(323c) Molecular Modeling Techniques for Understanding Homogeneous and Heterogeneous Nucleation In Organic Crystals

Crystallization is an important purification step in pharmaceutical and food industries to obtain high purity chemicals. Most of these industrially relevant molecules can exist in different crystal forms, known as polymorphs, which have different physical properties, which determine their suitability for different applications.¹ Nucleation is the key step by which the molecules aggregate together and grow to form the final crystal structure. The nature of solvent and the degree of super saturation can have profound effect on the nucleation mechanism and the polymorphic outcome. In the case of heterogeneous nucleation on external substrates, favorable interactions and epitaxial ordering can have an effect of nucleation mechanism. For rational synthesis of a given polymorph, it is imperative to understand the molecular mechanism of nucleation in small molecular organic crystals.

In this work, we study the nucleation mechanism in small molecule organic crystals by employing molecular simulations. We need sophisticated simulation techniques that can study rare events like nucleation in chemical systems. We discuss the utility of different methods such as aimless shooting² and string method in collective variables³ for such problems. Using these methods, the minimum free energy pathways for nucleation are elucidated. The application of methods, such as likelihood maximization, ² to screen the relevant collective variables in order to identify a good reaction coordinate will also be discussed. Specific applications involving nucleation from melt, in solution, and also in presence of external substrates will be presented.

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¹ A.Y. Lee and. A. S. Myerson, MRS Bulletin, 31, 881 (2006).

² B. Peters and B.L. Trout, J. Chem. Phys., 125, 054108 (2006).

³ Maragliano, L.; Fischer, A.; Vanden-Eijnden, E.; Ciccotti, G. J. Chem. Phys. 2006, 125.