(381d) Anticipate and Avoid Oiling out in Crystallization Using Molecular Dynamics Simulations

“Oiling out” is a phenomenon observed commonly in anti-solvent crystallization. The solute, instead of precipitating out of solution as a solid, forms a separate liquid phase with the anti-solvent. A significant effort is needed to recover the product from the oiled out solution. It can often lead to equipment damage if the mass solidifies into hard balls, etc. It is highly desirable to prevent such conditions that lead into oiling out phenomenon, especially in the regular production batches. Therefore, it is important to understand the molecular dynamics of the molecule from the clustering perspective which will help us to prevent crashing out of the compound as a solid or oil in the solution.

We have used molecular dynamics simulations for this purpose. We ran a series of simulations with the supersaturated solute in the presence of varying quantities of anti-solvent to investigate the differences in nucleated structures between onset of crystallization and oil-out phases. The simulations demonstrate that system can be triggered to nucleate into a separate liquid phase rather than forming a solid phase depending on the interfacial energy of the nucleated or seeded crystals. If the energy is favorable for adsorption of the “oil” molecules rather than API molecules, the system oils out.

We have identified conditions, such as solvent composition, mode of addition, degree of supersaturation, etc., that favor adsorption of one species over another to predict “oiling out” following a simple thermodynamic-and-kinetic model.

In our study, we used this approach to verify robustness of the crystallization protocol. In addition, the method also illustrates an example of the quality-by-design (QbD) approach where a range of crystals can be produced with varied particle size distribution by making small modifications to the procedure thereby avoiding oiling out.