(56b) 3D Printing for Rapid Prototyping of Innovative Process Equipment for Pharmaceutical Crystallization

The development of pharmaceuticals involves various stages with preclinical and clinical trials. A short time-to-market is essential to maximize the patent protection and to avoid any loss in potential revenues.[1] Furthermore, most pharmaceuticals in development do not reach commercial manufacturing. However, for those pharmaceuticals that do reach market, efficient and novel processing equipment can provide a competitive edge. Hence, rapid prototyping of processing equipment during development is important to minimize time-to-market, while maximizing early learning on processing. 3D printing is an attractive technology to fabricate customized and novel processing equipment almost instantaneously. However, despite this potential, the use of 3D printing during early pharmaceutical process development is still in its infancy.

3D printing has found applications for the fabrication of micro-reactors and to some extent for mesoscale reactors as well.[2] In contrast to reactors, the use of 3D printing to fabricate innovative designs of separators has received limited attention. For example, for crystallization, which is a key unit operation in many pharmaceutical processes, no studies on the use of 3D printing for rapid prototyping have been reported to the best of our knowledge. Pharmaceutical crystallization is complicated by the need to optimize intrinsic crystal quality attributes such as size distribution, which affects the performance of downstream processes and possibly the efficacy of the final product. Optimization of crystallization requires control over various mixing processes. 3D printing can be a flexible and rapid method to fabricate innovative structures of crystallizers for optimized mixing at all relevant scales during pharmaceutical development.

The objective of this work is to develop and characterize 3D printed prototypes of innovative crystallization equipment with different structures for mixing. Two cases will be investigated. A common feature of both cases is that the mixing mechanism does not require moving parts, which makes fabrication with 3D printing attractive.

The first case involves a 3D-printed airlift crystallizer for protein crystallization. Protein crystallization in an airlift crystallizer has not been reported yet, but is attractive as protein crystals are generally more fragile in comparison to crystals of small-molecule active ingredients.[3] Therefore, mild and homogeneous mixing conditions are required, which can be provided by airlift columns due to the low maximum shear forces.[4] An airlift crystallizer was designed and fabricated with a desktop stereolithography (SLA) printer. The hydrodynamics of the column have been characterized for lysozyme as model protein. A sufficiently high upward velocity in the column demonstrates practical feasibility for protein crystallization in an airlift crystallizer. Next, the crystallization performance of the airlift crystallizer is characterized in this work and compared to a conventional stirred tank crystallizer.

The second case involves antisolvent and reactive crystallization in continuous flow. Rapid mixing is achieved by using static mixers. The effectiveness of kenics-type of static mixers has previously been demonstrated for anti-solvent crystallization of ketoconazole [5]. In this work, Y-mixers and komax-type mixers have been designed and fabricated using a desktop stereolithography (SLA) 3D printer. Preliminary studies on reactive crystallization of barium sulfate have been conducted, which demonstrate practical feasible and reduced agglomeration when using the komax mixer in comparison to when using a Y-mixer. The stability of many stereolithography resins used for 3D-printed structures is good for aqueous-based system. However, pharmaceutical crystallization often involves organic compounds. Therefore, this case particularly focuses on the use of various 3D printing techniques to address stability issues for organic solvents. In the long term, this research aims to develop a platform around 3D printing, which allows users to select, design and fabricate innovative crystallization equipment rapidly to achieve shorter time-to-market and intensified pharmaceutical crystallization.

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. 16242916).

References

[1] G. Reklaitis, J. Khinast, and F. J. Muzzio, “Pharmaceutical engineering science—New approaches to pharmaceutical development and manufacturing,” Chem. Eng. Sci., vol. 65, no. 21, pp. iv–vii, Nov. 2010.

[2] A. K. Au, W. Huynh, L. F. Horowitz, and A. Folch, “3D-Printed Microfluidics,” Angew. Chemie - Int. Ed., vol. 55, no. 12, pp. 3862–3881, 2016.

[3] S. Tait, E. T. White, and J. D. Litster, “Mechanical Characterization of Protein Crystals”, Part. Part. Syst. Charact., vol. 25, no. 3, pp. 266-276, Sep 2008.

[4] A. Soare, R. Lakerveld, J. Van Royen, G. Zocchi, A. I. Stankiewicz, and H. J. M. Kramer, “Minimization of attrition and breakage in an airlift crystallizer,” Ind. Eng. Chem. Res., vol. 51, no. 33, pp. 10895–10909, Aug 2012.

[5] A. J. Alvarez and A. S. Myerson, “Continuous plug flow crystallization of pharmaceutical compounds,” Cryst. Growth Des., vol. 10, no. 5, pp. 2219–2228, May 2010.