(409b) Process Development to Avoid Meta-Stable Liquid-Liquid Phase Separation during Crystallization of API

Crystallization is a critical unit operation in the production of small molecule active pharmaceutical ingredients (APIs), as it often determines the form and powder properties of the product. Therefore, crystallization process development focuses on identifying conditions that are controlled and scalable. In general, liquid-liquid phase separation or oiling out of product are undesirable as they may lead to uncontrolled nucleation and growth of particles that impacts critical quality attributes, such as particle size and level of impurities. Therefore, understanding liquid-liquid phase equilibria and solubility of the compound is critical in designing crystallization processes.

This presentation will describe how we experimentally investigated the liquid-liquid phase separation that occurred during crystallization of a small molecule API in a ternary solvent system of tetrahydrofuran, acetone and water. Although these solvents are typically miscible, the presence of the API resulted in liquid-liquid phase separation at the seed point under some conditions. In-line process analytical tools such as ParticleViewer and FBRM were incorporated to detect and understand the phenomena. A detailed phase diagram was generated for the crystallization design space as a function of solvent composition, concentration of API in solution and temperature. Along with solubility data, the phase diagram was used to design a process that avoids liquid-liquid phase separation throughout the entire crystallization. In addition, we will describe the impact of wet-milling during seed age that was implemented to ensure that full desupersaturation was achieved, which was critical in avoiding phase separation.