The Use of Phase Diagram to Improve Crystallization Results

As already mentioned, crystallization is a unit operation, and the design of this process can lead to particles with desirable properties, such as particle size, the crystal phorm (in case of polymorphism), and crystal shape, they are called critical quality attributes when they have a significant impact in the drug substance as well the drug product or even in the downstream processability.

Historically this has been an experimental science, however within the amount of dates, instrumentation development as PAT (Process Analytical technology) as well as the scientific knowledge, this science has tremendous development in the last 10 years.

Not only the design can be used to improve the final product quality well the avoidance of issues, such as the already cited in the newsletter: polymorphism phase transition, non-uniformized in the particle size, oiling out, and impurity.

Here I will bring an example described In a paper on which they describe the selected crystallization process for a system with monotropic polymorphism. But first let's understand what is a phase diagram.

??????????? Phase diagram, as the name says is a graphical in which we can represent the different phases of a system. We can represent the correlation and dependence between parameters. The first ones that we learned from school are the pressure and the volume (P/V), in a curve called isotherm where the temperature remains constant over time, as well as isobaric (V/T), when the pressure is constant and isochoric (P/T), where the volume is constant. But in a reactor one variable that is useful to monitor can be the composition, and in this, we can construct phase diagrams with a composition as a variable, for example, the temperature over composition.

All the phase diagrams serve different purposes, and they can be easily assessed to obtain the desired product. They are a valuable tool: “They establish limits as to which features can be drawn in such diagrams that are fundamentally correct (but not necessarily known) and where, in the spirit of parsimony, creativity should be restrained”. Bernhard Rupp in his paper Origin and use of Crystallization Phase Diagram.

I have cited binary phase diagrams, but for example, in the case of co-crystals, where we desire to obtain a final product with two components, the active pharmaceutical ingredients, and the co-former, we start with a mixture of three components and to understand the best composition to obtain the desired product we can analyze the ternary phase diagram.

But how to use the phase diagram to improve the crystallization process, for example in the selection of a specific phorm. (The idea to better explain this I took from Gèrard Coquerel’s paper’s Crystallization of molecular system from solutions: phase diagrams, supersaturation, and other basic concepts.). I will use his example, based on a dimorth monotropic system.

A dimorph system means there exist only two forms, and a monotropic mean for the whole temperature range Gibbs energy for the stable form will always be lower than the metastable. Spontaneously, a phase transition from phorm more stable to metastable one, the opposite is possible. As expected for a dimorph monotropic system, in solution is possible to have the formation of both forms, depending on the kinetic: nucleation and growth. Considering Ostwald's rule of stages says nucleation is not necessarily the most thermodynamically stable, rather is the one closest in free energy to the mother phase”. So is possible that nucleation starts with the metastable phorm.

In a crystallization system, if we decrease the temperature at any composition, starting from the solubility curve of the stable form, we will reach the second curve of solubility corresponding to the metastable. In this case, if we only decrease the temperature at a solute constant composition, kinetically, in the system (not taking under discussion the metastable zone) there is no why only one phorm can start to nucleate and precipitate, both of them are possible.

Taking into account the Ostwald rule of stages decreasing temperature will induce the nucleation first of the metastable phorm, which means that the temperature-decreasing system will be more saturated in the metastable phorm in the beginning. And how to stimulate the system to provide phorm more stable? Using seeds of phorm stable can be an answer.

So in this case the knowledge of the diagram phase, identifying a monotropic system can lead to a strategy to improve the precipitation of one specific form, using for example seed. So this is just a glimpse of how the phase diagram knowledge can improve the obtention of solids. But keep in mind that the crystallization from a kinetic point of view can be easily influenced by “subtle variations such as chemical purity, stirring mode, resident time, any stress” from Gèrard Coquerel.

I hope you enjoy this article, and understood the application of phase diagrams to the crystallization system. So if you liked this text please subscribe to the newsletter, leave your like, and support my work of scientific dissemination. And if you think a friend could beneficiate from this, share with him. In the next text, I will bring more ideas on the solubility curve.