Impact of Solvent\nSelection and Temperature on Oiling-Out\nPropensity During Crystallization of a Pharmaceutical Drug Candidate\nBI 730357

Undesired liquid–liquid phase separation (LLPS),\noften referred\nto as “oiling-out” in the pharmaceutical industry, can\noccur during a crystallization process. Although oiling-out risks\ncan sometimes be mitigated through strategies such as changing solvent\nsystems or seeding, such an effort remains highly empirical and labor-intensive.\nTherefore, it is crucial to understand the physical mechanisms affecting\noiling-out risks and how it is impacted by process parameters. This\nwill enable the development of rational strategies to mitigate this\nphenomenon and more quickly arrive at robust solutions. In this research,\nwe systematically evaluated the impact of solvent selection and temperature\non the oiling-out risks using a model drug BI 730357. Our experimental\nresults indicate that the oiling-out limit is relatively insensitive\nto solvent selection, whereas the crystalline solubility of the drug\nappears to be a more determinant factor in oiling-out risks. Solvents\nwith high drug solubility are typically associated with high oiling-out\nrisks due to reduced maximum achievable supersaturation and vice versa.\nFurthermore, higher temperature was shown to favor oiling-out by reducing\nthe maximum achievable supersaturation. Modeling results obtained\nusing the SAFT-γ Mie equation of state agree with experimental\nobservations, with results ranging from qualitative to quantitative,\ndepending on the solvent system. These modeling results demonstrate\nthe utility of such predictive tools in solvent screening/selection\nand mapping the phase diagram for enhanced process understanding.\nThis combined experimental and modeling screening approach can effectively\nreduce experimental burden and development time. The results obtained\nfrom this study will also contribute to a broader understanding of\nthe phenomenon of oiling-out.