First-pass metabolism affects many oral medications and limits the attainment of their therapeutic level. It can be bypassed by administrating buccal dosage forms that allow systemic drug absorption via buccal mucosa. Drugs formulated as buccal medicaments should have an acceptable solubility in saliva. Numerous technologies had been experimented to increase the aqueous solubility of poorly water-soluble drugs e.g. solid dispersion technique. This technique is efficient for improving the solubility and dissolution rate of hydrophobic drugs and consequently improving their bioavailability. Domperidone is an antiemetic drug that undergoes extensive first-pass metabolism, having poor solubility in saliva and poor bioavailability. This study aimed to improve the aqueous solubility of domperidone at pH simulating saliva by preparing multicomponent solid dispersions using different carriers by solvent evaporation method. In vitro dissolution studies showed enhanced dissolution rates of all prepared systems with release kinetics approaching Higuchi model. Ternary solid dispersion (SD) of 1:9:0.25 drug/polyvinylpyrrolidone K30/pluronic F-127, respectively, achieved the highest dissolution rate. Physicochemical characterization of this SD using differential scanning calorimetry, Fouriertransform infrared spectroscopy, powder X-ray diffraction and scanning electron microscopy indicated the presence of an interaction between domperidone and polyvinylpyrrolidone K30 with evidence of drug amorphization that might be responsible for the enhanced dissolution rate.