Chronic lung infection with Pseudomonas aeruginosa is a major cause of increased morbidity and mortality in cystic fibrosis (CF) patients. Lung function and overall quality of life have improved as a result of the tobramycin inhalation solution (TIS). For determining the optimum combinations to deliver a large amount of tobramycin at the site of infection in the lung, three sets of TIS formulations have been designed in this study by changing the physicochemical properties of the drug solution for improving nebulizer performance. The CEN methodology for the determination of particle size distribution and aerosol output characteristics has been used for in-vitro assessment of tobramycin-tested formulations. All measurements were performed at ambient conditions. Different selected high-performance nebulizer delivery systems were used: two different designs of jet nebulizers and two new nebulizers based on vibrating mesh technology. The two jet nebulizers were Pari LC Plus® and Sidestream® powered by PariBoyN® and Medix AC 2000 Hi Flow compressors, respectively, with a fill volume 5ml. The vibrating-mesh nebulizers were high-frequency NE-U22 Omron® ultrasonic vibrating mesh and Aeroneb® Go electronic micropump nebulizers, with 2.5ml fill volume. In conclusion, the particle size distribution and aerosol output data in this study showed that significantly affected by the physicochemical properties of the drug solution such as osmolarity, pH, ionic strength, viscosity, density, and surface tension in conjunction with the nebulizer design on droplet size as well as aerosol output of TIS to maximize tobramycin delivery into the lungs with selected jet and ultrasonic vibrating mesh nebulizers. The probability of increasing tobramycin absorption in- vivo still required more investigations. Keywords: Cystic fibrosis; Tobramycin; TOBI®; nebulizer; jet nebulizers; ultrasonic vibrating mesh nebulizer; electronic micropump nebulizer; CEN method; surface tension; ion concentration; viscosity.