Impact of Solvent Selection and Temperature on Oiling-Out Propensity During Crystallization of a Pharmaceutical Drug Candidate BI 730357

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