(438e) An Investigation of the Kinetics and Thermodynamics of Nucleation through Composite Cluster Formation from Aqueous Solutions

Predicting the outcome of a crystallization process in terms of the resulting crystal structure has important applications in fine chemicals industries. Different polymorphs of active pharmaceutical ingredients have different solubilities and dissolution rates resulting in differential bioavailability. One main challenge in polymorph prediction is obtaining reliable nucleation rates. The small time and length scales associated with formation of critical nuclei and the stochastic nature of nucleation poses a challenge to experimental studies. Therefore, accurate computational prediction of free energy barriers is crucial for estimating nucleation rates. In this work, using NaCl nucleation from aqueous solution as a model system, we examine the free energy of nucleation through a non-classical nucleation mechanism. In contrast to the 1D classical nucleation theory, we obtain the free energy as a function of two structure specific nucleus size coordinates: crystalline and amorphous cluster sizes, using hybrid Monte Carlo/molecular dynamics simulations with umbrella sampling. The calculated free energy surface is verified by recovering the 1D profile as a function of the crystalline cluster size and comparing with literature results [1].

We demonstrate that, for the studied system, there is a thermodynamic preference for nucleation through a composite cluster, where the crystalline nucleus is surrounded by an amorphous layer. The computed free energy landscape matches the composite cluster model proposed by Iwamatsu [2] and the obtained phase specific thermodynamic properties through model fitting show that the amorphous phase is the least stable phase in the system, followed by the solution phase and the crystalline phase in increasing stability. Moreover, by obtaining phase specific diffusion coefficients through molecular dynamics simulations, we construct the full stochastic system for NaCl nucleation from solution and calculate the nucleation rate. This methodology can be applied to systems where multiple polymorphs are present to calculate polymorph specific nucleation rates.

[1] Jiang, Hao, et al. 2019. J. Chem. Phys. 150(12), p.124502

[2] Iwamatsu, M., 2011. J. Chem. Phys., 134(16), p.164508