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The aim of this study was to evaluate the effect of polymer carrier, hot melt extrusion and downstream processing parameters on the water uptake properties of amorphous solid dispersions.Three polymers and a model drug were used to prepare amorphous solid dispersions utilizing the hot melt extrusion technology. The sorption–desorption isotherms of solid dispersions and their physical mixtures were measured by the dynamic vapour sorption system, and the effects of polymer hydrophobicity, hygroscopicity, molecular weight and the hot melt extrusion process were investigated. Fourier transform infrared (FTIR) imaging was performed to understand the phase separation driven by the moisture.Solid dispersions with polymeric carriers with lower hydrophilicity, hygroscopicity and higher molecular weight could sorb less moisture under the high relative humidity (RH) conditions. The water uptake ability of polymer–drug solid dispersion systems were decreased compared with the physical mixture after hot melt extrusion, which might be due to the decreased surface area and porosity. The FTIR imaging indicated that the homogeneity of the drug molecularly dispersed within the polymer matrix was changed after exposure to high RH.Understanding the effect of formulation and processing on the moisture sorption properties of solid dispersions is essential for the development of drug products with desired physical and chemical stability.