Studying Secondary Nucleation for the Intensification of Continuous Crystallization

Project Information

SNICC

Grant agreement ID: 788607

DOI

10.3030/788607

Project closed

EC signature date 30 May 2018

Start date 1 July 2018

End date 31 March 2024

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 2 500 000,00

EU contribution

€ 2 500 000,00

Coordinated by

EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Switzerland

Periodic Reporting for period 4 - SNICC (Studying Secondary Nucleation for the Intensification of Continuous Crystallization)

Reporting period: 2023-01-01 to 2024-03-31

Summary of the context and overall objectives of the project

Many products in the chemical, food and pharmaceutical industry are produced as powders through a crystallization process. Continuous crystallization is used for the large-scale production of sugar, table salt, adipic acid, etc. and in the transition from batch to continuous manufacturing in the pharmaceutical industry. In continuous crystallization, the dominant pathway for the formation of crystals is secondary nucleation, whereby the formation of new crystals is promoted by the presence of existing ones.
Secondary nuclei may be formed at different rates from an existing crystal due to collisions or from the solution layer around it due to fluid shear. Understanding these complex phenomena latter requires clarifying the link between the behavior of a parent crystal at the microscale and the collective behavior of the ensemble of crystals suspended in a specific crystallizer.
The project SNICC intends to unveil the microscale mechanisms of secondary nucleation, and to bring its scientific understanding to a level where it can be exploited to model, design, operate, optimize and control continuous crystallization processes at any desired scale. To do so, SNICC has followed a three-pronged approach. First, mechanistic models have been developed that allow predicting the rate of secondary nucleation as a function of the crystallizer’s operating conditions and of the physico-chemical properties of the compound that is crystallized. Second, guided by these models, the most relevant factors that govern the secondary nucleation rate, have been identified and studied experimentally in detail. Third and finally, continuous crystallization has been studied at the process-scale through both experiments and modeling, whereby the models have been informed by the insights on secondary nucleation achieved at the micro-scale.
Thanks to the mechanistic nature of the models developed, the conclusions drawn from these studies are considered to be of general relevance, i.e. they apply to a wide range of compounds (organic and inorganic) and crystallizers (from microfluidics over vial-scale to liter-scale and beyond). The understanding of secondary nucleation achieved here will have a major impact on both the science of crystallization and the related industrial processes.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Five groups of activities have been performed: the study of fundamental phenomena at the micro-scale, namely secondary nucleation (i) from the solution layer that surrounds the parent crystal, and (ii) from the parent crystal itself; (iii) the experimental characterization of the relevant properties of secondary nuclei and their evolution; finally at the process-scale, (iv) the modeling of continuous crystallizers and (v) the development of experimental protocols and modeling tools. The main achievements for each activity are summarized here, while the details are reported in a total of 26 papers to date, to which eleven doctoral students have contributed.
Regarding the first two activities, two mechanistic models have been developed that describe how secondary nuclei are formed, either by mechanical means, or by interfacial phenomena in the solution layer. This highlights a key difference: if secondary nuclei are formed mechanically, they are of the same solid form as the parent crystal (same polymorph or handedness). If they form in the solution layer, they may assume any polymorphic or chiral form. Understanding the relative contributions of these two mechanisms is of immediate practical relevance for the pharmaceutical industry, where polymorphism and chirality are of paramount importance.
Regarding the third activity, a new monitoring device has been developed and utilized. This can detect both crystals and amorphous assemblies of molecules at the nanoscale. While the device was envisioned for the study of secondary nucleation only, it was found to be suitable for the monitoring of primary nucleation as well. Coupled with complementary modeling studies, it has helped to elucidate the relative importance of the two types of nucleation in crystallization.
In the scope of the fourth activity population balance models of continuous crystallization have been formulated and implemented. Thanks to a new theoretical framework, the stability of steady states in continuous crystallizer could be characterized effectively. Thorough numerical and experimental work has been carried out to confirm the theory.
Finally, the fifth activity focused on the development of experimental protocols to operate continuous crystallizers considering the relevant set of operational challenges and opportunities, and of modeling tools, which have partially been made available to the public, e.g. in the case of computational fluid dynamics simulations.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Progress beyond the state of the art has been achieved, typically by employing a combination of theory, simulation, and experiments.
At the microscale, the understanding of the relevant secondary nucleation mechanisms has been significantly deepened through the development of mechanistic models. These models have guided our experimental work, as they have revealed the important role of agitation and of the crystal’s surface properties in secondary nucleation. The availability of mechanistic models instead of empirical ones is expected to lead to significant improvements in the understanding of particularly of continuous crystallization.
In this spirit, we developed a new monitoring device that is able to observe the early stages of nuclei formation at the nano-scale, in the case of both secondary and primary nucleation, and to help estimating nucleation rates, which are notoriously difficult to obtain.
At the process-scale, we made significant progress in understanding the behavior of continuous crystallization processes of compounds that exhibit multiple solid forms (e.g. chiral and polymorphic species). In particular, we derived a new theory that predicts the stable steady state in continuous crystallizers as a function of operating conditions and crystallization kinetics. This theory, supported by experiments and simulations, is useful in providing ranges of operating conditions in which individual pure solid forms, both stable and metastable, are crystallized.
Finally, considering the crystallization of chiral compounds, a breakthrough has been achieved in clarifying the governing mechanism of solid-state-deracemization, which refers to a type of crystallization process in which a racemic suspension is transformed into an enantiopure one. Through the combination of theory, simulation, and experiments we could show that its underlying mechanism is both simple and ubiquitous and indeed, it does not even require secondary nucleation. This promises to support the further use of this process in industry, and to conceptualize the role it might have played in the origin of homochirality on Earth.

Mechanisms active during the growth of a crystal in a suspension.

Microscope images of L-glutamic acid (LGA) crystals produced in a continuous crystallizer.