Continuous crystallization is an attractive approach for the delivery of consistent particles with specified critical quality attributes (CQAs) attracting increased interest for the manufacture of high value materials including fine chemicals and pharmaceuticals. Oscillatory flow reactors (OFRs) offer a suitable platform to deliver consistent operating conditions under plug-flow operation whilst maintaining a controlled steady state. This review provides a brief overview of OFR technology before outlining the operating principles and summarizing applications, emphasizing the use for controlled continuous crystallization. Whilst significant progress has been made to date, areas for further development are highlighted that will enhance the range of applications and ease of implementation of OFR technology. These depend on specific application but include scale down, materials of construction suitable for chemical compatibility and encrustation mitigation and the enhancement of robust operation via automation, process analytical technology (PAT) and real-time feedback control.

A continuously seeded L-glutamic acid cooling crystallization process, in a continuous oscillatory baffled crystallizer, was designed and operated to deliver control over polymorphic form. Different feed solution concentrations and seed loadings of β L-glutamic acid crystals were examined. Steady-state operation, based on particle size distribution and polymorphic form, was demonstrated consistently after two residence times. Where bulk supersaturation remained in the range 2 -3, polymorphic phase purity of the thermodynamically stable β polymorph was retained. However, when bulk supersaturation exceeded this range to values of 3 -8, primary nucleation of the metastable α polymorph was observed and product crystals were a mixed phase. In the absence of seeding the system could not be operated without significant encrustation to the vessel surface thus leading to loss of control, whereas a continuously seeded approach allowed robust processing for at least 10 h.

Presentation and applied case study of a system-wide workflow which supports rapid, systematic and efficient continuous seeded cooling crystallisation process design, with the aim to deliver a robust, consistent process with tight control of particle attributes.