Secondary nucleation can bring the crystallization process into a more easily controlled state, and it is playing an important role in controlling crystal size distribution, polymorphism, and chirality of the crystal products, no matter whether in a batch or continuous crystallizer. Therefore, in this review, we revisit the research of secondary nucleation in the past 30 years to understand the fundamentals and application of secondary nucleation. First, we summarize the sources of secondary nuclei, that is, how secondary nucleation occurs. Then, we discuss the secondary nucleation threshold from the perspective of the metastable zone widths which are associated with the nucleation mechanism. Furthermore, we discuss how to employ secondary nucleation to regulate the properties of crystalline products (particle size distribution, crystal polymorphism, chirality, etc.). More importantly, we also discuss how polymorphism and chirality can act as a probe to explore the origin of secondary nucleation. Finally, we give conclusions and outlooks, mainly on the molecular nucleation mechanism and crystal growth dead zone of the current topic of secondary nucleation.

In this contribution, we experimentally determined the metastable zone width (MSZW) of adipic acid (AA) in different polar solvents to reveal the nucleation behavior. We performed analyses for different cooling rates, saturation temperatures and polar solvents. The findings showed that the MSZW increased as the cooling rate increased, or saturation temperature or polarity decreased. Here, we suggest that the hydrogen bond donor capacity decreases as the polarity of the solvent decreases, which weakens the solute and solvent interaction and makes the desolvation process more difficult during nucleation. Furthermore, we found that the MSZW is mainly determined by the cooling rate, when the cooling rate is large enough. On account of the classical nucleation theory, it was found that the sizes of the critical nucleus and Gibbs nucleation energy do not increase monotonously with increasing driving force. Moreover, this study confirms that solid–liquid interface tension is associated with crystallization driving force.