Design and development of polymeric nanoparticles by continuous manufacture using twin screw extrusion

  • Esther Jacobs

Student thesis: Doctoral ThesisDoctor of Philosophy


Nanoparticles have received significant attention due to their vast potential to treat a plethora of diseases. There is much interest and innovation within the field with the global market value of nanotherapeutics projected to be worth US$369.5 Billion by 2027 (Research and Market, 2020). Despite this, there is a significant lack of nanoparticles in the clinic; the ability to produce polymeric nanoparticles, reproducibly, and on a large scale remains a challenge. As a manufacturing tool, extrusion has been widely implemented in the pharmaceutical industry for a range of dosage forms due to the ability to implement continuous manufacturing.

This thesis explores the use of extrusion as a tool to continuously manufacture polymeric nanoparticles without the use of solvents or water for the first time. Firstly, this work developed a strategy for the manufacture of high drug-loaded amorphous solid dispersion (ASD) using twin-screw extrusion (TSE) for three drugs: indomethacin (IND), naproxen (NPX) and ibuprofen (IBU) with Eudragit® EPO (EPO). The design spaces were predicted through Flory-Huggins (FH) based theory, and the selected ASDs were manufactured using extrusion to produce high-drug loaded ASDs (HDASDs). Secondly, the enhanced physical stability was further confirmed by high relative humidity (RH) (95% RH) storage stability studies as well as long term stability studies (40°C, 75% RH). Through this work, we have demonstrated that by implementing predictive thermodynamic modelling, ASD formulation design can be integrated into the extrusion process design to ensure the desired quality of the final dosage form.

This was the foundation for developing polymeric nanoparticles, the initial investigations focusing on one of ASD manufacture of NPX and EPO. The initial feasibility study was conducted to confirm the plausibility of nanoparticle manufacture by TSE with a design of experiment (DoE) approach to highlight key process parameters. It was shown through this work that nanoparticles could be manufactured using extrusion. However, optimisation of process and formulation parameters was necessary for the nanoparticle formulations where there was poor nanoparticle recovery due to insufficient mixing. The carrier selection, in particular the viscosity of three sugar alcohol carriers, xylitol (XYL), sorbitol (SORB) and erythritol (ERY), was assessed in addition to predicted required shear rates in order to produce homogenous mixtures of nanoparticles. Additionally, the ability to scale up the process was investigated with promising results. It was shown that the longer residence time achieved with, the larger extruder resulted in increased nanoparticle recovery and improved content uniformity.

We have shown that extrusion can be used to make reproducible nanoparticles in a continuous fashion. Furthermore, we have shown from preliminary in vitro data that the nanoparticles can allow for controlled or targeted release based on the polymer selection. Further studies will focus on implementing this design to develop other nanoparticle systems and further in vivo analysis.
Date of AwardDec 2021
Original languageEnglish
Awarding Institution
  • Queen's University Belfast
SponsorsNorthern Ireland Department for the Economy
SupervisorGavin Andrews (Supervisor) & Justin Tian (Supervisor)


  • twin-screw extrusion
  • polymeric nanoparticles
  • nanoparticles
  • hot-melt extrusion
  • amorphous solid dispersions
  • Flory Huggins modelling
  • continuous manufacture
  • design of experiment
  • quality by design

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