dreis-Kühne SH, Rosenberg J, et al. Frozen in time: kinetically stabilized amorphous solid dispersions of Nifedipine stable after a quarter century of storage. Mol Pharm. 2017;14(1):183–92.CrossRefPubMedGoogle Scholar
  5. 5.
    Patil H, Tiwari RV, Repka MA. Hot-melt extrusion: from theory to application in pharmaceutical formulation. AAPS PharmSciTech. 2016;17(1):20–42.CrossRefPubMedGoogle Scholar
  6. 6.
    Lang B, McGinity JW, Williams RO. Hot-melt extrusion—basic principles and pharmaceutical applications. Drug Dev Ind Pharm. 2014;40(9):1133–55.CrossRefPubMedGoogle Scholar
  7. 7.
    Thiry J, Krier F, Evrard B. A review of pharmaceutical extrusion: critical process parameters and scaling-up. Int J Pharm. 2015;479(1):227–40.CrossRefPubMedGoogle Scholar
  8. 8.
    Eitzlmayr A, Koscher G, Reynolds G, Huang Z, Booth J, Shering P, et al. Mechanistic modeling of modular co-rotating twin-screw extruders. Int J Pharm. 2014;474(1–2):157–76.CrossRefPubMedGoogle Scholar
  9. 9.
    Rauwendaal C. Polymer extrusion. 5th ed. Carl Hanser: Munich; 2001.Google Scholar
  10. 10.
    Zecevic DE, Wagner KG. Rational development of solid dispersions via hot-melt extrusion using screening, material characterization, and numeric simulation tools. J Pharm Sci. 2013;102(7):2297–310.CrossRefPubMedGoogle Scholar
  11. 11.
    Zecevic DE. Solid dispersions via hot-melt extrusion—formulation and process aspects [dissertation]. Tübingen: Eberhard Karls Universität Tübingen; 2014.Google Scholar
  12. 12.
    Chokshi R, Hot-Melt Extrusion ZH. Technique: A Review. Iran J Pharm Res. 2010;3(1):3–16.Google Scholar
  13. 13.
    Tadmor Z, Gogos CG. Principles of polymer processing. 2nd ed. New Jersey: Wiley; 2006.Google Scholar
  14. 14.
    Gogos CG, Liu H, Wang P. Laminar dispersive and distributive mixing with dissolution and applications to hot-melt extrusion. Douroumis D, editor Hot-Melt Extrusion: Pharmaceutical Applications United Kingdom: John Wiley & Sons, Ltd. 2012:261–84.Google Scholar
  15. 15.
    Li M, Gogos CG, Ioannidis N. Improving the API dissolution rate during pharmaceutical hot-melt extrusion I: effect of the API particle size, and the co-rotating, twin-screw extruder screw configuration on the API dissolution rate. Int J Pharm. 2015;478(1):103–12.CrossRefPubMedGoogle Scholar
  16. 16.
    Verreck G, Decorte A, Heymans K, Adriaensen J, Liu D, Tomasko D, et al. Hot stage extrusion of p-amino salicylic acid with EC using CO2 as a temporary plasticizer. Int J Pharm. 2006;327(1–2):45–50.CrossRefPubMedGoogle Scholar
  17. 17.
    Guo Z, Lu M, Li Y, Pang H, Lin L, Liu X, et al. The utilization of drug–polymer interactions for improving the chemical stability of hot-melt extruded solid dispersions. J Pharm Pharmacol. 2014;66(2):285–96.CrossRefPubMedGoogle Scholar
  18. 18.
    Lakshman JP, Cao Y, Kowalski J, Serajuddin ATM. Application of melt extrusion in the development of a physically and chemically stable high-energy amorphous solid dispersion of a poorly water-soluble drug. Mol Pharm. 2008;5(6):994–1002.CrossRefPubMedGoogle Scholar
  19. 19.
    Liu X, Lu M, Guo Z, Huang L, Feng X, Wu C. Improving the chemical stability of amorphous solid dispersion with Cocrystal technique by hot melt extrusion. Pharm Res. 2012;29(3):806–17.CrossRefPubMedGoogle Scholar
  20. 20.
    Ghosh I, Vippagunta R, Li S, Vippagunta S. Key considerations for optimization of formulation and melt-extrusion process parameters for developing thermosensitive compound. Pharm Dev Technol. 2012;17(4):502–10.CrossRefPubMedGoogle Scholar
  21. 21.
    Munjal M, Stodghill SP, ElSohly MA, Repka MA. Polymeric systems for amorphous Δ9-tetrahydrocannabinol produced by a hot-melt method. Part I: chemical and thermal stability during processing. J Pharm Sci. 2006;95(8):1841–53.CrossRefPubMedGoogle Scholar
  22. 22.
    Haser A, Huang S, Listro T, White D, Zhang F. An approach for chemical stability during melt extrusion of a drug substance with a high melting point. Int J Pharm. 2017;524(1–2):55–64.CrossRefPubMedGoogle Scholar
  23. 23.
    DiNunzio JC, Brough C, Hughey JR, Miller DA, Williams RO III, McGinity JW. Fusion production of solid dispersions containing a heat-sensitive active ingredient by hot melt extrusion and Kinetisol® dispersing. Eur J Pharm Biopharm. 2010;74(2):340–51.CrossRefPubMedGoogle Scholar
  24. 24.
    Hughey JR, DiNunzio JC, Bennett RC, Brough C, Miller DA, Ma H, et al. Dissolution enhancement of a drug exhibiting thermal and acidic decomposition characteristics by fusion processing: a comparative study of hot melt extrusion and KinetiSol® dispersing. AAPS PharmSciTech. 2010;11(2):760–74.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Surasarang SH, Keen JM, Huang S, Zhang F, McGinity JW, Williams RO. Hot melt extrusion versus spray drying: hot melt extrusion degrades albendazole. Drug Dev Ind Pharm. 2016 Sep 12:1–15.Google Scholar
  26. 26.
    Kulthe VV, Chaudhari PD. Effectiveness of spray congealing to obtain physically stabilized amorphous dispersions of a poorly soluble thermosensitive API. AAPS PharmSciTech. 2014;15(6):1370–7.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Liu H, Zhu L, Wang P, Zhang X, Gogos CG. Effects of screw configuration on indomethacin dissolution behavior in Eudragit E PO. Adv Polym Technol. 2012;31(4):331–42.CrossRefGoogle Scholar
  28. 28.
    Flanagan F, Hein E, Choi R, Yang F, McQuade M, Neu C, et al. Measurement of hot melt extrusion thermal residence distributions. In: Society of Plastics Engineers ANTEC Conference Proceedings; 2016 May 23-25; Indianapolis, Indiana p 806–11.Google Scholar
  29. 29.
    Vigh T, Drávavölgyi G, Sóti PL, Pataki H, Igricz T, Wagner I, et al. Predicting final product properties of melt extruded solid dispersions from process parameters using Raman spectrometry. J Pharm Biomed Anal. 2014;98:166–77.CrossRefPubMedGoogle Scholar
  30. 30.
    Jovic Z, Zivanovic L, Protic A, Radisic M, Lausevic M, Malesevic M, et al. Forced degradation study of torasemide: characterization of its degradation products. J Liq Chromatogr Relat Technol. 2013;36(15):2082–94.Google Scholar
  31. 31.
    Kyeremateng SO, Pudlas M, Woehrle GH. A fast and reliable empirical approach for estimating solubility of crystalline drugs in polymers for hot melt extrusion formulations. J Pharm Sci. 2014;103(9):2847–58.CrossRefPubMedGoogle Scholar
  32. 32.
    DiNunzio JC, Miller DA. Formulation development of amorphous solid dispersions prepared by melt extrusion. In: Repka MA, Langley N, DiNunzio J, editors. Melt Extrusion. 1st ed. New York: Springer-Verlag; 2013. p. 161–203.CrossRefGoogle Scholar
  33. 33.
    Pharmaceutical Development Annex to Q8(R2) [Internet]. ICH; 2009. Available from: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q8_R1/Step4/Q8_R2_Guideline.pdf
  34. 34.
    Unlu E, Faller JF. RTD in twin-screw food extrusion. J Food Eng. 2002;53(2):115–31.CrossRefGoogle Scholar
  35. 35.
    Gryczke A. Hot-melt extrusion process design using process analytical technology. In: Repka MA, Langley N, DiNunzio J, editors. Melt Extrusion. 1st ed. New York: Springer-Verlag; 2013.Google Scholar
  36. 36.
    Kolter K, Karl M, Gryczke A. Hot-melt extrusion with BASF pharma polymers. 2nd ed. BASF SE: Ludwigshafen, Germany; 2012.Google Scholar
  37. 37.
    Filić D, Dumić M, Klepić B, Danilovski A, Tudja M, inventors; Pliva d.d., assignee. Amorphous torasemide modification. United States patent US 6,767,917 B1. 2004 Jul 27.Google Scholar
  38. 38.
    Alshahrani SM, Morott JT, Alshetaili AS, Tiwari RV, Majumdar S, Repka MA. Influence of degassing on hot-melt extrusion process. Eur J Pharm Sci. 2015;80:43–52.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Lehmkemper K, Kyeremateng SO, Heinzerling O, Degenhardt M, Sadowski G. Long-term physical stability of PVP- and PVPVA-amorphous solid dispersions. Mol Pharm. 2017;14(1):157–71.CrossRefPubMedGoogle Scholar
  40. 40.
    Wagner JR Jr, Mount EM III, Giles HF Jr. Extrusion: the definitive processing guide and handbook. 2nd. ed. Waltham, MA: William Andrew; 2014.Google Scholar
  41. 41.
    Yalçinyuva T, Kamal MR, Lai-Fook RA, Özgümüs S. Hydrolytic depolymerization of polyethylene terephthalate by reactive extrusion. Int Polym Process. 2000;15(2):137–46.CrossRefGoogle Scholar
  42. 42.
    Lim L-T, Auras R, Rubino M. Processing technologies for poly(lactic acid). Prog Polym Sci. 2008;33(8):820–52.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  • Rachel C. Evans
    • 1
    • 2
  • Samuel O. Kyeremateng
    • 1
  • Lutz Asmus
    • 1
  • Matthias Degenhardt
    • 1
  • Joerg Rosenberg
    • 1
  • Karl G. Wagner
    • 2
    Email author
  1. 1.Drug Product Development, AbbVie Deutschland GmbH & Co. KGLudwigshafenGermany
  2. 2.Department of Pharmaceutical Technology and BiopharmaceuticsUniversity of BonnBonnGermany

Personalised recommendations