Solvent and Crystallization

In this article, I would like to highlight the importance of solvent for the crystallization process, but I couldn’t find a better introduction to the theme as well described by Louis J Diorazio, David R. J. Hose, and Neil K Adlington, in their paper, Towards a more holistic framework for solvent selection:

“From the earliest training, chemists learn how solvent choice can affect reaction mechanisms, kinetics and stereo-, regio- and chemoselectivity patterns during synthesis steps. When tasked with developing their own process, the student soon learns however that it is not just synthetic steps that are affected by solvent choice. Molecular properties such as pKa, partitioning and azeotropic drying are all solvent-dependant and can significantly affect work-up and isolation. Despite this, it is all too easy for solvent considerations to be limited to dissolution of reaction components, operating temperature window and minimizing solvent residues in products.”

??????????? So important is the solvent selection that big companies like AstraZeneca Pfizer, GSK9 and Sanofi have developed a solvent guide, as well? American Chemical Society. The solvent choice for the crystallization is powerful, it can improve the product's attributes or it can ruinous the hole work. The solvent can influence in the target produty quality attributes, like polymorphism, solvate, crystal shape, particle size (e.g. in the antisolvent addiction), as in the process, purity, yield, filtration speed, residual solvent, and viscosity. For this, we need to choose the solvent based on its physical-chemical parameters.

But not only chemical properties influence the choice, but health, safety environment (HSE) impact, based for example in nontoxicity, noncarcinogenic and non-flammable. For this criterion in the pharmaceutical industry regulatory guide the choice of the solvent. The solvent choice will be guided by ICH QC3(R8), the guide for residual solvent. HSE lead to the concept of green chemistry and sustainability.

The GSK solvent selection for example combines physical properties with Health, safety environment (HSE) parameters. The academic research has incorporated Kinetic with Thermodynamic impact of solvent on the process.

The solvent's effect on the reaction rates is known, The donor-receptor electron property of the solvent can influence the nucleation step. If the solute-solvent has a strong interaction the nucleation will have a slower kinetic. In some cases, for example, for the enantiotropic system, will be possible to have a solid-solid transition and in some cases, this transition can be mediated by the solvent.

??????????? So if the DS and DP, the process sufer from so many influence by the solvent choice it is natural to give attention for this step. With the amount of experimental information and the computational tools QBD can be applied to improve the solvent choice, in special DOE can define the design space for the experiment.

If you are interested in learn more about crystallization, and solid critical qualities attributes, you are invited to our course, which will happen first online and then in the beautiful city of Niterói, in NAB, just in front of Sugar Loaf, Rio de Janeiro Bay and Christ the Redeemer, next year (2024). Couldn’t have a better combination to discuss applied science, practical knowledge with excellent teachers (Moussa boukerche and Maria Clara Ramalho Freitas) ?is an wonderful location. I dare you to find a better opportunity.

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