TY - THES

T1 - Development of a PAT-controlled process for the production of pharmaceutical polymers with low drug concentration

AU - Heindl, Nikolaus

N1 - embargoed until null

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - Extrusion

KW - Compoundieren

KW - Prozess

KW - Micro Feeder

KW - Doppelschneckenextruder

KW - active pharmaceutical ingredient

KW - Wirkstoff

KW - API

KW - drug eluting polymers

KW - Prozesscharakterisitk

KW - Feeder

KW - process analytical tool

KW - PAT

KW - capability Analyse

KW - polyvinylpyrrolidone-vinyl acetate

KW - PVP

KW - Kollidon

KW - Polymer Matrix

KW - Pharma

KW - Schraubengeometrie

KW - powder guiding system

KW - UV/Vis Spektrometer

KW - Hochleistungsflüssigkeitschromatographie

KW - HPLC

KW - feed Rate

KW - Extrudat

KW - kontinuierlich

KW - hot melt extrusion

KW - compounding

KW - process

KW - micro-feeder

KW - twin-screw extruder

KW - active pharmaceutical ingredient

KW - API

KW - drug eluting polymers

KW - process characteristics

KW - feeder

KW - process analytical tool

KW - PAT

KW - capability analysis

KW - polyvinylpyrrolidone-vinyl acetate

KW - Kollidon

KW - polymer matrix

KW - pharma

KW - screw geometry

KW - powder guiding system

KW - UV/Vis spectrometer

KW - high pressure liquid chromatography

KW - HPLC

KW - feed rates

KW - extrudate

KW - continuous

M3 - Master's Thesis

ER -