Microfluidic crystallization is a promising method to produce active pharmaceutical ingredient (API) crystals of extremely narrow size distribution and controlled polymorphic form. The microfluidic crystallization system consists of fine Teflon capillary tubes (50 to 300 µm I.D.) and a T-junction and were originally designed and used for chromatographic applications. A continuous oil phase and a supersaturated aqueous phase are introduced to a T-junction where the aqueous phase is segmented into monodisperse drops. Nucleation and growth occur in these very small, uniformly sized drops under highly controllable temperature, flow and anti-solvent addition conditions. By confining crystal growth, controlled nucleation and growth without agglomeration is achieved and effects of growth rate dispersion are overcome. The novelty of the process was shown by production of lactose and lysozyme crystals (Dombrowski et al., 2007 and Dombrowski, 2007). The process is now used to produce seed API crystals of a controlled polymorphic form. Flufenamic acid is used as the model API. The key point in microfluidic crystallization is to obtain one crystal per one drop. Using temperature cycles (applying different temperatures for nucleation and growth), the process is optimized to increase overall nucleation rates without producing multiple crystals in a single drop.

References

Dombrowski, R. D, Litster, J. D, Wagner, N. J and He, Y. (2007). Crystallization of alpha-lactose monohydrate in a drop based microfluidic crystallizer, Chem. Eng. Sci., Vol 63, pp 4802-4810.

Dombrowski, R. D. (2007) Crystallization in a Drop Based Microfluidic Crystallizer, Ph.D Thesis, The University of Queensland.