Crystallization is a solid-liquid separation and a purification technique commonly used in pharmaceutical industry. Liquid-liquid phase separation (LLPS) or oiling out is seen increasingly common in pharmaceutical crystallization. As the name suggests, oiling out refers to emergence of oil-like droplets in the solutions upon cooling or antisolvent addition. LLPS is often undesirable as it results in quality issues of the final active pharmaceutical ingredient (API) such as not meeting the purity specifications, polymorphic failure and/or fragile morphology of the final API. In addition, oiling out can lead to operational challenges such as the API sticking to the walls of the crystallizer and agitator, causing problems in reactor cleaning and compliance issues. In this work, the author studied a small molecule which tend to oil out in a solvent-antisolvent mixture during the antisolvent crystallization process. A systematic approach was applied to mitigate the oiling out of the API. First, the solubility of the API was estimated in the different solvent: antisolvent ratios and at different temperatures. It was found the oil was stable at certain solvent: antisolvent ratios and the temperature had a slight effect on the oiling out region in the phase diagram. An array of process analytical technology (PAT) tools was used to study the crystallization process. The initial solute concentration, the presence of different salt complex from the prior reaction step, seeding point and the rate of antisolvent addition were found to be the critical parameters. Various strategies were explored to mitigate the oiling out issue. This work will present the strategies that were employed and the scientific rationale behind those strategies. Further, this work will highlight the importance of the use of PAT tools to design and develop the crystallization process of the API that tend to oil out.
