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Inline UV/Vis spectroscopy as PAT tool for hot-melt extrusion

Drug Delivery and Translational Research volume 8, pages 1595–1603 (2018)Cite this article

Abstract

Hot-melt extrusion on co-rotating twin screw extruders is a focused technology for the production of pharmaceuticals in the context of Quality by Design. Since it is a continuous process, the potential for minimizing product quality fluctuation is enhanced. A typical application of hot-melt extrusion is the production of solid dispersions, where an active pharmaceutical ingredient (API) is distributed within a polymer matrix carrier. For this dosage form, the product quality is related amongst others to the drug content. This can be monitored on- or inline as critical quality attribute by a process analytical technology (PAT) in order to meet the specific requirements of Quality by Design. In this study, an inline UV/Vis spectrometer from ColVisTec was implemented in an early development twin screw extruder and the performance tested in accordance to the ICH Q2 guideline. Therefore, two API (carbamazepine and theophylline) and one polymer matrix (copovidone) were considered with the main focus on the quantification of the drug load. The obtained results revealed the suitability of the implemented PAT tool to quantify the drug load in a typical range for pharmaceutical applications. The effort for data evaluation was minimal due to univariate data analysis, and in combination with a measurement frequency of 1 Hz, the system is sufficient for real-time data acquisition.

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References

  1. Leuenberger H. New trends in the production of pharmaceutical granules: batch versus continuous processing. Eur J Pharm Biopharm. 2001;52(3):289–96. https://doi.org/10.1016/S0939-6411(01)00199-0.

    CAS  Article  PubMed  Google Scholar 

  2. Constable DJC, Dunn PJ, Hayler JD, Humphrey GR, Leazer JJL, Linderman RJ, et al. Key green chemistry research areas—a perspective from pharmaceutical manufacturers. Green Chem. 2007;9(5):411–20. https://doi.org/10.1039/B703488C.

    CAS  Article  Google Scholar 

  3. ICH. Q8(R2)—pharmaceutical development. 2009. ICH - Homepage.

  4. Yu LX, Amidon G, Khan MA, Hoag SW, Polli J, Raju GK, et al. Understanding pharmaceutical quality by design. AAPS J. 2014;16(4):771–83. https://doi.org/10.1208/s12248-014-9598-3.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. Yu LX. Pharmaceutical quality by design: product and process development, understanding, and control. Pharm Res. 2008;25(4):781–91. https://doi.org/10.1007/s11095-007-9511-1.

    CAS  Article  PubMed  Google Scholar 

  6. Plumb K. Continuous processing in the pharmaceutical industry: changing the mind set. Chem Eng Res Des. 2005;83(6 A):730–8. https://doi.org/10.1205/cherd.04359.

    CAS  Article  Google Scholar 

  7. 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. https://doi.org/10.1080/03639040701498759.

    CAS  Article  Google Scholar 

  8. Hasa D, Perissutti B, Grassi M, Zacchigna M, Pagotto M, Lenaz D, et al. Melt extruded helical waxy matrices as a new sustained drug delivery system. Eur J Pharm Biopharm. 2011;79(3):592–600. https://doi.org/10.1016/j.ejpb.2011.07.012.

    CAS  Article  PubMed  Google Scholar 

  9. Douroumis D. Hot-Melt Extrusion: Pharmaceutical Applications. John Wiley and Sons; 2012. https://doi.org/10.1002/9780470711415.

  10. Breitenbach J. Melt extrusion: from process to drug delivery technology. Eur J Pharm Biopharm. 2002;54(2):107–17. https://doi.org/10.1016/S0939-6411(02)00061-9.

    CAS  Article  PubMed  Google Scholar 

  11. Gurunath S, et al. Amorphous solid dispersion method for improving oral bioavailability of poorly water-soluble drugs. J Pharm Res. 2013;6(4):476–80.

    CAS  Google Scholar 

  12. Jones DS, et al. Thermodynamically stable amorphous drug dispersions in amorphous hydrophilic polymers engineered by hot melt extrusion. Chem Eng Res Des. 2014;92(12):2046–54.

    Article  Google Scholar 

  13. Saerens L, Vervaet C, Remon JP, de Beer T. Process monitoring and visualization solutions for hot-melt extrusion: a review. J Pharm Pharmacol. 2014;66(2):180–203. https://doi.org/10.1111/jphp.12123.

    CAS  Article  PubMed  Google Scholar 

  14. Netchacovitch L, Thiry J, de Bleye C, Chavez PF, Krier F, Sacré PY, et al. Vibrational spectroscopy and microspectroscopy analyzing qualitatively and quantitatively pharmaceutical hot melt extrudates. J Pharm Biomed Anal. 2015;113:21–33. https://doi.org/10.1016/j.jpba.2015.01.051.

    CAS  Article  PubMed  Google Scholar 

  15. Rücker G, Neugebauer M, Willems GG. Instrumentelle pharmazeutische Analytik. 2nd ed. Stuttgart: Wissenschaftliche Verlagsgesellschaft mbH; 1992.

    Google Scholar 

  16. Hitzer P, Bäuerle T, Drieschner T, Ostertag E, Paulsen K, van Lishaut H, et al. Process analytical techniques for hot-melt extrusion and their application to amorphous solid dispersions. Anal Bioanal Chem. 2017;409(18):4321–33. https://doi.org/10.1007/s00216-017-0292-z.

    CAS  Article  PubMed  Google Scholar 

  17. Coates PD, Barnes SE, Sibley MG, Brown EC, Edwards HGM, Scowen IJ. In-process vibrational spectroscopy and ultrasound measurements in polymer melt extrusion. Polymer. 2003;44(19):5937–49. https://doi.org/10.1016/S0032-3861(03)00544-5.

    CAS  Article  Google Scholar 

  18. Fischer D, Sahre K, Abdelrhim M, Voit B, Sadhu VB, Pionteck J, et al. Process monitoring of polymers by in-line ATR-IR, NIR and Raman spectroscopy and ultrasonic measurements. C R Chim. 2006;9(11–12):1419–24. https://doi.org/10.1016/j.crci.2006.06.006.

    CAS  Article  Google Scholar 

  19. Almeida A, Saerens L, de Beer T, Remon JP, Vervaet C. Upscaling and in-line process monitoring via spectroscopic techniques of ethylene vinyl acetate hot-melt extruded formulations. Int J Pharm. 2012;439(1–2):223–9. https://doi.org/10.1016/j.ijpharm.2012.09.037.

    CAS  Article  PubMed  Google Scholar 

  20. Saerens L, Dierickx L, Quinten T, Adriaensens P, Carleer R, Vervaet C, et al. In-line NIR spectroscopy for the understanding of polymer-drug interaction during pharmaceutical hot-melt extrusion. Eur J Pharm Biopharm. 2012;81(1):230–7. https://doi.org/10.1016/j.ejpb.2012.01.001.

    CAS  Article  PubMed  Google Scholar 

  21. Wahl PR, Treffer D, Mohr S, Roblegg E, Koscher G, Khinast JG. Inline monitoring and a PAT strategy for pharmaceutical hot melt extrusion. Int J Pharm. 2013;455(1–2):159–68. https://doi.org/10.1016/j.ijpharm.2013.07.044.

    CAS  Article  PubMed  Google Scholar 

  22. Kelly AL, Halsey SA, Bottom RA, Korde S, Gough T, Paradkar A. A novel transflectance near infrared spectroscopy technique for monitoring hot melt extrusion. Int J Pharm. 2015;496(1):117–23. https://doi.org/10.1016/j.ijpharm.2015.07.025.

    CAS  Article  PubMed  Google Scholar 

  23. Saerens L, Dierickx L, Lenain B, Vervaet C, Remon JP, Beer TD. Raman spectroscopy for the in-line polymer-drug quantification and solid state characterization during a pharmaceutical hot-melt extrusion process. Eur J Pharm Biopharm. 2011;77(1):158–63. https://doi.org/10.1016/j.ejpb.2010.09.015.

    CAS  Article  PubMed  Google Scholar 

  24. Saerens L, Segher N, Vervaet C, Remon JP, de Beer T. Validation of an in-line Raman spectroscopic method for continuous active pharmaceutical ingredient quantification during pharmaceutical hot-melt extrusion. Anal Chim Acta. 2014;806:180–7. https://doi.org/10.1016/j.aca.2013.11.020.

    CAS  Article  PubMed  Google Scholar 

  25. ICH. Q2(R1)—validation of analytical procedures. 1994. ICH - Hompeage.

  26. Netchacovitch L, Thiry J, de Bleye C, Dumont E, Cailletaud J, Sacré PY, et al. Global approach for the validation of an in-line Raman spectroscopic method to determine the API content in real-time during a hot-melt extrusion process. Talanta. 2017;171:45–52. https://doi.org/10.1016/j.talanta.2017.04.060.

    CAS  Article  PubMed  Google Scholar 

  27. Netchacovitch L, Dumont E, Cailletaud J, Thiry J, de Bleye C, Sacré PY, et al. Development of an analytical method for crystalline content determination in amorphous solid dispersions produced by hot-melt extrusion using transmission Raman spectroscopy: a feasibility study. Int J Pharm. 2017;530(1–2):249–55. https://doi.org/10.1016/j.ijpharm.2017.07.052.

    CAS  Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Institute of Solids Process Engineering, TU Dortmund University, Emil-Figge-Straße 68, 44227, Dortmund, Germany

    Jens Wesholowski, Sebastian Prill & Markus Thommes

  2. ColVisTec AG, Max-Planck-Straße 3, 12489, Berlin–Adlershof, Germany

    Andreas Berghaus

Authors
  1. Jens Wesholowski
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  2. Sebastian Prill
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  3. Andreas Berghaus
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  4. Markus Thommes
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Correspondence to Markus Thommes.

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Wesholowski, J., Prill, S., Berghaus, A. et al. Inline UV/Vis spectroscopy as PAT tool for hot-melt extrusion. Drug Deliv. and Transl. Res. 8, 1595–1603 (2018). https://doi.org/10.1007/s13346-017-0465-5

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  • DOI: https://doi.org/10.1007/s13346-017-0465-5

Keywords

  • Inline measurement
  • Process analytical technology
  • Process monitoring
  • Quality by Design
  • Twin screw extrusion
  • UV/Vis spectroscopy