In the present study, the drug–polymer miscibility and molecular interaction of budesonide in polymers (PVP/VA E 735, 635 and 535) systems were studied, by using three techniques including, calculation of Hansen solubility parameters, analysis of melting points depression, and measurement of glass transition temperature (Tg). Budesonide nanoparticles were prepared by sonication technique. The combined effect of four significant formulation variables, namely, polymer and surfactant concentrations, time and amplitude of sonication on particle size, polydispersity, drug loading and entrapment efficiency of drug was investigated by apply 24 factorial design. The drug/ polymer blend was considered miscible depending on the results of three approaches. The results of calculated values of miscibility parameter (χ) for each pair were negative ranging from - 2.012to -1.948. Single Tg and positive deviation from Gordon-Taylor model for all ratios of drug–polymer binary mixtures. Produced amorphous budesonide nanoparticles, depending on choice of polymer and process parameters contained from 97% to 99% drug, with particle size diameter varying in size from 641-357 nm. It was found that clear evidence on effect VA ratio on percent entrapment efficiency and particle size of budesonide.