A robust new tool for online solution-phase sampling of crystallizations

Abstract

Current PAT tools struggle to provide real time solid-phase composition data for crystallizations. HPLC offers a variety of benefits over other solution-phase PATs and can be used to infer solid-phase composition when combining total (solid plus solution phase) sampling with solution-only sampling. However, the selective solution-phase sampling of supersaturated solutions is extremely challenging. We herein present a dynamically flushed in situ filtration device that attaches to the tip of Mettler-Toledo's EasySampler probe and makes use of its mechanical motion to avoid surface fouling. Filter functionality was tested under both increasing saturation (via cooling or antisolvent addition) as well as decreasing saturation (via heating or solvent addition), illustrating its accuracy, reliability and versatility. The utility of the filter tip was highlighted by monitoring the classical resolution of TBZ, an important drug precursor.