Growth promotion by H2O in organic solvent-selective isolation of a target polymorph

This paper reports the marked promotion of crystal growth by small amounts of H2O in organic solvents for isolating the desired polymorph of a neurokinin-1 receptor antagonist. In dry organic solvents, regardless of solubility, the growth rate of the target polymorph was too slow for a robust and efficient crystallization process. It was found that the overall growth rate constant of the target polymorph increases linearly with H2O concentration in organic solvent along with a distinct crystal morphology transition from needles to platelets. An in situ real-time FTIR analyzer and an in situ real-time particle analyzer were employed in the growth kinetics measurements. The finding of this study enabled the rational design of a robust and efficient crystallization process with 100% polymorphic purity at >98% yield. The mechanistic role of H2O in the observed growth promotion is discussed.