General Understanding of Nucleation and Growth

Looking for better AFI quality, in the form of the critical quality attributes or critical process atributes, the crystallization control is essential. But what are the steps in the crystallization process? All start with Nucleation and growth, kinetic process driven by thermodynamic. There is a phase transition, from the solution to the crystalline solid.

Nucleation occurs first in the the supersaturated zone, while growth on the metastable zone (if you need to understand better the solubility curve, you are invited to check the previews article of this series) or the paper: Semi-automated identification of the phase Diagram for Enantiotropic Crystallization Using ATR-FTIR spectroscopy and laser backscattering. A work in which they build experimentally the phase diagram ( the solubility curve) for an enantiotropic system (systems for which there are phase transitions from a stable polymorth to another stable one as a function of temperature).

??????????? First, what is the driving force of nucleation? The Why nucleation occurs. The driving force is the difference of the chemical potential of the solute in the supersaturated solution to the saturated one. Is expected that for the beginning of the crystallization, the method should always favor obtention of the supersaturation: Cooling, add antisolvent, evaporation, seeds or by chemical reactions.

There are important theories to understand nucleation kinetics, like the first principle, Nyult and KBHR, Of course for, just like most of you they are only names. But the idea is use my effort to make a correlation between the nucleation kinetic to mapping the polymorphic behavior, to control the system for isolation of the target polymorph.

For example, the induction time ( the time from a constant concentration on a supersaturated solution till the time of formation of the first crystals) were correlated to the nucleation kinetics, in the paper of Siqi Fan (Energetic Materials Frontiers 2 (2021) 62–68) . For the system, they found a decrease in the induction time as supersaturation increases.

I would like to point out one interesting correlation for the system and the temperature. In one side the increase of temperature can favor the kinetic of the system. However the driving force of the system can be decreased from the change of the temperature.

Nucelation is related to the polymorth, while growth is correlated to the crystal shape. A sophisticated work describes how selection of the crystallization solvent can influence the crystal habit (Entitled: Downstream Processability of Crystal Habit- Modified Active Pharmaceutical Ingredient, from Nawin Pudasaini and coworkers). Faces of the crystal can display different rates and form different habits. They have correlated the crystal habit to properties like flow hate, flowability, bulk density, tensile strength, and effective angle of internal friction.

??????????? There is an increase in the development of instrumentation from the control of the crystallization process, from the development to the scale-up. We from Solid Consult Pharma have partners that conduct consulting for the crystallization process as well as partners for the instrumentation for your lab, crystallizers as well probes.

??????????I hope from this text you can understand the correlation between the phase diagram, and the steps of crystallization, and how a better understanding of the nucleation and growth can improve the drug substance's solid attributes.