Characterization of a Modular Microfluidic Section for Seeded Nucleation in Multiphase Flow

Abstract

We present a proof-of-concept modular nucleation section for seeded multiphase flow crystallization of an active pharmaceutical ingredient. The setup can be used in four different modes of operation (with or without off-line prepared seeds and with or without a stream of microbubbles). The setup is characterized to provide insights into the design and operation of crystallization processes. First, the performance of the off-line continuous seeding platform is established via the seed delivery efficiency for constant and oscillatory flows. Second, the yields of seeded and unseeded crystallization are evaluated in the presence and absence of microbubbles. A statistically significant increase in the net crystal mass and net yield was measured when comparing unseeded and seeded crystallization, which can be attributed to the increased nucleation rates as a result of secondary nucleation. Third, the clogging behavior of the presented continuous microcrystallizer is discussed. Finally, also the crystal size distribution is analyzed: the mean crystal size decreases for both single- and two-phase flow when seeds are introduced. The presence of microbubbles resulted in a higher net yield and slightly smaller crystals compared to that of the single-phase flow. This work highlights the importance of a holistic characterization approach for continuous microfluidic crystallizers.