Atomic force microscopy was used to investigate the influence of mechanical processing (milling) on the surface stability of salbutamol sulfate. Phase imaging, a development of tapping mode(TM) atomic force microscopy, was used to elucidate variations in the physico-mechanical properties on the surface of salbutamol sulfate crystals by measuring the phase lag of an oscillating tip in contact with the surface. Simultaneous measurements of topographical and phase images indicated an increase in disorder on the surface as milling time was increased. Specific regions oil the milled samples, independent of topography, showed large variations in phase shift (>30degrees). These regions (not observed on the crystalline salbutamol sulfate) suggested large differences in the physical properties on the surface. It is therefore reasonable to conclude that these regions were likely attributed to mechanically induced amorphous domains. (C) 2003 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 92:611-620, 2003.