(402d) Revealing Polymorphic Phase Transformations in Polymer-Based Hot Melt Extrusion Processes

The pharmaceutical industry is exploring new manufacturing technologies such as hot melt extrusion (HME) that enables continuous formulation of complex products for peroral administration. To date, aside from thermal stability, the polymorphic stability of an active pharmaceutical ingredient (API) is thought to be a prerequisite when HME is employed to produce solid dosage pharmaceutical formulations. Polymorphism, a phenomenon that enables molecules to exhibit multiple crystalline phases, is one of the most scrutinized critical quality attributes during the manufacturing of solid dosage formulations. Polymorphism is estimated to occur in 80% of molecules with pharmaceutical applications, affecting properties of the solid state (stability, solubility, dissolution rate, and bioavailability), and therefore, the quality and efficacy of the final drug product. The unsubstantiated notion that undesired polymorphic phase transformations might occur during the HME process limits the application of this technique to produce crystalline solid dispersions for a narrow set of APIs that are both thermally stable and monomorphic (∼20%). The present study aims to understand polymorphic phase transformations occurring during the production of crystalline solid dispersions by decoupling the effect of critical process parameters (CPPs) that accompany a HME process (temperature, drug-polymer composition, polymer properties such as molecular weight, and residence time) to relate them to the polymorphic outcome of the formulated product. Other relevant CPPs such as pressure, shear stress, and their combination with temperature, composition, and residence time will be explored in future investigations. Since conventional laboratory hot melt extruders (1) do not allow the independent study of CPPs, (2) require considerable quantities (10−800 g/h) of materials per experiment, and (3) do not permit in situmonitoring along the process, this work probed the effect of CPPs on the polymorphic phase transformations of physical mixtures using a combination of polarized optical hot-stage microscopy (HSM), offline powder X-ray diffraction (PXRD), and in situtime-resolved PXRD. Such an approach served to identify correlations among the selected CPPs and, therefore, will help to minimize the number of experiments needed to be tested in future laboratory-scale HME processes. This work demonstrates that flufenamic acid (FFA), one of the most polymorphic APIs known, thus far, can be processed with polyethylene glycol (PEG) as polymeric carrier using temperature-simulated HME. At temperatures above the transition point of FFA forms III and I (42 °C), the induction time of the polymorphic phase transformation is longer than the average reported residence time in conventional HME processes (5 min). Moreover, it was demonstrated that thorough understanding of the thermodynamic and kinetic design space for the PEG-FFA system leads to polymorphic control in the produced crystalline solid dispersions. Ultimately, this investigation helps to gain fundamental understanding of the processing needs of crystalline solid dispersions, which will lead to the broader application of HME as a continuous manufacturing strategy for drug products containing APIs prone to polymorphism, representing about 80% of all APIs.