The drug-drug interaction of two pMDI (pressure metered dose inhaler) combination products budesonide-formoterol fumarate dihydrate and salmeterol xinafoate-fluticasone propionate were investigated using in situ atomic force microscopy (AFM), equipped with a liquid cell filled with model a propellant, and Raman spectroscopy. Electron microscopy images of the budesonide-formoterol formulation suggested discrete particulates while the salmeterol-fluticasone formulation appeared agglomerated. Based on the analysis of the AFM curves, it is proposed that interactions in the budesonide-formoterol system (cohesion and adhesion) are dominated by van der Waals forces while interactions between salmeterol and fluticasone are of a chemical nature. Such observations are further substantiated by analysis of the Raman maps produced from pMDI actuations deposited on Andersen cascade impactor plates. The relevance of such synergy between particulates of different chemical nature is discussed. In particular, it is anticipated that strong interactions between particles could lead to heteroflocculation, increase aerosol particle size and consequently reduction of the respirable fine particle fraction. (C) 2011 Elsevier Inc. All rights reserved.