AAPS PharmSciTech

, 20:6 | Cite as

Moisture Monitoring in Fluid-Bed Granulation by Multi-Resonance Microwave Sensor: Applicability on Crystal-Water Containing Donepezil Granules

  • Johanna PetersEmail author
  • Wolfgang Taute
  • Claas Döscher
  • Michael Höft
  • Reinhard Knöchel
  • Jörg Breitkreutz
Research Article


Multi-resonance microwave sensors have recently been introduced for moisture monitoring of pharmaceutical particulates up to > 20% residual moisture. The extended measuring range compared to previous systems as well as the microwave moisture values independent of other physical attributes make them promising process analytical technology (PAT) tools for various pharmaceutical production processes. However, so far, research focused on measurements on raw materials or drug-free model granulates and has neither evaluated the applicability for materials with crystal water containing excipients nor for active ingredients. In this study, possible influence of crystal water was evaluated using lactose monohydrate and donepezil hydrochloride, an active pharmaceutical ingredient (API) against dementia. The study clearly showed that the contained hydrate does not cause interferences and is not monitored by the applied frequencies. Material-related limits measuring lactose monohydrate were only observed above typical granulation moistures and could be explained using raw resonance curves. Furthermore, the inclusion of donepezil hydrochloride into the monitored formulations and varied process parameters demonstrated the versatility of the microwave resonance sensor system. Inlet air temperature, spraying rate, and air flow were varied according to a 23 full factorial experimental design. A predictive model (R2 = 0.9699, RMSEC = 0.33%) could be established using samples produced with different process parameter settings adjusted according to the corner points of the full factorial design and validated on the center point granulation processes (RMSEV = 0.38%). Thereby, performance on actual formulations and conditions faced during process development could be thoroughly assessed, and hence, another key requirement for applicability in formulation development could be met.


microwave resonance technology moisture sensor process analytical technology (PAT) lactose monohydrate donepezil 



This project was funded by the German Federal Environmental Foundation (Deutsche Bundesstiftung Umwelt, DBU, Project No. 30816).


  1. 1.
    Zografi G. States of water associated with solids. Drug Dev Ind Pharm. 1988;14(14):1905–26. Scholar
  2. 2.
    United States Pharmacopeial Convention, Inc, U.S. Pharmacopoeia-National Formulary [USP 41 NF 36]. Rockville: Water content; 2018. p. 6687–6691.Google Scholar
  3. 3.
    European Directorate for the Quality of Medicines & HealthCare, European Pharmacopoeia. 9th ed.. Strasbourg: Water: micro determination; 2017. p. 172Google Scholar
  4. 4.
    European Directorate for the Quality of Medicines & HealthCare, European Pharmacopoeia. 9th ed. Strasbourg: Loss on drying; 2017. p. 53Google Scholar
  5. 5.
    Watano S, Terashita K, Miyanami K. Development and application of infrared moisture sensor to complex granulation. Bull Univ Osaka Prefect Ser A. 1991;39(2):187–97.Google Scholar
  6. 6.
    Frake P, Greenhalgh D, Grierson SM, Hempenstall JM, Rudd DR. Process control and end-point determination of a fluid bed granulation by application of near infra-red spectroscopy. Int J Pharm. 1997;151(1):75–80. Scholar
  7. 7.
    Rantanen J, Lehtola S, Rämet P, Mannermaa J-P, Yliruusi J. On-line monitoring of moisture content in an instrumented fluidized bed granulator with a multi-channel NIR moisture sensor. Powder Technol. 1998;99(2):163–70. Scholar
  8. 8.
    Rantanen J, Antikainen O, Mannermaa J-P, Yliruusi J. Use of the near-infrared reflectance method for measurement of moisture content during granulation. Pharm Dev Technol. 2000;5(2):209–17. Scholar
  9. 9.
    Burggraeve A, Monteyne T, Vervaet C, Remon JP, de Beer T. Process analytical tools for monitoring, understanding, and control of pharmaceutical fluidized bed granulation: a review. Eur J Pharm Biopharm. 2013;83(1):2–15. Scholar
  10. 10.
    da Silva CAM, Butzge JJ, Nitz M, Taranto OP. Monitoring and control of coating and granulation processes in fluidized beds—a review. Adv Powder Technol. 2014;25(1):195–210. Scholar
  11. 11.
    Rantanen J, Jørgensen A, Räsänen E, Luukkonen P, Airaksinen S, Raiman J, et al. Process analysis of fluidized bed granulation. AAPS PharmSciTech. 2001;2(4):13–20. Scholar
  12. 12.
    Jørgensen A, Rantanen J, Karjalainen M, Khriachtchev L, Räsänen E, Yliruusi J. Hydrate formation during wet granulation studied by spectroscopic methods and multivariate analysis. Pharm Res. 2002;19(9):1285–91. Scholar
  13. 13.
    Halstensen M, de Bakker P, Esbensen KH. Acoustic chemometric monitoring of an industrial granulation production process—a PAT feasibility study. Chemom Intell Lab Syst. 2006;84(1–2):88–97. Scholar
  14. 14.
    Tsujimoto H, Yokoyama T, Huang CC, Sekiguchi I. Monitoring particle fluidization in a fluidized bed granulator with an acoustic emission sensor. Powder Technol. 2000;113(1):88–96. Scholar
  15. 15.
    Wang HG, Senior PR, Mann R, Yang WQ. Online measurement and control of solids moisture in fluidised bed dryers. Chem Eng Sci. 2009;64(12):2893–902. Scholar
  16. 16.
    Buschmüller C, Wiedey W, Doescher C, Plitzko M, Breitkreutz J. In-line monitoring of granule moisture and temperature throughout the entire fluidized-bed granulation process using microwave resonance technology: part I. Pharm Ind. 2009;71(8):1403–8.Google Scholar
  17. 17.
    Buschmüller C, Wiedey W, Doescher C, Plitzko M, Breitkreutz J. In-line monitoring of granule moisture and temperature throughout the entire fluidized-bed granulation process using microwave resonance technology: part II. Pharm Ind. 2009;71(9):6–12.Google Scholar
  18. 18.
    Buschmüller C, Wiedey W, Döscher C, Dressler J, Breitkreutz J. In-line monitoring of granule moisture in fluidized-bed dryers using microwave resonance technology. Eur J Pharm Biopharm. 2008;69(1):380–7. Scholar
  19. 19.
    Peters J, Taute W, Bartscher K, Döscher C, Höft M, Knöchel R, et al. Design, development and method validation of a novel multi-resonance microwave sensor for moisture measurement. Anal Chim Acta. 2017;961:119–27. Scholar
  20. 20.
    Peters J, Bartscher K, Döscher C, Taute W, Höft M, Knöchel R, et al. In-line moisture monitoring in fluidized bed granulation using a novel multi-resonance microwave sensor. Talanta. 2017;170:369–76. Scholar
  21. 21.
    Roßteuscher-Carl K, Fricke S, Hacker MC, Schulz-Siegmund M. Influence of in line monitored fluid bed granulation process parameters on the stability of ethinylestradiol. Int J Pharm. 2015;496(2):751–8. Scholar
  22. 22.
    Buschmüller C., In-line monitoring of granule moisture in fluidized bed granulators using microwave resonance technology as novel PAT tool, Dissertation, Düsseldorf, Heinrich-Heine-Universität, 2009.Google Scholar
  23. 23.
    Lourenço V, Herdling T, Reich G, Menezes JC, Lochmann D. Combining microwave resonance technology to multivariate data analysis as a novel PAT tool to improve process understanding in fluid bed granulation. Eur J Pharm Biopharm. 2011;78(3):513–21. Scholar
  24. 24.
    Corredor CC, Bu D, Both D. Comparison of near infrared and microwave resonance sensors for at-line moisture determination in powders and tablets. Anal Chim Acta. 2011;696(1–2):84–93. Scholar
  25. 25.
    Austin J, Gupta A, McDonnell R, Reklaitis GV, Harris MT. A novel microwave sensor to determine particulate blend composition on-line. Anal Chim Acta. 2014;819:82–93. Scholar
  26. 26.
    Magee TRA, McMinn WAM, Farrell G, Topley L, Al-Degs YS, Walker GM, et al. Moisture and temperature dependence of the dielectric properties of pharmaceutical powders. J Thermal Anal Calorim. 2013;111(3):2157–64. Scholar
  27. 27.
    McLoughlin CM, McMinn WAM, Magee TRA. Physical and dielectric properties of pharmaceutical powders. Powder Technol. 2003;134(1–2):40–51. Scholar
  28. 28.
    European Directorate for the Quality of Medicines & HealthCare, European Pharmacopoeia. 9th ed. Strasbourg: Bulk and tapped density of powders; 2017. p. 359–62Google Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  1. 1.Heinrich-Heine-University DüsseldorfInstitute of Pharmaceutics and BiopharmaceuticsDüsseldorfGermany
  2. 2.Christian-Albrechts-University KielInstitute of Electrical Engineering and Information TechnologyKielGermany
  3. 3.Döscher Microwave Systems GmbHHamburgGermany

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