Salting out the polar polymorph: Analysis by alchemical solvent transformation

We computationally examine how adding NaCl to an aqueous solution with alpha- and gamma-glycine nuclei alters the structure and interfacial energy of the nuclei. The polar gamma-glycine nucleus in pure aqueous solution develops a melted layer of amorphous glycine around the nucleus. When NaCl is added, a double layer is formed that stabilizes the polar glycine polymorph and eliminates the surface melted layer. In contrast, the non-polar alpha-glycine nucleus is largely unaffected by the addition of NaCl. To quantify the stabilizing effect of NaCl on gamma-glycine nuclei, we alchemically transform the aqueous glycine solution into a brine solution of glycine. The alchemical transformation is performed both with and without a nucleus in solution and for nuclei of alpha-glycine and gamma-glycine polymorphs. The calculations show that adding 80 mg/ml NaCl reduces the interfacial free energy of a gamma-glycine nucleus by 7.7 mJ/m(2) and increases the interfacial free energy of an alpha-glycine nucleus by 3.1 mJ/m(2). Both results are consistent with experimental reports on nucleation rates which suggest: J (alpha, brine) < J(gamma, brine) < J(alpha, water). For gamma-glycine nuclei, Debye-Huckel theory qualitatively, but not quantitatively, captures the effect of salt addition. Only the alchemical solvent transformation approach can predict the results for both polar and non-polar polymorphs. The results suggest a general "salting out" strategy for obtaining polar polymorphs and also a general approach to computationally estimate the effects of solvent additives on interfacial free energies for nucleation. c 2014 AIP Publishing LLC.