Theophylline (Thyo) is used as treatment of respiratory tract conditions like asthma and chronic obstructive pulmonary disease (COPD). Unfortunately, Thyo differs in concentration from patient to other to reach therapeutic effect due to difference in clearance. Using the design of experiment (DoE) to developed and characterized nanocomposites for an inhaler delivery using Thyo as a model drug. Thyo as hydrophobic drug was incorporated into polymer of amide-disulfide nanoparticles to form Thyo-polymer nanocomposites. The independent variables were amount of polymer, calcium chloride, and Thyo; whereas the dependent variable was loading efficiency, and particle size. Using full factorial design by Minitab 18 software. The Thyo-polymer nanocomposites were prepared by using three levels of polymer (50, 100, and 200 mg), four levels of calcium chloride (150, 300, 600, and 1200 mg) and four levels of Thyo (50, 100, 200, and 400 mg). The analysis of the models was carried out using graphical analysis such as Pareto chart, surface and contour plots, main effect plots, interaction plots, normal probability plot and residuals versus plots. Analysis of variance (ANOVA) is structured to obtain the significant independent variables affecting the dependent response by using P-value lower than 0.05. The optimized formulation was contained loading 81.6% (w/w) of Thyo with 104 nm particle size. This formula can be prepared using 176 mg of polymer, 150 mg of CaCl2, and 216 mg of Thyo. The release of Thyo from the nanocomposites occurs in two release steps; the first release step started from the beginning up to 60 minutes with maximum release 50%. The second-stage release occurred up to 1400 minutes with complete releases of 80%. In addition, the results of next generation impactor analysis demonstrated that 23.97% of the nominated dose in each puff reached the lower parts of the respiratory system. Finally, physicochemical characteristics of this nanocomposite demonstrated their suitability for pulmonary drug delivery.