Which structure-property-process relationships govern semi-solid extrusion 3D printing? A stepwise and multi-parametric optimization protocol for pharmaceutical applications

Semi-solid extrusion 3D printing (SSE-3DP) emerges as a powerful technology for producing customized soft-matter pharmaceutical products. However, its implementation is limited by the lack of standardized, mechanistically grounded optimization strategies that address the multifactorial nature of printability. Herein, a stepwise and multi-parametric protocol is proposed to streamline the optimization of materials printed via SSE-3DP through a comprehensive structure–property–performance framework. Two gelatin-based model inks, differing in the content of PEG-40 hydrogenated castor oil (PEG40 HCO), were used to validate the approach. Rheology, texture, thermal-imaging and contact angle measurements were performed as part of the pre-printing workflow to elucidate ink structure and interfacial behavior, while width, length, collapse, pentagram and z-stack assays were carried out to optimize the 3DP quality in-process, and macro and scanning electron microscopy (SEM) imaging were introduced as post-characterization validation tools. Rheological analysis revealed that PEG40 HCO lowers the Sol–Gel crossover temperature, increases viscoelastic moduli and reduces creep compliance, indicating enhanced resistance to deformation during extrusion. These property changes translated into higher extrusion forces and increased susceptibility to clogging, quantitatively predicted by texture analysis (R² ≥ 0.94). Interfacial studies identified acrylic as the optimal printing bed. Line fidelity was primarily governed by print speed, while controlled porosity emerged from the coupled optimization of filament spacing and printing path design. SEM confirmed that PEG40 HCO induces mesoscale reorganization of the gelatin network, yielding improved mechanical stability and geometric fidelity. Overall, this work provides a comprehensive and adaptable framework for SSE-3DP, advancing material-process-design optimization in 13 steps.