The analysis of the release kinetics from a delivery system containing amorphous and/or nanocrystalline drug requires the evaluation of many parameters among which the water solubility of the amorphous/nano-crystalline drug is one of the most important. This, in turn, needs the determination of the drug melting enthalpy/temperature dependence on the curvature radius of the crystalline phase (thought, for the sake of simplicity, of spherical shape). Accordingly, this paper is aimed to develop a general theoretical approach devoted to model the melting enthalpy/temperature variation with nanocrystals radius, the solubility dependence on nano-crystals radius and the release process from an ensemble of polymeric particles (crosslinked polyvinylpyrrolidone) containing a poorly water soluble drug (nimesulide) in its amorphous and nano-crystalline status. Drug loading was achieved by means of drug and polymer co-grinding. This study allowed the determination of the nanocrystals fraction and size distribution in the co-ground systems, the drug solubility increase of nano-crystals and the estimation of amorphous drug solubility. This approach yielded to the conclusion that, in the case of nimesulide, a significant increase of solubility occurs for the amorphous form and for nanocrystals characterised by radii lower than 4 nm. (C) 2012 Elsevier Ltd. All rights reserved.