From print settings to printlet performance: a study on critical quality attributes in pellet-based direct extrusion additive manufacturing.

Fused Filament Fabrication (FFF) is a widely used additive manufacturing technique for personalized pharmaceutical dosage forms but requires filaments with specific mechanical and physical properties, limiting formulation flexibility. To address this, pellets could be used as feedstock material for direct extrusion additive manufacturing (DEAM) where a conventional filament printing head is replaced by a single-screw extrusion unit. This study explores the potential of pellet-based DEAM through a design-of-experiments approach using a formulation unsuitable for FFF. Brittle filaments containing 60% anhydrous theophylline and 40% Soluplus® (m/m) were prepared via hot melt extrusion and shredded into pellets. The study evaluated the effects of process parameters during twin-screw extrusion (screw speed, barrel and die temperature) on various pellet characteristics, including content uniformity, API degradation, shape, size, flowability and friability. Die temperature exerted the most significant impact on the friability and visual quality of the pellets. A full factorial screening design evaluated the impact of four printing parameters (print temperature, infill, overlap and extrusion multiplier) on critical quality attributes of the 3D printed tablets, including tablet mass, content uniformity, drug degradation, mechanical properties, dissolution, dimensions, and porosity. Infill, extrusion multiplier, and overlap significantly influenced tablet mass. The tablet brittleness index was a reliable indication of the brittleness of the printlets, the tensile strength was mainly influenced by infill. Porosity was correlated with in vitro dissolution, both influenced by infill and extrusion multiplier. An increase in print temperature significantly enhanced the dissolution rate. All pellet runs and 3D printed tablets maintained excellent content uniformity without API degradation, regardless of the heating cycles. Pellet-based DEAM proved to be a promising approach for manufacturing oral solid dosage forms with versatile properties and fewer material constraints compared to FFF. The extrusion multiplier was identified as a new key process parameter, enabling personalized medicine by tailoring dose, porosity and dissolution profiles.