(301c) Fluid Shear-Induced Secondary Nucleation in the Context of Solution Crystallization: Fact or Fiction?

Secondary nucleation is defined as the crystallization phenomenon in which the formation of new crystals is catalyzed by the presence of priorly formed ones. Despite being recently recognized as the most dominant crystallization phenomenon in industrial crystallizers, a profound fundamental understanding of its underlying mechanism remains lacking [1]. Nevertheless, more insights into how secondary nucleation takes place, would be invaluable for a plethora of industrial applications: ranging from the production of agrochemicals and bulk chemical catalysts, to around 90% of all pharmaceutical products [2].

Although it may appear trivial at first sight, experimental studies investigating the fundamentals of secondary nucleation are considered to be among the most challenging ones in the field of solution crystallization [3]. This is because the absence of multiple interfering crystallization phenomena has to be ensured, and partly explains the lack of fundamental knowledge on the topic. All these interferences need to be eliminated before valuable conclusions can be drawn on the studied secondary nucleation mechanism.

The main aim of this work is to isolate and experimentally study one of these proposed secondary nucleation mechanisms: fluid shear-induced secondary nucleation. This specific mechanism has been claimed to be experimentally detected by several scientists and hypothesizes that secondary crystals originate from a complex ‘crystal-solution boundary layer’ around seed crystals present in solution [4-6]. Fluid shear is then considered sufficient to sweep ‘aggregates’ present in this complex boundary layer into the liquid bulk, where they grow towards secondary crystals [7].

To overcome the aforementioned issue of interfering crystallization phenomena, this study presents five experiments performed using custom-made setups, all specifically designed to isolate fluid shear-induced secondary nucleation.

The innovative aspect of this work lies in the adopted experimental procedures. While literature mainly focuses on avoiding attrition (i.e. crystal breakage), it was opted here to take the rigorousness of the control experiments for (1) initial breeding and (2) primary nucleation one step further. On one hand, different washing procedures were tested to identify their effectiveness in eliminating initial breeding. On the other hand, the usage of an inert object with the same shape as seed crystals (to mimic locally increased fluid shear values) was pioneered here. Where initial breeding describes how small crystalline fines detach from seed crystal surfaces upon introduction in solution, primary nucleation explains how crystals form directly in bulk solution.

Despite all five experiments being specifically designed to isolate fluid shear-induced secondary nucleation, the intended secondary nucleation mechanism could not be experimentally found. Moreover, individual experiments each spotlight one of the weak spots identified in experimental procedures from literature. While the first two experiments indicate the importance of selecting an adequate seed crystal washing procedure (initial breeding), the following two experiments stress the need for numerous primary nucleation control experiments. Interestingly, the last experiment hints at another unexpected interference: high enough fluid shear values can also cause seed crystal breakage or attrition. Overall, these results clearly suggest that the phenomenon of fluid shear-induced turns elusive when adhering to a set of control experiments that are more strict than currently present in literature.

Although these results cannot serve as definite proof for the possible inexistence of fluid shear-induced secondary nucleation, the followed experimental procedures provide a nuanced starting point for a broader discussion on how control experiments should be correctly executed in this research field. Indirectly, these controversial results also fuel a much broader ongoing debate on the working mechanisms of secondary nucleation.

[1] Hoffmann, J. et al. Faraday Discuss. 235, 109–131 (2022)

[2] Erdemir, D. et al. Acc. Chem. Res. 42, 621–629 (2009)

[3] Anderson, M. W. et al. Faraday Discuss. 235, 219–272 (2022)

[4] Yousuf, M. et al. Cryst. Growth Des. 18, 6843–6852 (2018)

[5] Cashmore, A. et al. Cryst. Growth Des. 24, 4975–4984 (2024)

[6] Anwar, J. et al. Angew. Chemie Int. Ed. 54, 14681–14684 (2015)

[7] Powers, H. E. C. Nature 178, 139–140 (1956)