(567a) 3D Printed Static Mixers for Continuous Reactive Crystallization

Crystallization is an important unit operation in the pharmaceutical industry for separation and purification of intermediate chemical compounds and active pharmaceutical ingredients. The driving force for crystallization is the supersaturation of the solution, which is defined by the difference between the solute concentration and its solubility. There are various methods to create supersaturation. In anti-solvent or reactive crystallization, different process streams are mixed together to generate supersaturation. Consequently, mixing plays an important role in the performance of anti-solvent or reactive crystallization. Initially, mixing is required to obtain a homogeneous solution to obtain predictable bulk nucleation and to prevent local nucleation, which may occur due to concentration gradients¹. Once crystals are formed, mixing is needed to maintain the crystals in suspension. Plug-flow behavior is typically desired to provide a uniform residence time for each crystal and hence deliver uniform product quality attributes such as crystal shape and size. Tubular crystallizers can provide plug-flow behavior if mixing is fast in radial direction but slow in axial direction. One of the methods to approach such mixing patterns involves static mixers. A kenics-type static mixer has previously been demonstrated to be useful for achieving plug-flow conditions for anti-solvent crystallization of ketoconazole.² However, other types of static mixers such has Komax, SMX, or low pressure drop (LPD) mixers have not been studied for their application as a tubular crystallizer.³ Additionally, the mixing elements of these static mixers can be optimized for a given application.⁴ Finally, the mixing requirements may change when the process material flows from the entrance to the outlet of the tubular crystallizer. In particular, in the first part of the crystallizer, rapid mixing of liquid process streams needs to be achieved, whereas large crystals need to be kept in suspension further downstream. Fouling and plugging should be avoided when the crystal mass increases. Therefore, when using a static mixer as a tubular crystallizer, the structure and dimensions of the internals may need to change for optimal operation. These requirements for customization and the absence of any moving parts call for 3D printing to be used as the preferred fabrication method of tubular crystallizers based on static mixers.

The objective of this work is to design, fabricate and characterize tubular crystallizers with different designs for static mixing for reactive crystallization. Stereolithography is identified as the most suitable 3D printing technique among the four major techniques, because it allows for fabrication of leak-proof parts and easy removal of uncured resin from the flow channel.⁵ Reactive crystallization of barium sulphate is conducted in a Y-mixer and komax-type mixer fabricated using a commonly available desktop stereolithography 3D printer (Form 2, FormLabs) with clear resin. The results demonstrate practical feasibility of using 3D printing to fabricate innovative tubular crystallizers and a reduced agglomeration is observed in the komax mixer compared to a conventional Y-mixer. Subsequently, reactive crystallization of an active pharmaceutical ingredient, salicylic acid from sodium salicylate and an acid, will be investigated. COMSOL simulations show that a kenics-type static mixer with a standard design provides faster mixing compared to a Y-mixer, komax or a LPD mixer. COMSOL simulations will be used to optimize the different static mixers for the rate of mixing and to minimize zones with low liquid velocity where crystals might settle. Finally, the crystallization performance in terms of yield, crystal size distribution and degree of agglomeration will be characterized experimentally in the 3D printed tubular crystallizer. This work demonstrates a novel type of application of 3D printing in which there is a clear benefit of customization and fabrication speed.

Acknowledgement: The work described in this abstract was supported by a grant from the Research Grants Council of the Hong Kong Special Administrative Region, China, Project No. 16214418.

References

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