In the pharmaceutical industry, solid form screening plays an important role to discover forms that exhibit desired physicochemical properties for drug product development. This work describes an approach to meet this objective by the transformation of undesirable solvates to hydrates or cosolvates with water via solid-state solvent exchange. Case studies of two drug substances, imatinib mesylate and linagliptin, are discussed, where linaglipitin methanol/ethanol solvate was converted to an iso-structural hydrate and, similarly, imatinib mesylate methanol−water cosolvate was converted to a predominantly watercontaining cosolvate. Through quality by design based optimization, temperature and relative humidity were identified as critical process parameters that impacted the rate of solvent exchange during humidification. In addition, crystallization parameters that impacted the crystal size were found to play a key role in determining the extent of solvent exchange. This unexpected effect of crystal size was investigated through single crystal structure elucidation and molecular modeling, which showed the solvent to be residing in channels oriented along the length of the crystal. The dimensions of these channels determined the ease of solvent exchange by controlling the rate and extent of diffusion of solvent molecules. With these case studies, this paper provides insight on robust process development for solid-state solvent exchange with an in-depth understanding of molecular level phenomena and critical process parameters.
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