(583c) Understanding of Polymorphic Phase Transformation of Artemisinin in Polymer-Based Formulation

Hot-melt extrusion (HME) and additive manufacturing have emerged as novel processing technologies for pharmaceutical formulations compared to conventional techniques. The advantages of polymer-based techniques to obtain e.g., crystalline solid dispersions include e.g., the reduction in number of unit operations needed, cost-effectiveness, solvent-free nature, and continuous manufacturing. However, potential polymorphic phase transformations (PPT) of the active pharmaceutical ingredients (APIs) during the processing have limited their applications¹. To broaden their use as alternative solid dosage formulation strategies, the impact of the critical process parameters (CPPs)^2,3 such as temperature, pressure, and shear stress on PPT need to be understood. This study employs temperature-simulated extrusion (TS-E), temperature-pressure-simulated extrusion (TPS-E), and temperature-pressure-shear stress simulated extrusion (TPSS-E) to understand the impact of the CPPs on PPT,^2,3 individually and coupled. Artemisinin (ART), an antimalarial drug with an enantiotropic relationship between form I and II (Tp = 130 °C), was used as the model API dispersed in polyethylene glycol (PEG 4 000, 10 000), acting as polymeric carrier. No PPT induction time for the metastable ART II to ART I was detected for TS-E after 3 h. However, the induction time decreases when mechanical stress (pressure, shear stress) is applied. Though the average PPT induction times measured were significantly longer than the average reported residence time in conventional extrusion processes (5 min). Thus, this work demonstrates that the understanding of the thermodynamics and kinetics boundaries for PPT in an API-polymer system, leads to control of the polymorphic form in crystalline solid dispersions.

Reference:

1. Sanabria Ortiz, Karina, et al. "Polymorphism in solid dispersions." Crystal Growth & Design 2 (2019): 713-722.
2. Reyes Figueroa, Francheska, et al. "Polymorphic Phase Transformations in Crystalline Solid Dispersions: The Combined Effect of Pressure and Temperature." Crystal Growth & Design 5 (2022): 2903-2909.
3. Hernández Espinell, José R., et al. "Solvent-Mediated Polymorphic Transformations in Molten Polymers: The Account of Acetaminophen." Molecular Pharmaceutics 7 (2022): 2183-2190.