Burst drug release is often considered a negative phenomenon resulting in unexpected toxicity or tissue irritation. Optimal release of a highly soluble active pharmaceutical ingredient (API) fromhypromellose (HPMC) matrices is technologically impossible; therefore, a combination of polymers is required for burst effect reduction.Promising variant could be seen in combination of HPMC and insoluble Eudragits® as water dispersions. These can be applied only on API/insoluble filler mixture asover-wetting prevention. The main hurdle is a limited water absorption capacity (WAC) of filler. Therefore, the object of this study was to investigate the dissolution behavior of levetiracetam fromHPMC/Eudragit®NE matrices using magnesium aluminometasilicate(Neusilin®US2) as filler with excellent WAC. Part of this study was also toassess influence of thermal treatment on quality parameters of matrices. The use of Neusilin® allowed the application of Eudragit® dispersion to API/Neusilin®mixture in one step during high-shear wet granulation. HPMC was added extragranularly.Obtained matrices were investigated for qualitative characteristics, NMR solid-state spectroscopy (ssNMR), gel layer dynamic parameters, SEM, and principal component analysis (PCA). Decreasein bursteffect (max. of 33.6%) and dissolution rate, increase in fitting to zero-order kinetics, and paradoxical reduction in gel layer thickness were observed with rising Eudragit® NE concentration. The explanation was done by ssNMR, which clearly showed asignificant reduction of the API particle size (150–500 nm) in granules as effect of surfactant present in dispersion in dependence on Eudragit®NE amount. This change in API particle size resulted in a significantly larger interfacebetween these two entities. Based on ANOVA and PCA, thermal treatment was not revealed as a useful procedure for this system.