(702a) Tailored Generation of Metastable Polymorph during Formulation

Metastable polymorphs of active pharmaceutical ingredients (APIs) can improve physicochemical properties, e.g., solubility and dissolution rate, which in turn impact the bioavailability and processing characteristics. However, accessing these forms through solution crystallization, often requires, e.g., additives, seed crystals, or hazardous solvents that are not favorable for pharmaceutical manufacturing. Moreover, harvesting metastable polymorphs before they convert to more stable form via solvent-mediated polymorphic phase transformation may be difficult due to competing thermodynamic and kinetic factors. The transformation may also be triggered by thermal and mechanical stresses encountered in conventional solid dosage formulation processes, e.g., tableting. Consequently, understanding the processing boundaries to generate formulations containing desired metastable polymorphs of APIs remains a key challenge.

Polymer-based formulation approaches enabled by, e.g., hot-melt extrusion and 3D-printing experience growing interest as alternatives to conventional tableting. For instance, crystalline solid dispersions embed the crystalline API in a polymeric matrix. It has been reported that the induction time for polymorphic phase transformation in polymer melts, can be controlled, allowing to either delay a transformation or theoretically access and stabilize metastable forms.^1,2 To prove the latter, this study presents the phase transformation of a stable form I to the desired metastable form II during the processing of the model system Artemisinin (antimalarial drug) and polyethylene glycol (PEG) into a crystalline solid dispersion using temperature-pressure-shear simulated extrusion. The experimental results reveal how the critical process parameters (temperature, pressure, shear stress, composition, residence time) affect the solid form transformation into the favorable metastable form II, while being formulated into a crystalline solid dispersion, thus enabling process intensification.

References:

(1) Hernández Espinell, J. R.; Toro, V.; Yao, X.; Yu, L.; Lopéz-Mejías, V.; Stelzer, T. Solvent-Mediated Polymorphic Transformations in Molten Polymers: The Account of Acetaminophen. Mol. Pharm. 2022, 19 (7), 2183.

(2) Reyes Figueroa, F.; Hernández Espinell, J. R.; Manivel, S.; Yu, L.; Zhang, G. G. Z.; López-Mejías, V.; Stelzer, T. Process Controlled Polymorphic Phase Transformation in Crystalline Solid Dispersions: Impact of Temperature, Pressure, and Shear Stress. Cryst. Growth Des. 2024, 24 (21), 8866–8875.