Polymorphic Phase Transformations in Crystalline Solid Dispersions: The Combined Effect of Pressure and Temperature

Potential polymorphic phase transformations (PPTs) during the processing of active pharmaceutical ingredients (APIs) have limited the application of hot-melt extrusion (HME) and three-dimensional printing (3DP) as alternative technologies to enable polymer-based formulations such as crystalline solid dispersions (CSDs). To successfully implement CSDs as alternative solid dosage formulation strategies, the effect of the critical process parameters (CPPs) on PPTs of APIs needs to be well understood. This study extends the fundamental understanding of the CPP's effect on PPTs through temperature–pressure-simulated extrusion (TPS-E) employing the model compound flufenamic acid (FFA) in poly(ethylene glycol) (PEG 4 000, 10 000, and 20 000). The TPS-E results revealed a 24% reduction in the average PPT induction time compared to temperature-simulated extrusion (TS-E) performed without pressure. This work demonstrates that CSDs containing FFA III, metastable at the process temperature, can be generated by TPS-E because the PPT induction time is longer than the average reported residence time in conventional extrusion processes (5 min). Ultimately, this study demonstrates that thorough understanding of the thermodynamic and kinetic boundaries of an API–polymer system, the CPPs (temperature, pressure, composition, and residence time), and critical material attributes (molecular weight of PEG) leads to polymorphic control in the produced CSDs.