(284d) Process Intensification through Continuous Spherical Crystallization Using an Oscillatory Baffled Crystallizer

Of current interest in the pharmaceutical industry is the development of continuous processes either within or for the manufacture of final drug products. These processes include, but are not limited to, drug synthesis, crystallization, formulation and tableting/encapsulating. Crystallization is the key link in going from drug synthesis to final formulation, and can often be the bottleneck in downstream process efficiency. For these reasons, there has been increased importance in the development and control of continuous crystallization systems of active pharmaceutical ingredients to produce crystals of good physical, processing, and biopharmaceutical properties. Continuous spherical crystallization (CSC) is a process intensification technique that can address many of the present flaws of traditional crystallization systems.

Peña & Nagy¹ studied and showed the benefits of CSC as a process intensification technique whereby both internal (primary crystals) and external (agglomerates) properties can be controlled experimentally through a decoupled CSC approach in a two-stage mixed suspension mixed product removal (MSMPR) crystallizer; providing the means by which both biopharmaceutical (bioavailability, dissolution) and manufacturing (flowability, filtration, drying) properties can be simultaneously adapted to meet desired quality specifications. Tahara et al.² also presented the value of the CSC technique using a one-stage MSMPR to make spherical API particles with a recycle stream; allowing for reduced anti-solvent consumption given many crystallization systems require low solution to anti-solvent ratios. Aside from these recent studies, previous CSC of a model drug compound was first carried out by Kawashima et al.³

Herein a novel concept and method in the area of process intensification though continuous spherical crystallization is proposed, which is based on performing crystallization/spherical agglomeration in oscillatory baffled crystallizer (OBC) system. OBCs are similar to plug flow crystallizers (PFCs) in that they are both tubular crystallizers, however, the OBC has periodically spaced orifice baffles with oscillatory motion overlapped on net flow.⁴ This allows for operations similar to PFCs without the high flowrates, high residence times and long crystallizer length while maintaining good mixing. The system allows for both coupled and decoupled nucleation, growth and agglomeration mechanisms. Decoupling through spatially distributed solution, solvent, anti-solvent and bridging liquid addition will offer more degrees of freedom for the control of each mechanism. This allows for products tailored to biopharmaceutical benefit and efficacy (e.g. bioavailability, dissolution, morphology) and processing efficiency (e.g. filtering, drying, & friability), while continuously producing particles with desired properties in an efficient manner and productivity at the manufacturing level.

In this work, a model oscillatory baffled crystallizer (OBC) consisting of seven segments was evaluated for both coupled and decoupled spherical crystallization systems. For coupled systems nucleation, growth and agglomeration occur from the onset as the solution contains bridging liquid. For spatially distributed (decoupled) systems nucleation and growth occur in the first four segments due to solution and anti-solvent addition, while bridging liquid is added at the end of the fourth segment making the final three segments agglomeration zones. The OBC will be evaluated for feasibility, control of crystallization mechanisms and final product properties.

1. R. Peña; Z. K. Nagy. Process Intensification through Continuous Spherical Crystallization Using a Two-Stage Mixed Suspension Mixed Product Removal (MSMPR) System. Crystal Growth & Design, 2015, 15(9), 4225-4236.
2. K. Tahara; M. Oâ??Mahony; A. S. Myerson. Continuous Spherical Crystallization of Albuterol Sulfate with Solvent Recycle System. Crystal Growth Design, 2015, 15, 5149â??5156.
3. Kawashima, Y.; Kurachi, Y.; Takenaka, H. Preparation of spherical wax matrices of sulfamethoxazole by wet spherical agglomeration technique using a CMSMPR agglomerator. Powder Technology, 1982, 32, 155â??161.
4. S. Lawton; G. Steele; P. Shering; L. Zhao; I. Laird; X.-W. Ni. Continuous crystallization of pharmaceuticals using a continuous oscillatory baffled crystallizer. Organic Process Research & Development, 2009, 13(12), 1357â?? 1363.