Continuous-flow in-line solvent-swap crystallization of vitamin D₃

Abstract

A continuous tandem in-line evaporation–crystallization is presented. The process includes an in-line solvent-swap step, suitable to be coupled to a capillary based cooler. As a proof of concept, this setup is tested in a direct in-line acetonitrile mediated crystallization of Vitamin D₃. This configuration is suitable to be coupled to a new end-to-end continuous microflow synthesis of Vitamin D₃. By this procedure, vitamin particles can be crystallized in continuous flow and isolated using an in-line continuous filtration step. In one run in just 1 min of cooling time, ∼50% (w/w) crystals of Vitamin D₃ are directly obtained. Furthermore, the polymorphic form as well as crystals shape and size properties are described in this paper.