(694e) The pH-Dependent Amorphous Precipitation Behavior of a Small Molecule API

The amorphous precipitation of APIs is less understood than crystallization, but as small molecule APIs become more complex, precipitation may become more commonplace for their isolation. This presentation will focus on a case study of a small molecule API that was isolated via precipitation and exhibited unpredictable filtration behavior during the isolation, which also resulted in greater entrained solvent and slower drying. Literature suggests a variety of root causes including temperature and mixing. These were investigated, but the strongest contributor was found to be the pH of the slurry. The API was precipitated into water and has a pKa close to neutral but only has trace solubility, so slight basification of the slurry could fully deprotonate the API. However, previous studies had demonstrated both a potential for epimerization and hydrolysis impurity formation at higher pH, so a systematic study of the impact of pH on both filtration behavior and impurity formation was completed giving a wide range of pH where filtration was improved with minimal impact on product quality and process scalability. Multiple bases used in the process were investigated, and a trace kicker of strong base (0.001-0.002 molar equivalents of KOH), was found to be sufficient to decrease filtration time by up to 2 orders of magnitude, while minimizing impurity formation. This process was successfully demonstrated at 10+ kg scale in multiple batches both for this molecule and another API with similar structure and was found to be robust to long process hold times.