The aim of our work was to determine the main factors which can influence the preparation of matrices and to choose the best parameters for the production of inert matrix granules with a high-shear granulator. Matrices were formulated, which contained hydroxypropyl methylcellulose (HPMC) as a matrix-forming agent, together with lactose monohydrate and microcrystalline cellulose as filler. There was a good correlation between the erosion time of the matrix comprimates and the water uptake of the different powder mixtures. The powder mixtures containing at least 40% of HPMC exhibited very similar properties to those of pure HPMC. Granules were prepared from the powder mixture with 30% of HPMC. The optimum amount of granulating fluid (water) was determined according to the quantity of the particles with optimum size. A 2 4 full factorial design was used to determine the operational parameters of the granulation for this composition. A significantly lower amount of waste was attained with a long spheronization time and slow dosing. The gel-forming properties of the HPMC, and hence the slower wettablity mean that the most important factors are those that affect the wettability of the powder mixture, and thus the factors which increase the time of wetting are relevant during the formulation of this matrix system. There was a relationship between the wetting of the powder mixture and forming of granules prepared with high-shear granulator. (c) 2007 The Institution of Chemical Engineers. Published by Elsevier B.V. All rights reserved.