Process Controlled\nPolymorphic Phase Transformation\nin Crystalline Solid Dispersions: Impact of Temperature, Pressure,\nand Shear Stress

Understanding the processing boundaries to generate crystalline\nsolid dispersions (CSDs) containing metastable polymorphs remains\nan untapped challenge for the application of hot-melt extrusion (HME)\nand three-dimensional printing (3DP) as polymer-based formulation\napproaches. Hence, to successfully implement CSDs as alternative solid\ndosage formulations, the effect of critical process parameters (CPPs)\non potential polymorphic phase transformations (PPTs) needs to be\nexamined. This study extends the current knowledge on the influence\nof CPPs through temperature–pressure–shear simulated\nextrusion (TPSS-E) using the model system flufenamic acid (FFA) and\npoly(ethylene glycol) (PEG). The TPSS-E results revealed a significant\nreduction in the average PPT induction time (53%) compared to previous\ntemperature–pressure simulated-extrusion (TPS-E) studies without\nshear stress. However, TPSS-E control experiments performed at 25\n°C showed no PPT. This suggests that temperature is the most\ncritical parameter in determining whether a PPT will occur, while\npressure and shear stress significantly accelerate the PPT kinetics\nfrom the metastable (FFA III) to the stable form (FFA I) at elevated\ntemperatures. These results demonstrate that for an enantiotropic\nsystem like FFA forms I and III (transition point = 42 °C), it\nis possible to control the metastable polymorph in CSDs during extrusion\nprocesses if the thermodynamic and kinetic boundaries, the CPPs, and\nmaterial attributes of the drug-polymer system are well understood\nand controlled. The work presented here expands on the application\nof HME and 3DP as polymer-based formulation strategies for CSDs containing\nmetastable polymorphs.