An integrated high-throughput screening approach for purification of solid organic compounds by trituration and crystallization in solvents

Helming Tan, Maggie Reed, Kyung H. Gahm, Tony King, Mina Dilmeghani Seran, Tracy Bostick, Van Luu, David Semin, Janet Cheetham, Rob Larsen, Mike Martinelli, Paul Reider

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


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 HPLC. Using a mixture of acetylsalicylic acid containing salicylic acid as the impurity, we investigated the effects of material loading per sample and impurity level on product purity/solubility under both screening and scale-up conditions and evaluated the thermodynamic behavior of product-impurity-solvent interactions based on an isothermal ternary phase diagram. During a further case study, a binary solvent system was identified, and the synergistic effect of binary components was demonstrated for purification of an Amgen compound containing three impurities. This high-throughput screening approach is valuable as an integrated part of process development to identify the thermodynamically favored solvent conditions for purification of pharmaceutical compounds.

Original languageEnglish (US)
Pages (from-to)58-65
Number of pages8
JournalOrganic Process Research and Development
Issue number1
StatePublished - Jan 2008
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Physical and Theoretical Chemistry
  • Organic Chemistry


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