3D printing in the preclinical space vs late development

Although there is great potential in the combination of HME and pharmaceutical 3DP, the integration of these processes via simplified extrusion techniques which are better suited for early developmental stages remains underexplored. This research therefore aimed to investigate the feasibility of combining single screw HME with FDM 3DP as a formulation and manufacturing strategy for ASDs intended for solid oral dosage forms, with a focus on practical applicability in preclinical and early-stage pharmaceutical development.

ITZ was selected as the model poorly water-soluble drug based upon its established formulation challenges and frequent use in ASD research. Formulations consisting of polymers were designed to facilitate the formation of ASDs while maintaining sufficient thermal and mechanical properties to allow for successful downstream processing. Single screw HME was utilized to prepare ASD extrudates under optimized processing conditions to achieve effective drug-polymer mixing while minimising thermal and mechanical stress.

While single screw HME represents a simpler and more material efficient alternative to twin screw extrusion, its suitability for ASD preparation and subsequent 3DP has not been extensively studied. <br><br>In the first part of the experimental study, ITZ based ASDs were prepared by single screw HME and evaluated in terms of processability and solid-state behaviour (Chapter 3). Extrudates were assessed for physical appearance, mechanical strength and suitability for filament production.

Differential scanning calorimetry and powder X-ray diffraction were employed to confirm amorphous drug incorporation and to assess the impact of extrusion conditions on solid state stability. The results from these studies demonstrated that ASDs could be successfully prepared utilizing single screw HME provided that appropriate formulation compositions and processing parameters were employed. Following extrusion, filaments suitable for FDM 3D printing were produced using a Soluplus based ASD system (Chapter 4).

This chapter investigated whether substitution of the polymer system influenced formulation performance, particularly in terms of in vitro drug release, while maintaining printability within the same single screw HME FDM workflow. Formulation and design variables influencing drug release were investigated using the initial HPMCAS based ASD system (Chapter 5). This chapter examined the impact of tablet internal structure and the inclusion of disintegrants on the performance of FDM 3D-printed tablets, while maintaining a constant formulation base and processing workflow.

Variations in infill design were employed to assess the effect of internal geometry on tablet integrity and dissolution behaviour, alongside evaluation of disintegrants as a strategy to modulate drug release within 3D-printed dosage forms. In Chapter 6, HPMCAS based 3D printed ASD tablets were compared with conventionally manufactured ASD tablets and crystalline drug formulations to evaluate the influence of manufacturing route on formulation performance. <br><br>Solid state characterisation techniques, including differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM), were used to assess the physical state of itraconazole following extrusion and 3DP alongside evaluation of microstructural features of the resulting dosage forms.

In vitro dissolution testing was conducted throughout the study to assess the impact of formulation composition, tablet design, and manufacturing route on drug release behaviour. Overall, this work demonstrates that single screw HME can be effectively integrated with FDM 3DP to produce ITZ based ASDs suitable for SODFs. The findings show that amorphous drug incorporation and dissolution performance can be maintained across extrusion, filament production and 3DP when appropriate formulation and processing conditions are applied.

In pharmaceutics, particularly for emerging technologies such as 3DP, the published literature predominantly focuses on successful outcomes, with less emphasis placed on practical limitations and processing challenges. By reporting both positive and negative experiences, the current study has provided a more accurate representation of the opportunities and challenges associated with the integration of HME and pharmaceutical 3DP.

Rather than positioning 3DP as inherently superior to conventional manufacturing, this work highlights its value as a flexible and material efficient formulation tool, particularly suited to early stage and preclinical development where adaptability and efficient use of limited drug substance are paramount. <br><br><i>Thesis is embargoed until 31 July 2031.</i><br>