Tracking prenucleation molecular clustering of salicylamide in organic solvents

Crystal nucleation shapes the structure and product size distribution of solid-state pharmaceuticals and is seeded by early-stage molecular self-assemblies formed in host solution. Here, molecular clustering of salicylamide in ethyl acetate, methanol, and acetonitrile was investigated using photon correlation spectroscopy. Cluster size steadily increased over 3 days and with concentration across the range from undersaturated to supersaturated solutions. Solute concentration normalized by solubility provided more sensitive characterization of molecular-level conditions than concentration alone. In saturated solution, cluster size is independent of solvent, while at equal supersaturation, solvent-dependent cluster size increases as methanol < acetonitrile < ethyl acetate, commensurate with increasing nucleation propensity. In ethyl acetate, with largest prenucleation clusters, the driving force required for nucleation is lowest, compared to methanol with smallest clusters and highest driving force. To understand solvent− solute effects, we performed IR spectroscopy supported by molecular simulations. We observe solute−solvent interaction weakening in the same order: methanol < acetonitrile < ethyl acetate, quantifying the weaker solvent−solute interactions that permit the formation of larger prenucleation clusters. Our results support the hypothesis that nucleation is easier in weaker solvents because weak solute−solvent interactions favor growth of large clusters, as opposed to relying solely on ease of desolvation.