New computational methods for solute precipitate nucleation

Solute precipitate nucleation is important to a wide variety of processes including pharmaceutical crystallization, biomineralization, and material synthesis. However, methods for simulating these multicomponent nucleation processes lag far behind methods for simpler single component nucleation processes. The impasse stems from the difficulty combining rare events methods with simulation frameworks that maintain a constant chemical potential (supersaturation) as a nucleus grows in solution. The formation of a nucleus is a completion between the chemical potential reward for the formation of a stable phase and penalty for the formation of an interface. The penalty for the formation of an interface is the only reason a barrier to nucleation exists in the classical picture. The ability of solvents and additives to preferentially reduce the interfacial free energy of one polymorph over another may be an important factor in polymorph selection. Accordingly, interfacial free energies are a central focus of this thesis.;We present new simulation methodologies to model solute precipitate nucleation and determine the structure and interfacial free energy of nuclei in solution. We introduce the Potts lattice gas (PLG), as a model for solute precipitate nucleation. Using the PLG, we developed the mitosis method to calculate the interfacial free energy of nuclei in solution. For mechanistic studies of polymorph selection order parameters must be developed that distinguish polymorphs. To solve this problem, we developed polymorph specific local RMSD order parameters. These order parameters are used to analyze the effects of the additive NaCl on the structure of glycine nuclei in solution, providing insight into polymorph selection. For a quantitative analysis of the effects of additives on the interfacial free energy of nuclei, we present a new application of free energy perturbations. Applying this method to glycine, we show that NaCl preferentially reduces the interfacial free energy of γ-glycine nuclei over α-glycine nuclei in aqueous solution, as implied by experiments. The methodologies presented here provide a framework for determining the effects of additives and solvents on the interfacial free energy and structure of nuclei in solution.