We investigated the effect of L-leucine coating on particle integrity, aerosolization properties, cellular interaction, viability and drug permeation properties of combination drug powder particles for dry powder inhalation. The powder was prepared using an aerosol flow reactor method to combine a water-soluble β-agonist drug, salbutamol sulphate, and corticosteroid, beclomethasone dipropionate, into fine particles which were subsequently encapsulated and coated with L-leucine nanocrystals. Dissolution profiles showed a faster dissolution of beclomethasone dipropionate, while leaving the salbutamol dissolution unhampered when compared with their physical mixture. Permeation of beclomethasone dipropionate across a differentiated Calu-3 cell monolayer was increased but also time-dependent recrystallization of the drug on top of the Calu-3 cell monolayer was observed. The particles were further investigated for cytocompatibility in three different pulmonary (Calu-3, A549 and BEAS-2B) and one human macrophage (THP-1) cell lines showing excellent tolerability. They also elicited low reactive oxygen species generation in pulmonary BEAS-2B and macrophage THP-1 cell lines. The inhalable drug powders coated with leucine offer thus an interesting alternative for the delivery of poorly soluble drugs to the lung.