Abstract: In this study, mechanical activation (ball- and cryomilling) was successfully applied to obtain co-amorphous mixtures of two BCS class II drugs, simvastatin (SVS) and glipizide (GPZ). This pharmacologically relevant combination of two drugs could produce a promising candidate for formulations intended for combination therapy of metabolic disorders. The co-amorphous SVS-GPZ mixtures (molar ratios 2:1, 1:1 and 1:2) were characterized with respect to their thermal properties, possible molecular interactions, dissolution properties and physical stability, and compared to the behaviour of pure amorphous forms and their physical mixtures. Flory-Huggins interaction parameter predicted the absence of favourable SVS-GPZ interactions and thus immiscibility of the components. Nonetheless, formation of single phase co-amorphous mixtures with mixture ratios of 2:1, 1:1 and 1:2 was detected by differential scanning calorimetry (DSC). The observed single, concentration dependent T_gs were found to be lower than predicted by the Gordon-Taylor equation indicating absence of intermolecular interactions between the two drugs which was verified by Fourier transform infrared spectroscopy (FTIR) spectral data analysis. By formation of co-amorphous single-phase mixtures only the dissolution rate of GPZ could be improved. The co-amorphous mixtures showed improved storage stability compared to the pure amorphous forms and the amorphous physical mixtures. It was concluded that this was attributable to the molecular level mixing of SVS with GPZ upon milling and GPZ is acting as an anti-plasticizer in these mixtures.