Maneuvering Around Liquid-Liquid Phase Separation (LLPS) to Enable Development of Robust Crystallization Processes.

Anti-solvent and/or cooling crystallizations are commonly employed in purification of pharmaceutically relevant molecules. In addition, the crystallizations are also typically tasked with isolating solids with controlled physical properties. During development of multi-solvent crystallizations, it is not unusual to observe Liquid-Liquid Phase Separation (LLPS), commonly referred to as “oiling out”. LLPS is generally undesirable due to its detrimental impact on purity and physical properties as well as due to the challenges it brings in during scale-up. LLPS is impacted by multiple parameters such as solute concentration, solvent composition, and temperature. Understanding of such a dynamic phase diagram, in addition to the kinetic parameters, is paramount to achieve a predictable process scale-up.

In this presentation, we detail a methodology to develop a hybrid anti-solvent / cooling crystallization process maneuvering around the LLPS boundaries. Use of automated Lab reactors (ALR) equipped with Process Analytical Technologies (PAT) is highlighted for performing data-rich experiments quickly. The generated data is further modelled with thermodynamic equations for enhanced process understanding. Finally, we will present a case study to showcase how the above-referenced methodology was utilized for enhanced process understanding and for development of a robust and scalable crystallization process.

All authors are employees of AbbVie and may own AbbVie stock. AbbVie sponsored and funded the study; contributed to the design; participated in the collection, analysis, and interpretation of data, and in writing, reviewing, and approval of the final publication.