Deciphering the Molecular Mechanisms of Organic Crystallization

Crystallization is a central part of several physiological, pathological processes, in the manufacturing of pharmaceuticals, fine chemicals, semiconductors, and many other engineered materials. Organic solvents are extensively used for crystallization of organic small molecules such as active pharmaceutical ingredients and organic molecules like porphyrins. Fundamental studies on organic crystallization are important as solution thermodynamics plays an important role in crystal growth rates. Solvent structuring and solute–solvent interactions are yet unexplored realms of organic crystallization, whereas aqueous crystallization where the H-bonds of water molecules play an important role of controlling the solution thermodynamics is relatively well understood. In this work we address the effects of factors like solute-solvent interactions, solvent viscosity, and solvent size. We determine the solution thermodynamics of etioporphyrin I crystallization from a line of five organic solvents highlighting the role of several solute- solvent interactions. We use these solubility measurements and complement them with X-ray diffraction and UV-vis spectroscopy of the solution phase. From the thermodynamics data we shed light on the solute-solvent interactions. For organic solvents with weak solvent -solvent bonds, solvent structuring at the crystal interface is weak resulting in a lower activation energy barrier for solute incorporation into the growth sites. We showed that the solute-solvent interactions govern the mode of solute incorporation into the growth sites. Results on the growth mechanism of etioporphyrin I reveal that an incoming solute molecule occupies a state where it is only partially attached to the kink and this state precedes full incorporation. The stability of this intermediate state dictates the activation barrier for growth and, ultimately, the crystal growth rate. We explored the composition of the solute species that exist in the solution and incorporate in the crystal and found out that, at least in one case, that of etioporphyrin I, a continuum of solute dimers are present in the solution and reform on their way to a kink into a growth competent conformation. This latter mechanism fully deviates from the assumption of the classical theories of crystal nucleation and growth, which posit that only solute monomers can associate to the kinks. On exploring the mechanisms employed by foreign additives to impact the propagation of steps on a crystal surface we demonstrate that certain modifiers may exert dual action, by blocking both the kinks and the steps. These novel finding will help us control crystallization process development with desired end product features like crystal shape, size and from.