Experimental nucleation rate determination for crystallization in solution has been acknowledged as an important topic for a long time, as it improves the design and control of industrial crystallization processes, and offers insights into the mechanisms of nucleation. Characterization of nucleation rates in large volume batch crystallizers has been widely studied in the past, which has led to the development of a variety of models linking the nucleation rate to the metastable zone width and induction time. These methods remain important due to their role in industrial crystallization. More recently, the use of microfluidic platforms has resulted in the development of methods to obtain nucleation rates based on the stochastic nature of nucleation. This has opened new pathways for understanding nucleation on a molecular level. This review presents a critical overview of nucleation rate determination methods: large volume batch crystallizer models (Part I), and microfluidic and microvial models (Part II) are presented in terms of equations, advantages and limitations. Published experimental nucleation rate values are summarized (SI). A critical discussion of experimental nucleation rate determination is given (Part III). The objective of the review is to be a starting point for researchers attempting to experimentally characterize nucleation behavior.

Nucleation kinetics play a fundamental role in the design and control of crystallization processes. Understanding how crystallization conditions impact different nucleation mechanisms and the overall nucleation kinetics will lead to...

Cooling crystallization of small organic molecules from solution is an important operation for the separation and purification of drug products. In this research, shear-induced nucleation from a supersaturated solution is...

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.

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