Holistic point of view on the Crystallization process from a curious crystallographer scientist.

I am back from my vacation in Amazonia Forest with Yawanawa tribe, an amazing experience, and I hope the ones interested can enjoy before die. ?Now I will keep the newsletter giving a holistic point of view in crystallization. For sure it is not an easy task, it is a wide range topic, and it has been developing fast in the last few years. So, my hope here is to bring some important points for the subscribed to this newsletter and help than in the design of the process. I invite the ones who want to share information with us all in the comments or send it privately.

The crystallization process is important for the pharmaceutical industry, in synthetic as well as protein-based therapeutics, cosmetic, agrochemical, and food industries. The main challenge of crystallization is its particularity for each molecule, and for each system a comprehension on the Kinetics, thermodynamics, and hydrodynamics.

I remember during my chemistry PhD, some of the engineering graduation students were explaining to me about the unit process and there was a state in a stirring system where a vortex can be formed. The formation of a vortex can lead to a flow unsteadiness and non-uniformity, for example incorporating air. And if like me from this you are able to understand that this is the iceberg point in which I am completely aware of how intricate is the crystallization process.

The crystallization process starts with nucleation, originating from a supersaturated solution. The metastable zone is where the nucleation and after growth give origin to the solid. There are several methods for crystallization, that are used to access the supersaturated solution, like cooling, addition of antisolvent, seeding, chemical reaction, evaporation, and others.

To choose a solvent to obtain a solution we need to attend to regulatory aspects (ICH guideline Q3C R8 In the pharmaceutical industry for example) as well as chemical ones. At a point the solute must be chemically soluble in the solvent, from another point of view, it needs to be secure for the chosen application. There as some platforms that can be used to choose the best solvent.

For each method and system specific crystallizers can be selected, like fluid bed crystallizers, stirred tank crystallizers (Batch and/or continuous – CSTR), Crystallizers with a Scraped Heat Exchanger, and so on.

The importance of controlling the process is to adjust critical solid parameters, such as crystal shape, polymorph, co-crystal, salt, and particle size. With the objective of obtaining a pure product under selected specifications, minimizing costs, with fewer process steps, and increasing yield. Sometimes some choices have to be made, for example, to have a more easily manipulated process the cooling method can be chosen over antisolvent, even though yield can decrease, it is a company strategy, that will be incorporated into the process design.

With the development of process analytical technology (PAT), many inline analyses can be done, reducing time and process cost.

So I hope with the overview you can understand the holist point of view on crystallization, is just a summary of important points about crystallization, and for sure the the design and scale up is always a challenge.