Abstract Objectives The aim of this work was to investigate the use of liquisolid technique to sustain the release of a model highly soluble drug, diltiazem HCl, from liquisolid matrices containing Polyox, a recently proposed matrix-forming hydrophilic polymer as an alternative to hypromellose. Methods Polyox-based liquisolid formulations prepared using several non-volatile solvents (i.e. polysorbate 80, polyethylene glycol, polyethylene glycol 200 and polyethylene glycol 600) and then characterised using differential scanning calorimetry and powder X-ray diffraction. The influence of solvent on retarding the release of diltiazem HCl from Polyox-based liquisolid tablets compared to conventional physical mixture tablets was studied. Key findings Liquisolid tablets exhibited greater retarding properties compared to conventional tablets. The use of polysorbate produced a slower release pattern of the drug from diltiazem hydrochloride (DTZ) liquisolid tablets compared to propylene glycol and polyethylene glycol (200 and 600). The release retardation was decreased with the increase in the concentration of the drug within drug:solvent liquid medication used. Solid-state analysis suggested the presence of a fraction of the drug mass in a solubilised state within polysorbate in liquisolid powders. Conclusion Polyox-based matrix tablets prepared using liquisolid technique in the presence of a carefully selected non-volatile solvent could produce desirable, more sustained release profiles of highly water-soluble drugs compared to conventional physical mixture tablets.