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.

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.

Crystallization at production scale (>10 kg) is typically a poorly understood unit operation with limited application of first-principles understanding of crystallization to routine design, optimization, and control. In this study, a systematic approach has been established to transfer an existing batch process enabling the implementation of a continuous process in an oscillatory baffled crystallizer (OBC) using ultrasound. Process analytical technology (PAT) was used to understand and monitor the process. Kinetic and thermodynamic parameters have been investigated for lactose sonocrystallization using focused beam reflectance measurement (FBRM) (Mettler Toledo) and mid-infrared spectroscopy (mid-IR) (ABB) in a multiorifice batch oscillatory baffled crystallizer (Batch-OBC). This platform provides an ideal mimic of the mixing, hydrodynamics and operating conditions of the continuous oscillatory flow crystallizer (COBC) while requiring only limited material. Full characterization of the hydrodynamics of the COBC was carried out to identify conditions that deliver plugflow behavior with residence times of 1−5 h. The results show that continuous crystallization offers significant advantages in terms of process outcomes and operability, including particle size distribution (mean particle size <1500 μm) of alpha lactose monohydrate (LMH), as well as reduced cycle time (4 h compared to the 13−20 h in a batch process). Continuous sonocrystallization was performed for the first time at a throughput of 356 g•h −1 for 12−16 h. During the run at near plug flow, with supersaturation and controlled nucleation using sonication, no issues with fouling or agglomeration were observed. This approach has demonstrated the capability to provide close control of particle attributes at an industrially relevant scale. 50 principle of OBC has been described elsewhere. 4,5 The basic 51 design comprises a tubular network containing periodically 52 spaced orifice baffles superimposed with oscillatory motion of a 53 fluid. Oscillatory flow mixing has been developed and 54 investigated as a process intensification technology to achieve 55 efficient and controlled mixing in tubular crystallizers. Unlike 56 conventional tubular crystallizers in which the mixing is caused 57 by the turbulent net flow, the mixing achieved in an OBC is 58 mainly obtained by fluid oscillations and thereby the residence 59 time distribution within the device can be adjusted by the 60 oscillatory conditions and net flow rate allowing longer 61 residence times in short reactors and hence is more suitable 62 for slower processes like crystallization. 7−12 Previous studies 63 have shown that processing in an OBC resulted a greater 64 regularity of crystal shape with fewer defects and better control 65 over the crystallization process. A recent review provides a 66 detailed description of OBCs for crystallization as well as 67 summarizing the relevant literature. 63 These are attributed to 68 the uniform mixing when compared to a batch stirred tank 69 system. 3 Batch to ...

Using antisolvent crystallisation of salicylic acid as the model process, we report our experimental investigation into the temporal and spatial steady states of solution concentration and mean crystal size in a continuous oscillatory baffled crystallizer. The evolutions of the two parameters over time and distance along the crystallizer are measured for a variety of operating conditions. The results show that the attainment of long term temporal and spatial stabilities (>100 residence times) for the solute concentrations are easily achieved, whereas the temporal steady states of the mean crystal size are more difficult to accomplish, even though the spatial steady states have been obtained. A simplified population balance model is applied to the experimental data for the determination of nucleation and growth kinetic parameters. From which both the solution concentration and the mean size were predicted and matched to experimental values reasonably well. In addition, we have identified and executed the conditions of long term steady states for extended operation of 6.25. h to produce close to 1. kg of crystal product with minimal variation in crystal size (±3.01. μm)

We report a method for observing and quantifying antisolvent crystallization (acetone/water system) of paracetamol in an oscillatory baffled crystallizer (OBC). With the help of optical means, paracetamol crystals passing the light sheet are recorded by a CCD camera. This allows the mass of crystals to be tracked with time and in turn the instantaneous and overall averaged crystal mass growth rates to be evaluated. By the standard sampling method, the overall averaged crystal growth rate and the percentage recovery of crystals were also determined. This work shows that there is a high correlation in data between the optical and the sampling techniques, validating the accuracy and reliability of the system. Our data are also consistent with previous work in this field.

This work aims to show the viability of applying video imaging techniques to the cooling crystallization of paracetamol in an oscillatory baffled crystallizer for the determination of the metastable zone width and crystal size distribution. From these data, the effects of supersaturation and mixing on metastable zone width and mean particle size are examined. Both sets of data are in good agreement with previous studies in a stirred tank and oscillatory baffled crystallizers. Finally, utilizing the Kubota's interpretation of metastable zone width, we demonstrated that the video imaging techniques are as sensitive to nucleation events as FBRM probes

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This work aims to show the potential of applying video imaging techniques to antisolvent crystallization of paracetamol in an oscillatory baffled crystallizer for the determination of crystal size distribution and mean crystal size with a high level of accuracy in comparison with the values measured with a Mastersizer. From these data, the effects of supersaturation, addition rate, and mixing on growth rate are examined and crystal growth kinetics extracted for various operational parameters. The kinetic data so generated are in good agreement with these from previous studies in stirred tank systems. It was found that the degree of supersaturation has the most significant effect on the overall growth rates, followed closely by the degree of mixing and then the rate of antisolvent addition. Both the kinetics and process data could be used as the tool for the design and operation of antisolvent crystallization.