Development of a PAT-controlled process for the production of pharmaceutical polymers with low drug concentration

Nikolaus Heindl

Research output: ThesisMaster's Thesis

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Abstract

Aim and motivation for this master thesis was the development of a novel continuous hot-melt extrusion-based compounding process, where a micro-feeder is added to a standard twin-screw extruder. Target of this innovative production method is to produce extrudates with an active pharmaceutical ingredient (API) loading, which reaches a concentration as little as 0,1 ω/ω%. By reaching such low concentration-levels, this method could be applied for the production of drug eluting polymers, in a continuous process. The low API concentrations were enabled by the implementation of a novel microfeeder into the compounding process. The main objective was to assess the underlaying process characteristics and parameters for the production of extrudates with an API concentration of 0,1 to 0,5 ω/ω%. Furthermore, the implementation of an in-line process analytical tool (PAT) was assessed and investigated. Additionally, a capability analysis of the applied key technologies, with special emphasis on the microfeeder was performed. Ultimately, a comparison between a pre-blend production method and the newly developed compounding process was performed. The tested formulation was comprised of Fenofibrate as API and polyvinylpyrrolidone- vinyl acetate (Kollidon® VA64) as polymer matrix. For the compounding process, a pharma-grade twin-screw extruder was used with an optimized screw geometry to suit the processes requirements. Additionally, a new powder guiding system was developed, to facilitate the integration of the microfeeder into the process. A UV/Vis spectrometer as PAT was integrated, to analyze, inline, the extrudates API concentration. The extrudates were furthermore analyzed by high pressure liquid chromatography (HPLC). A capability analysis of the microfeeder showed reproduceable feed rates with sufficient accuracy between 85 % (for 1 g/h) and 97 % (for 5 g/h) for various rates over a timespan of two hours. The implementation of the UV/Vis based PAT showed the feasibility of the concept, in principle, did however encounter certain obstacles in the execution due to problems with weak signal-intensity. Off-line API content analysis of the extrudates via HPLC successfully verified the capability of the compounding processes. In several different compounding processes, the feasibility and reproducibility of the process was assessed and proven. In a complimentary compounding experiment, the variability of the API concentration during ongoing processing was successfully shown. The intended concentration of API in the extrudates was met with an average of more than 90 % accuracy. A comparison between this experiment and an extrusion experiment based on the pre-blend production method showed superiority of the new microfeeder based compounding method in terms of accuracy for higher API concentration. In conclusion it can be said, that this thesis’ main objective, the development of a continuous compounding process for extrudates with API concentrations down to 0,1 ω/ω%, was successfully accomplished within the realms of possibility.
Translated title of the contributionEntwicklung eines PAT-kontrollierten Prozesses für die Herstellung von pharmazeutischen Polymeren mit geringer Wirkstoffkonzentration
Original languageEnglish
QualificationDipl.-Ing.
Awarding Institution
  • Montanuniversität
Supervisors/Advisors
  • Holzer, Clemens, Supervisor (internal)
Publication statusPublished - 2020

Bibliographical note

embargoed until null

Keywords

  • hot melt extrusion
  • compounding
  • process
  • micro-feeder
  • twin-screw extruder
  • active pharmaceutical ingredient
  • API
  • drug eluting polymers
  • process characteristics
  • feeder
  • process analytical tool
  • PAT
  • capability analysis
  • polyvinylpyrrolidone-vinyl acetate
  • Kollidon
  • polymer matrix
  • pharma
  • screw geometry
  • powder guiding system
  • UV/Vis spectrometer
  • high pressure liquid chromatography
  • HPLC
  • feed rates
  • extrudate
  • continuous

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