(468b) In-Silico Molecular Simulation Methods for Crystal Nucleation in Solution

Background: The study of crystal nucleation poses major challenges for both experimental and simulation studies. The stochastic nature of nucleation, combined with its uncanny ability to amplify the effect of minute molecular-level details, make it very difficult to achieve consistent experimental results even for simple systems. Molecular simulation studies are also challenging, as nucleation is a rare event with a free energy barrier that includes a substantial entropic contribution. Additionally, some of the common assumptions in molecular simulations, such as periodic boundary conditions (which can result in serious finite size artifacts) and constant number of molecules, can greatly bias the results. All theories of nucleation focus on parameters of the solid phase (like number of molecules in the solid), but there is evidence from computational studies that parameters from the solution phase could be equally important.

Results: We defined the liquid order parameters for four different solvents (acetonitrile, ethanol, methanol and water) containing urea at five different concentrations. The behavior of each solvent in the nucleation process has a direct correlation with its nucleation mechanism (i.e. one- or two-step mechanism) found in previous studies, showing that we could predict the behavior and/or pathway using the solvent physical and thermodynamic properties. Additionally, these results can be extended to other solutes in the drug discovery industry.

Conclusions: We show some of the first studies that uses solvent order parameters to predict the behavior of the nucleation of crystals in solution. Consequently, we could generalize this procedure to other liquid structures, which will enable us to generate order parameters for any solvent of interest.