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The deep understanding of products and processes has become a requirement for pharmaceutical industries to follow the Quality by Design principles promoted by the regulatory authorities. With this aim, SeDeM expert system was developed as a useful preformulation tool to predict the likelihood to process drugs and excipients through direct compression. SeDeM system is a step forward in the rational development of a formulation, allowing the normalisation of the rheological parameters and the identification of the weaknesses and strengths of a powder or a powder blend. However, this method is based on the assumption of a linear behavior of disordered systems. As percolation theory has demonstrated, powder blends behave as non-linear systems that can suffer abrupt changes in their properties near to geometrical phase transitions of the components. The aim of this paper was to analyze for the first time the evolution of the SeDeM parameters in drug/excipient powder blends from the point of view of the percolation theory and to compare the changes predicted by SeDeM with the predictions of Percolation theory. For this purpose, powder blends of lactose and theophylline with varying concentrations of the model drug have been prepared and the SeDeM analysis has been applied to each blend in order to monitor the evolution of their properties. On the other hand, percolation thresholds have been estimated for these powder blends where critical points have been found for important rheological parameters as the powder flow. Finally, the predictions of percolation theory and SeDeM have been compared concluding that percolation theory can complement the SeDeM method for a more accurate estimation of the Design Space., (Copyright © 2016 Elsevier B.V. All rights reserved.)