Effect of Acetonitrile-Based Crystallization Conditions on the Crystal Quality of Vitamin D₃

To design an integrated continuous crystallization setup that is directly coupled to a photochemical synthesis in flow, the crystallization of vitamin D₃ was studied in detail. Because of the high solubility of the vitamin in the reaction solvent tert-butylmethyl ether, a solvent swap to acetonitrile was necessary. While other methods use a multistep procedure, with the proposed approach, crystalline vitamin D₃ can be obtained within one crystallization step. The influence of crystallization parameters, such as the initial concentration of vitamin D₃, stirring as well as cooling temperature, rate, and time, on the obtained results in terms of yield, crystal shape, polymorphism, and particle size distribution are discussed in detail.