The integration of 3D printing into the pharmaceutical sciences opens new possibilities for personalized medicine. Poly(lactide) (PLA), a biodegradable and biocompatible polymer, is highly suitable for biomedical applications, particularly in the context of 3D printing. However, its processability often requires the addition of plasticizers. This study investigates the use of phase diagram modeling as a tool to guide the rational selection of plasticizers and to assess their impact on the thermodynamic and kinetic stability of PLA-based amorphous solid dispersions (ASDs) containing active pharmaceutical ingredients (APIs). Thermodynamic stability against API recrystallization was predicted based on the API solubility in PLA and Plasticizer-PLA carriers using the Conductor-like Screening Model for Real Solvents (COSMO-RS), while the kinetic stability of the ASDs was evaluated by modeling the glass transition temperatures of the mixtures. Two APIs, indomethacin (IND) and naproxen (NAP), with differing glass-forming abilities (i.e., recrystallization tendencies), and three plasticizers, triacetin (TA), triethyl citrate (TEC), and poly(L-lactide-co-caprolactone) (PLCL), were selected for investigation. The physical stability of ASD formulations containing 9 wt% API and plasticizer to PLA in two ratios, 10:81 and 20:71 w/w %, was monitored over time using differential scanning calorimetry and X-ray powder diffraction and compared with phase diagram predictions. All formulations were predicted to be thermodynamically unstable
however, those containing no plasticizer or with TEC and TA at 10 wt% were predicted to exhibit some degree of kinetic stability. Long-term physical studies corroborated these predictions. The correlation between the predicted phase behavior and long-term physical stability highlights the potential of phase diagram modeling as a tool for the rational design of ASDs in pharmaceutical 3D printing.