Holistic Point of View on the Crystallization Process from a Curious Crystallographer Scientist

Nowadays to be competitive not only the product must be of good quality and innovative, but also the process to obtain the product. A faster, economical as well sustainable process is highly demanded.

To manipulate the process to obtain crystalline products is desirable some knowledge that many of us were asking during the university, Why should I learn this? Topics like Kinetics, thermodynamic as well fluid. I remember well I have never been the kind of person who complains about the subjects, but I do remember, at the end of the period to see the fluid topics, it was like Greek for me, and for worse, in the end of the semester, when I was already exhausted. Now everything makes so much sense.

Seeing crystallization from a holistic point of view, for me englobes scientific knowledge, about Kinetic, thermodynamics, fluid dynamics, solid-state (as supramolecular chemistry, self-assembly, crystal engineering), physicochemical characterization As well from commercial point of view, innovation (with use for example of Process analytical technology) intellectual property (concerning the methodology to obtain the final product, for ex. Polymorphs and co-crystals) and competitivity: cheaper, fast, safe (in accordance with regulatory concerns), and sustainable (environmental as well social).

If you are interested in a case to contextualize the importance of the kinetic in the crystallization process, the case of ritonavir, an anti-HVI has been used as an example. If some of you don’t know this case, I invite you all to read my article:

The Famous Abbott Case: Thermodynamics, Kinetics, and Solubility. The phase transition caused by seeds.

We can use the thermodynamic, like free energy, as a function of temperature to conclude if is there a possibility to occur a solid-solid transition (case of an enantiotropic solid) or if there isn’t any possibility (case of a monotropic solid). But in the case of ritonavir, a monotropic solid was obtained and the transition occurred. Why? Because the kinetic product was a metastable product, the reason why in crystallization is necessary to understand the phase diagram of the desired product.

The solubility curve is very useful in the compression of the system, and the crystallization process is a result of the manipulation on the knowledge of this points. Desired solid quality attributes can be obtained from these. From the solubility curve, we can identify the saturated as well as metastable area, the necessary condition for a system starts to nucleate. After nucleation the growth process takes place. The desired particle size as well as crystal shape are consequences of this last process. To those interested in patents related to the manipulation of crystal habit I can cite the patente US 2006/0078573 methods of modifying crystal Habit.

There are some methodologies for crystallization, as well as crystallized system. Elegant use of DOE can be used to improve and achieve the desired CQA like crystal size, like stirrer speed, seed size, and seed loading to improve the crystal size. For choosing the best methodology like cooling, anti-solvent and reactive crystallization, depends on the criteria of the company. For example, some can give up of the yeld and chose a simple methodology, like cooling, since if during the process something goes wrong ate least is possible to restart again, what some time with the use of antisolvent can’t be done.

Well here is just the iceberg top, there are so much more to consider when we are dealing with crystallization process. But from here I hope to have show how many areas are important to understand crystallization process, in the search for the best quality drug.

I hope you can enjoy the texts.

If all the contents I share are not sufficient, you are invited to participate in our webinar that will occur on days 27 and 28 of August/2023:

Sólidos e Cristaliza??o na Indústria Farmoquímica e Farmacêutica.

Or register to our course, Solid and Crystallization in API Manufactures and Pharmaceutical Industry. It will be a six-month project, where we expect to develop a community to share information with people who love solid-state science like us.

The teacher of the course will be me Dra. Maria Clara Ramalho Freitas, Funder of Solid Consult Pharma and ex-full professor at Universidade Federal Rural do Rio de Janeiro, and Dr. Moussa Boukerche, a Ph.D. in Chemical Engineering, with 25 years of industry experience.

I also would like to invite you to share your knowledge with us.

#consultoria #industriafarmaceutica #polimorfismo #polymorphism #XRD #DRX #IFA #API #caracteriza??odesólidos #solidcharacterizations #crystalsolutions #industriafarmaceutica #posgraduando #medicamentos #medicin #consultoria #consulting #industriafarmaceutica #polimorfismo #polymorphism #XRD #DRX #IFA #API #caracteriza??odesólidos #solidcharacterizations #crystalsolutions #industriafarmaceutica #posgraduando #Oralsolidformulation #osf #science #ciência #blockbusterdrug