A laminar-flow tubular crystallizer was used for seedless continuous flow crystallization of an active pharmaceutical ingredient, namely, Brivaracetam, which has a polymorphic behavior: rod-shaped crystals and a pseudo-polymorphic solvated, needle-like crystal. The combination of fast cooling at 20 °C/s and high supersaturation values between 4 and 11 resulted in the discrimination of nucleation and growth of only the desired crystalline form even though its solubility curve is very close to the one of the undesired needle shape. Crystal nucleation and the start of crystal growth occur inside the tubular crystallizer; high flow rates prevent clogging of the crystallizer. Further crystal growth may be, if desired, stopped via immediate filtration. In this way, an industrially applicable continuous crystallizer is proposed. It is also demonstrated that the presence of restrictions in the tubing drastically increases the nucleation rate. A literature survey points out that induced turbulence can occur under current flow conditions using said restrictions.

The development of a continuous flow antisolvent crystallization protocol for a commercial active pharmaceutical ingredient, Brivaracetam, is described. To obtain increased nucleation kinetics of the desired crystalline form, solutions of Brivaracetam/isopropyl acetate are injected into micrometric tubing and mixed with a refrigerated antisolvent hexane. In this way very high supersaturation conditions are induced shortly after mixing. Residence times below 1 s after mixing in short tubular crystallizers are necessary for the desired, but thermodynamically unstable, crystals to grow. Arresting all crystal growth by immediate removal of the antisolvent containing mother liquors by continuous filtration or by casting the product onto filter paper prevents the formation of the thermodynamically stable pseudopolymorphundesired due to its needle shape and solvated nature. Sufficient solid material output can be generated in order to be implemented in actual processing conditions if combined with suited continuous filtration units.