Drug substance purification by crystallization is a key interface in going from drug substance synthesis to final formulation and can often be a bottleneck in process efficiency. There has been increased importance in the development of continuous crystallization systems of active pharmaceutical ingredients to produce crystals with targeted physical and biopharmaceutical properties. Continuous spherical crystallization (CSC) is a process intensification technique that can address many of the present flaws (e.g., size distribution, downstream processing efficiency) of traditional crystallization systems. In this study, a novel concept and method in the field of process intensification through continuous spherical crystallization is proposed. This study is based on performing crystallization/spherical agglomeration in an oscillatory flow baffled crystallizer (OFBC). OFBCs are comparable to plug flow crystallizers (PFCs) in that they are both tubular crystallizers; however, the OFBC has periodically spaced orifice baffles with oscillatory motion overlapped on the net flow. Independent crystallization mechanisms can theoretically be achieved through spatially distributed solution, solvent, antisolvent, and bridging liquid addition, offering more control of each mechanism. However, our studies showed that the OFBC allowed for spatially distributed addition of solvents but achieving control of each mechanism individually was not attainable due to the back mixing of the system.

Oscillatory flow strategies through baffled tubular reactors provide an efficient approach in improving process kinetics through enhanced micromixing and heat transfer. Known to have high surface area to volume ratios, oscillatory flow baffled reactors (OFBR) generate turbulence by superimposing piston driven oscillatory flow onto the net flow generated by a pump. By tuning the oscillating parameters (amplitude and frequency), one can tailor the residence time distribution of the system for a variety of multiphase applications. Using a microscope camera, principal component image analysis, and pulse tracer injections, a novel noncontact approach has been developed to experimentally estimate dispersion coefficients in two geometrically different systems (DN6 and DN15, Alconbury Weston Ltd.). The paper also introduces for the first time a novel scaled-down version of the commercially available DN15 OFBR, the DN6 (about 10 times smaller scale), and provides a comprehensive experimental investigation of the effect of oscillation parameters on the residence time distributions (RTD) in both systems. The oscillation amplitude was found to have a significant positive correlation with the dispersion coefficient with 1 mm providing the least amount of dispersion in either system. Oscillation frequency had a less significant impact on the dispersion coefficient, but optimal operation was found to occur at 1.5 Hz for the DN6 and 1.0Hz for the DN15. Until now, OFBR literature has not distinguished between piston and pump driven flow. Pump driven flow was found to be ideal for both systems as it minimizes the measured dispersion coefficient. However, piston driven turbulence is essential for avoiding particle settling in two phase (solid-liquid) systems and should be considered in applications like crystallization.

Continuous protein crystallization is a cost-effective alternative to traditional chromatographic purification techniques. However, proteins characteristically have slow growth rates, requiring long crystallization times to generate particles large enough for efficient isolation. In this work, spherical crystallization using an emulsion solvent diffusion (ESD) based methodology is proposed to produce large lysozyme agglomerates in an oscillatory baffled crystallizer (OBC). Process sensitivity analysis was performed to investigate the effect of the process parameters on the product's crystal size distribution at two different scales. The concentration of ethanol in the bulk phase was found to have a significant effect on the crystallization kinetics, as its diffusivity drives supersaturation at the droplet interface. Although controlling supersaturation is important in determining product quality, maintaining droplet suspension near the injection site is critical for process longevity, as fouling is most likely to occur in this high supersaturation region. Similarly, in scaling this process, the ratio of droplet diameter to tube diameter plays a significant role in the formation of encrust. Increasing the size of the droplets, relative to the diameter of the system, increases the role of wall effects in distorting the final product quality. Overall, these tunable process parameters make the OBC an ideal platform for spherical protein crystallization.

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Fouling, encrustation, and lack of polymorphic form control are some of the major drawbacks of continuous oscillatory baffled crystallizers (COBCs), which can lead to clogging, undesired crystal form generation, and process failure. To counter these drawbacks, seeding with crystals is a methodology to not only control nucleation mechanism and crystal size distribution (CSD) but also provide polymorphic form control. Consistent manual preparation of seeds for continuous crystallization is labor-intensive and often economically infeasible. Furthermore, any fluctuations of seed quality can impact the startup dynamics. In this work, a proof-of-concept and the benefits of continuous in situ seed generation was demonstrated with an integration of a mixed suspension mixed product removal (MSMPR) crystallizer with a COBC via a continuous combined cooling antisolvent crystallization (CCAC). First, a CCAC solubility design space of metastable (form II) and stable forms (form I) of ortho-aminobenzoic acid was developed to identify operating regimes for selective polymorphic form generation. Second, the in situ form I seed generation experiments, with the COBC, prolonged steady-state generation of the crystal product for more than eight residence times. The crystal product generated from the combined system with segmented cooling had a higher mean size and narrower size distribution when compared to the product obtained from a single-stage MSMPR experiment. Polymorphic control coupled with continuous seed generation in the combined system generated a uniform crystal product with no seed wash out occurring. Lastly, the importance of the method of slurry transport for the combined system was highlighted in experiments utilizing mechanical pump transfer compared to gravimetric transfer. Overall, these proof-of-concept experiments demonstrated the feasibility and benefits of using the integrated MSMPR–COBC crystallization system, utilizing the MSMPR crystallizer for continuous in situ seed generation providing for the robust operation of the COBCs.