Nowadays, the optimization of process/formulation parameters represents an important step in research, and the design of experiment (DoE) approach is getting great attention in the field of pharmaceutical technology. In order to understand the relationship among input variables and response(s) or directly to find optimal process settings while achieving high efficiency and low costs at the same time, response surface methodology (RSM) is widely used. A suitable tool for RSM application when having 2–4 independent factors is Box-Behnken design (BBD), which is also sufficient to fit a quadratic model. The present study was focused on investigating of mannitol-based microparticles prepared by the spray drying method and intended for pulmonary administration mediated by inhalation. The effects of spray drying process parameters on the particle size were investigated employing BBD and DoE data analysis. Mass median aerodynamic diameter (MMAD) was selected as the characteristic of particle size. Particles of the MMAD in the interval of 1– 5 μm reach the deep lungs represented by small airways and alveoli, which is desired.