Mechanistic insights into semi-solid extrusion 3D printing of indomethacin-nicotinamide cocrystal-loaded oral fast-dissolving films

The growing demand for personalized medicine requires adaptable dosage forms capable of addressing challenges associated with poorly soluble drugs. Cocrystals offer a powerful strategy to enhance solubility, while semi-solid extrusion (SSE) 3D printing enables flexible, patient-tailored manufacturing. This study establishes a systematic framework for developing oral fast-dissolving films (OFDFs) incorporating indomethacin-nicotinamide (IND-NIC) cocrystals using SSE 3D printing. Critical Material Attributes (CMAs), HPMC-glycerol base, sodium starch glycolate (SSG), and varying cocrystal loadings, were systematically adjusted to evaluate their influence on key ink and film Critical Quality Attributes (CQAs). All inks displayed desirable shear-thinning behaviour, with IND-NIC cocrystals and SSG synergistically reinforcing the structural network for reliable extrusion and shape fidelity. Solid-state analyses (XRPD, DSC, PLM, Raman microscopy) confirmed preservation of the cocrystal form throughout ink preparation, printing, and short-term storage. The 3D printed OFDFs exhibited uniform thickness, weight, and drug content with minimal variability across batches, and displayed humidity-dependent mechanical behaviour that varied with cocrystal loading. All formulations achieved rapid drug release, exceeding 80 % IND dissolution within 30 min. Dissolution profiles were consistent across cocrystal loadings and remained statistically equivalent for films printed from inks stored for up to 2 days, as well as for the 3-day redispersed ink, confirming that the structural reinforcement required for printability does not compromise rapid release performance. Overall, this work provides mechanistic insight into the formulation-process-performance relationships governing SSE 3D printing of cocrystal-loaded OFDFs and highlights the potential of this green, low-temperature platform for decentralized, patient-centric manufacturing of fast-dissolving dosage forms.