To overcome the limitations of nanoparticles for respiratory drug delivery, we prepared nano-composites containing micro-particles as drug carriers for targeting the lungs. The aim of present study was preparation of Clarithromycin (CLM) loaded poly Lactide-co-Glycolide (PLGA) nanoparticles (NPs) and evaluation of aerodynamic behavior of co-spray dried NPs with different carriers. Mannitol and lactose were employed as dry powder carriers for inhalation and the effects of L-leucine as a third component for increasing the yield and fine particle fraction (FPF) of powders were investigated. PLGA was employed as a GRAS (Generally Regarded As Safe) polymer and the NPs were prepared by emulsification solvent evaporation technique in different conditions. We assessed physicochemical characteristics of the NPs in terms of particles size, poly dispersity index (PDI), entrapment efficiency, drug loading, release profile, thermal behavior, morphology and aerodynamic performance. Particle size of NPs was between 78 and 347 nm and drug loading of NPs varied from 0.08% to 7.44% in different formulations. Thermal analysis demonstrated the merging of drug into the polymer matrix and drug release profiles appeared to consist of two phases with an initial rapid release followed by a slower exponential stage. After co-spray drying of NPs with sugar based carriers, spherical particles with size range of 5.3 to 8.9 mu m were harvested. The presence of L-leucine in formulations resulted in significant increase of yield as well as FPF of particles. (C) 2013 Elsevier B.V. All rights reserved.