This work investigated the use of the USP III apparatus in discriminating simulated fed and fasted conditions as well as ionic strength on veegum-polyethylene (PEO) (called clay-PEO matrices hereafter) matrices. The successful formulations were characterised using differential scanning calorimetry (DSC) and evaluated for their physical properties. Isothermal calorimetry (ITC) was used to evaluate the thermodynamics of the complexation processes. The effect of agitation sequences on the matrices as evaluated from the USP III suggested an increase in polymer content to significantly decrease the burst release experienced using diltiazem hydrochloride (DILT) as a model cationic drug. The manufacturing methods showed superior performance in relation to a decrease in burst release over the physical manufactured counterparts. The clay-PEO matrices also showed robustness (no matrix failure) in up to 0.2 M ionic strength solutions mimicking the upper limit experienced in the GI tract. ITC results revealed that the binding between DILT and PEO was enthalpy and entropy-driven. Furthermore, the binding between veegum and DILT in the presence of PEO was shown to be enthalpy-driven and entropically unfavourable, which was also the case for the binding between veegum and PEO thus giving insights to how the matrices were performing on a molecular level.