Particle size reduction, particularly nanonization, is a non-specific, universal approach to improve the bioavailability of poorly soluble drugs. The decreased particle size of drug nanocrystals leads to a distinct increase in surface area. Due to the increased surface area the rate of dissolution will be proportionally raised, leading to a better absorption of the poorly soluble drug. Various technologies for the production of drug nanocrystals are known, e.g., pearl milling (Nanocrystal technology, elan/Nanosystems), high pressure homogenization in water (DissoCubes, SkyePharma) or alternatively in non-aqueous media or water-reduced media (Nanopure, PharmaSol Berlin). A first combinative technology (precipitation followed by high pressure homogenization) is known as NANOEDGETM technology (Baxter). Relatively long milling times, high numbers of homogenization cycles or solvent residues are typical drawbacks of the existing technologies. In order to overcome the limitations of the existing technologies a new combination method was developed for the production of ultra-fine submicron suspensions. The method involves an evaporation step to provide a solvent-free modified starting material followed by high pressure homogenization to produce ultrafine drug nanocrystals. In this study it could be shown that modified hydrocortisone acetate was particularly suitable to be further processed by high pressure homogenization. In comparison to jet-milled hydrocortisone acetate powder the high pressure homogenization of spray-dried hydrocortisone acetate powder resulted in much more homogeneously dispersed nanosuspensions. By using co-processed, spray-dried material (9:1 drug/poloxamer 188 ratio) the required number of homogenization cycles to obtain nanosuspensions was distinctly reduced. In case of the modified material only 1 homogenization cycle at 1500 bar was sufficient to obtain a particle size smaller than that after 20 homogenization cycles using the jet-milled drug powder. The obtained nanosuspensions have shown excellent long-term storage stability.