The purpose of this study is to evaluate the influence of sodium iodide, sodium chloride and sodium sulfate on the formation efficiency of sulfamerazine nanocrystals by wet ball milling. Sulfamerazine was milled using zirconium oxide beads in a solution containing polyvinylpyrrolidone (PVP) and a sodium salt (iodide, chloride or sulfate). Particle size distributions were evaluated by light diffraction before and after milling. High-performance liquid chromatography was utilized to determine the amount of PVP adsorbed onto sulfamerazine surface. Lyophilized nanocrystals were further characterized by differential scanning calorimetry and dissolution testing. Sulfate ion had more profound effect on reducing particle size via milling than iodide or chloride. We linked our findings to Hofmeister ion series, which indicates that sulfate ions tends to break the water structure, increases the surface tension and lowers the solubility of hydrocarbons in water. We hypothesized that the addition of sulfate ions dehydrated the PVP molecules and enhanced its adsorption onto the sulfamerazine particle surfaces. Consequently, the adsorbed PVP helped to stabilize of the nanosuspension. The nanocrystals that were obtained from the lyophilized milled suspensions exhibited a notable increase in dissolution rate. The addition of sodium sulfate enhanced the formation efficiency of sulfamerazine nanocrystals.