Optimizing post-printing drying conditions for point-of-care manufacturing of SSE-3D printed medicines

Post-printing drying conditions could affect the quality of oral use printlets elaborated by semi-solid extrusion (SSE) 3D printing, yet their systematic characterization as Critical Process Parameters (CPPs) remains limited. This study evaluated the influence of temperature (20-40°C) and relative humidity (20-80%) on acetazolamide printlets drying process using a full factorial design (n = 27). Response variables included weight stabilization time (the time required for the batch to complete drying, operationally defined as achieving constant weight), disintegration time, dissolution profile, tensile strength, and morphological parameters. General Linear Model analysis, Principal Component Analysis, hierarchical clustering, Response Surface Methodology (RSM), and machine learning (ML) approaches were applied. Temperature accounted for 54% of weight stabilization time variance (SOBOL analysis), while humidity contributed 30% and their interaction 12%. A humidity threshold near 60% was identified; below this point drying kinetics remained stable. RSM models achieved R² values ranging from 0.255 to 0.980, with weight stabilization time showing the best fit. ML validation using Support Vector Regression confirmed RSM predictions (r = 0.984 at experimental points). Six distinct processing regimes were identified through cluster analysis. Multi-objective optimization identified 38°C and 40% relative humidity as optimal drying conditions. Experimental verification yielded a weight stabilization time, completing the drying process in 1.67 h, disintegration time of 182.80 ± 0.69 s, and 90.29 ± 2.01% drug dissolved at 60 min. Optimized air-dried printlets achieved 97% of freeze-dried dissolution performance (90.29% vs 93.28%) with reduced infrastructure requirements. These findings establish controlled drying conditions as CPPs for SSE 3DP and provide a framework for rapid point-of-care manufacturing of optimized individualized medicines.