An Integrated High-Throughput Screening Approach for Purification of Solid Organic Compounds by Trituration and Crystallization in Solvents

Trituration and crystallization are essential techniques for purification of intermediates and drug substances in pharmaceutical process development. Traditionally, identifying the optimal solvent conditions for impurity rejection adopts an empirical approach that can be a time and material consuming process. On the basis of thermodynamic considerations for optimizing the purity and the yield of the crystal product, it is necessary to conduct screening experiments with the crude product in different solvents including mixtures of solvents. In this report, we describe the development and the implementation of a high-throughput screening workflow in a 96-well array format for identifying the optimal purification conditions. The impure samples were first triturated at room temperature and subsequently subjected to a thermal cycle in 96 unique solvents or solvent mixtures at a volume of 0.6 mL per well. The compound solubility and the impurity profiles of both supernatant and recovered solid were analyzed by ...