Salt effects on aqueous solubility and microsphere entrapment efficiency of a model ionic drug (quinidine sulfate) were studied. Poly-D,L-lactic acid (PLA) microspheres were prepared using an O/W solvent evaporation method with various electrolytes added in different concentrations to the aqueous phase. Salts affect microsphere drug loading by changing the aqueous solubility of both the drug and the organic solvent (dichloromethane, DCM). Quinidine sulfate solubility was depressed by either a common ion effect (Na(2)SO(4)) or by formation of new, less soluble drug salts (e.g., bromide, perchlorate, thiocyanate) for which solubility products (K(sp)) were estimated. Inorganic salts depress DCM aqueous solubility to different extents as described by the Hofmeister series. NaClO(4) and NaSCN depressed drug solubility to the highest extent, resulting in microspheres with high drug loading (e.g., >90%). Other salts such as Na(2)SO(4) did not depress quinidine sulfate solubility to the same extent and did not improve loading. The use of a cosolvent (ethanol) in the organic phase improved microsphere drug loading and resulted in a uniform microsphere drug distribution with smooth release profiles.