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Studying Secondary Nucleation for the Intensification of Continuous Crystallization

Periodic Reporting for period 3 - SNICC (Studying Secondary Nucleation for the Intensification of Continuous Crystallization)

Periodo di rendicontazione: 2021-07-01 al 2022-12-31

Many products in the chemical, food and pharmaceutical industry are produced as powders through a crystallization process.
Continuous crystallization has been for decades the process of choice for large-scale production, for instance of sugar, table salt, adipic acid, and has become more recently a key component of the new paradigm, i.e. the continuous manufacturing of active pharmaceutical ingredients.
All product crystals of continuous crystallization processes are formed through secondary nucleation, which is both ubiquitous and elusive.
Research has left several key questions unanswered, such as about where and how secondary nuclei are formed, either from the parent crystal due to collisions or from the solution layer around it due to fluid shear; or about the rate at which secondary nuclei are generated, with which properties, and under which conditions; or, also, about the coupling between the parent crystal microscale and the collective behavior of the ensemble of crystals suspended in a specific continuous 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.
It aims at creating a comprehensive knowledge about secondary nucleation at the microscale, applicable to any type of compound, and at establishing guidelines for the intensification of continuous crystallization, based on the use of newly developed full models of different types of continuous crystallizers.
This will have a major impact on both the science of crystallization and the related industrial processes.
Building on the recognized experimental and theoretical expertise on crystallization at all relevant scales of the PI and his lab, a team consisting of 4 PhD students and 2 postdocs will work for five years on this challenging, interdisciplinary project.
The SNICC project has engaged so far seven PhD students, two of which, who have already graduated, only partially, and five full time (with their graduation coming in the second part of the project. It has also enaged a post-doc research associate. There are still funds to hire 1-2 personds between now and the end of the project.
The overall aim of SNICC is that of improving the performance of continuous crystallization processes, through enhanced control of secondary nucleation. To this aim, two complementary objectives have been defined: first, at the micro-scale the understanding and modelling of the different mechanisms yielding secondary nuclei, as they are triggered by the interaction of particles among themselves, with the internals of the crystallizer and with the fluid flow; second, at the macro-scale the investigation and description of the behaviour of the suspension in the crystallizer, so as to be enable the prediction of the macro-scale events that trigger the micro-scale generation of secondary nuclei.
The work so far has covered both the microscale and the macroscale, through both theoretical and experimental activities.
At the microscale, we have been able to elucidate two mechanism of formation of secondary nuclei, by attrition and by interaction of the pre-nucleation clusters with the surface of the seed crystals. The impact of the attrition based mechanism on the evolution crystallization in an experimental set-up has also been assessed. A novel set up for the characterization of pre-nucleation clusters has been designed, built up and tested, and is now ready for measurements.
At the macroscale, we have set up a number of tools based on computational fluid dynamics, which are allowing to operate batch and continuous crystallizers in a more controlled way. Some of the results obtained through computational fluid dynamics about the fluid dynamics of particle-laden suspensions have been validated using advanced spectroscopic techniques.
Moreover, we have extended the investigation of fundamental aspects of nucleation, using microfluidic devices, and we have exploited computational fluid dynamics to characterize and understand precipitation processes, including crystallization by spherical agglomeration.
Summarizing, in the first part of the project we have created background knowledge and a suite of tools necessary in the course of the second part of the project. As such the first part of the project has been successful, though - due to the preparatory character of some of the things we have done - the output in terms of publications is still somewhat limited.
Both at the microscale and at the macroscale, progress beyond the state of the art has been achieved.
At the microscale, the secondary nucleation mechanisms that have been elucidated are either new or better understood. The set up for the measurement of subcritical clusters is also novel, and promises to deoliver important expeirmental results that will be comparatively assessed with the theoretical models developed.
At the macroscale, the main progress is related to the coupling of computational fluid dynamics and population balance equations, in combination with experimental measurements. We have been able to exploit the results of computational fluid dynamics in a very effective way to guide the experimentation.

There are three directions in which we expect major results in the second part of the project:
- the integration of the microscale and and macroscale reults into better and more accurate first-principles models of crystallization processes; such models will have to be validated experimentally;
- the design and optimization of better continuous crystallization processes thanks to a better understanding and control of secondary nucleation and of the other concomitant mechanisms;
- the application of all these findings to a number fo systems of interest, namely pharmaceuticals (e.g. for a better control either of the size and shape of crystals, or of polymorphism), nutricionals (e.g. lactose), chiral compounds (for the continuous purification of one enantiomer through solid state deracemization), freeze drying (i.e. insofar nucleation phenomena happening in the freezing vials are a combination of primary and secondary nucleation).

We are confident that these objectives can be achieved, thus fulfilling the goals and expectations of the project.