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.

Microfluidic Crystallization for Screening of Spherical Particles of Pyraclostrobin

“…Collectively, LLPS has a kinetic advantage in competition with nucleation, consequently resulting in a prolonged nucleation induction duration. To overcome this nucleation barrier, our approach involves the incorporation of ultrasound and agitation within the microfluidic crystallization system, aimed at enhancing the crystallization process and assessing the influence of diverse factors on the production of spherical particles. , …”

“…To overcome this nucleation barrier, our approach involves the incorporation of ultrasound and agitation within the microfluidic crystallization system, aimed at enhancing the crystallization process and assessing the influence of diverse factors on the production of spherical particles. 47,48 3.3. Mixing Performance of Microchannels.…”

Acoustic Streaming to Control the Nucleation Kinetics of Paracetamol in a Tubular Microcrystallizer

“…Since one of the objectives of the presented work was to solely develop a nucleation section for a continuous microcrystallization platform (in a similar way as done before for a multiphase flow microcrystallizer , ), only a few larger crystals were produced and the majority of the obtained crystals were too small to be significantly affected by the acoustophoretic effect. Although measurement of the crystal size distribution was impossible, streaming did not seem to impact this product crystal size disparity considerably.…”

“…For sample collection from the microcrystallizer effluent, a similar procedure was followed as described by Devos et al: 42 the outlet flow of the microcrystallizer was filtered (Merck, MF-Millipore, 0.22 μm pore size) using a vacuum pump (VP 100 C Vacuubrand, VWR) to remove the mother liquor and to prevent further crystallization after collection. The filters were measured at the start of each experiment and after they were used (Mettler Toledo XS105 Dual Range balance, 0.01 mg precision).…”

“…55 Such recirculation flows are also characteristic for two-phase flow 10,55 and have been shown to affect nucleation of paracetamol from aqueous solution in microcrystallizers. 42,56 Nucleation is potentially impacted in two ways: first, through the introduction of zones with higher local fluid shear as shown in the previous section, and second, through changes in the residence time distribution. For instance, Valitov et al have recently shown that at low flow rates acoustic streaming changes the residence time distribution and increases the nucleation rate.…”