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Mapping Solvate Behavior of an API Intermediate

In support of process development toward an API of interest, a robust isolation of intermediate A was sought. Stable form screening revealed multiple solvated and unsolvated polymorphs of this intermediate, of which two, a solvate A • 2 ROH and unsolvated Form I, were further developed to support the isolation process. Subsequently, a two-stage isolation was devised in which the intermediate was first isolated as the solvate and then reslurried in a second solvent to effect desolvation and conversion to the targeted, unsolvated Form I. This process was reliable on laboratory scale, but upon scale-up, an unanticipated reversion to the solvate was observed during the reslurry operation. In-situ Raman spectroscopy was used to rapidly characterize the boundary between A • 2 ROH and unsolvated Form I as a function of solvent composition and temperature, which revealed strong dependence on both parameters. Using this information, the process conditions were optimized, enabling reliable operation to obtain the desired, unsolvated form in subsequent plant campaigns.

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Eric Standley
Eric Standley