A series of co-engineered macrolide-mannitol particles were successfully prepared using azithromycin (AZ) as a model drug. The formulation was designed to target local inflammation and bacterial colonisation, via the macrolide component, while the mannitol acted as mucolytic and taste-masking agent. The engineered particles were evaluated in terms of their physico-chemical properties and aerosol performance when delivered via a novel high-payload dry powder Orbital™ inhaler device that operates via multiple inhalation manoeuvres. All formulations prepared were of suitable size for inhalation drug delivery and contained a mixture of amorphous AZ with crystalline mannitol. A co-spray dried formulation containing 200 mg of 50:50 w/w AZ:mannitol had a 57.6% ± 7.6% delivery efficiency with the fine particle fraction (≤ 6.8 µm) of the emitted aerosol cloud being 80.4% ± 1.1%, with minimal throat deposition (5.3 ±0.9%) Subsequently, it can be concluded that the use of this device in combination with the co-engineered macrolide-mannitol therapy may provide a means of treating bronchiectasis.