Concomitant Precipitation of Solid-State Miscible Product-Impurity Phases in Solution Crystallization - Part 2: Industrial Case Studies

Three industrial case studies are presented from the pharmaceutical companies Boehringer-Ingelheim and Merck & Co., Inc. (Rahway, NJ) demonstrating how solid-state miscible impurities can coprecipitate during scale-up of crystallizations resulting in significant purity challenges. This second part contribution outlines how the underlying impurity retention mechanism was identified via the Solubility-Limited Impurity Purge (SLIP) test, which allowed the project teams to establish appropriate mechanism-based root-causes. The workflow and thermodynamic model introduced in part 1 of this paper series were used to guide the teams toward finding thermodynamically robust solutions for this previously unreported impurity retention mechanism. Different approaches were employed based on the prevailing solid-state miscibility, solid form landscapes, and solvent solubilities. In the first case study, an impurity present at 6% could be purged in a single crystallization by switching the crystal form. In case studies 2 and 3, solvent switches enabled the teams to reject precipitating impurities originally present at 14% and 3.5%, respectively. The presented examples showcase how mechanistic understanding of impurity retention in crystallization can be used to arrive at thermodynamically robust solutions while saving time and resources.