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.

As a demonstration of an alternative to the challenges faced with batch pharmaceutical manufacturing including the large production footprint and lengthy time-scale, we previously reported a refrigerator-sized continuous flow system for the on-demand production of essential medicines. Building on this technology, herein we report a second-generation, reconfigurable and 25 % smaller (by volume) continuous flow pharmaceutical manufacturing platform featuring advances in reaction and purification equipment. Consisting of two compact [0.7 (L)×0.5 (D)×1.3 m (H)] stand-alone units for synthesis and purification/formulation processes, the capabilities of this automated system are demonstrated with the synthesis of nicardipine hydrochloride and the production of concentrated liquid doses of ciprofloxacin hydrochloride, neostigmine methylsulfate and rufinamide that meet US Pharmacopeia standards.

Traditional pharmaceutical manufacturing is based on a complex supply chain that is vulnerable to spikes in demand and interruptions. Continuous pharmaceutical production in compact modules is a potential solution that allows for drug manufacturing when and where it is needed with significantly shorter lead times. As part of the Pharmacy on Demand (PoD) initiative, we demonstrate the potential for end-to-end manufacturing of multiple drug substances in reconfigurable devices, under common industrial constraints, and within a challenging manufacturing time frame. A new set of refrigerator-sized modules was constructed for the synthesis, isolation, and formulation of several drugs, with focus on achieving high manufacturing throughputs, and allowing for the production of pharmaceutical tablets. Their operation is demonstrated with the synthesis and formulation of USP-compliant tablets of diazepam, diphenhydramine hydrochloride, and ciprofloxacin hydrochloride, as well as liquid formulations of lidocaine hydrochloride and atropine sulfate.