Large-scale crystallization of acetaminophen trihydrate by a novel stirring technique

Abstract

We succeeded in selective and large-scale (liter-order) crystallization of acetaminophen trihydrate by a novel solution-stirring method for the first time. The method arose from our observation that the stirring ball efficiently induced turbulent flow of the solution, and thereby nucleation of trihydrate. Pure trihydrate crystallized with high probability (100%) even in a solution volume of 1 l. In addition, mass production of acetaminophen form II (metastable phase) was achieved using solution-mediated phase transformation. We conclude that this stirring method could produce industrial crystallization of unstable polymorphs such as the metastable phase and hydrate.