The motivation for this study was to find an adequate substitute for lactose as carrier in dry powder inhalers and to overcome some drawbacks inherent to lactose. Mannitol appears to be the ideal replacement of lactose because it lacks the risk of transmitting the transmissible spongiform encephalopathy, mannitol does not carry reducing groups, that may cause chemical interactions with drugs such as proteins, and is highly crystalline even upon spray drying. Spray drying in turn is a dedicated technology to prepare carrier particles for dry powder inhalers. Typically spherical particles are generated constituting comparable interparticle forces to every drug particle attached to their surface. This study shows, that mannitol particles of different surface roughness can be prepared by spray drying at different outlet temperatures, providing the opportunity of tailoring the contact area respectively the interparticle interactions between the drug and the carrier. The emergence of different surface roughness was attributed to different crystallization mechanisms. Surface roughness was quantified by confocal laser-scanning microscopy. Quantitative Raman spectroscopy revealed, that the spray dried products consist mainly of the thermodynamically stable modification I besides small amounts (5 to 15%) of the metastable modification II, irrespective of the drying temperature and the crystallization mechanisms taking place. This renders mannitol a most suitable substitute of lactose for the use in dry powder inhalers. (C) 2011 Elsevier B.V. All rights reserved.