Process Intensification through Continuous Spherical Crystallization Using an Oscillatory Flow Baffled Crystallizer

Abstract

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.

Particle design via spherical agglomeration: A critical review of controlling parameters, rate processes and modelling

“…The authors, therefore, implied that increased agglomerate collisions contribute to the agglomerate compaction process. Peña et al [59] found that a high concentration of solids did not yield efficient agglomeration, or operation, for their benzoic acid system using a continuous oscillatory flow baffled crystalliser; requiring operating conditions that significantly differed from previous benzoic acid studies in various systems to achieve spherical agglomeration [37,46,56].…”

Mixing performance in continuous oscillatory baffled reactors

“…However, these recom mendations are not always used in practice. For example, many continuous crystallization processes in oscillatory baffled reactors have been operated with velocity ratios near the upper limit of the recommended range, or even with higher values, to ensure solid suspension and uniform particle size and distribution (Briggs et al, 2015;Kacker et al, 2017;Peña et al, 2017;Siddique et al, 2015;Zhao et al, 2014). Indeed, whilst RTD mea surements are a good means to characterize mixing in COBRs for operations that require long residence times (e.g.…”

Positioning for a sustainable future—Role of chemical engineers in transforming pharmaceutical process development

“…Some of the pain points around management of secondary nucleation issues that are inherent to agitated crystallizers need to be addressed. Impeller free crystallizers such as oscillatory baffled crystallizers 39,40 and fluidic oscillators 41 pose viable technology options and need concerted efforts for further development and consistent deployment.…”