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Carboxymethyl starch (CMS) with pH sensitivity modulated by the protonation ratio (PR 0–100%) and the degree of substitution (DS 0.07–0.20) was synthesized in aqueous medium. The properties of CMS excipient and the mechanism of acetaminophen release from monolithic tablets in simulated gastric fluid (SGF, pH 1.2) and in simulated intestinal fluid (SIF, pH 6.8) were investigated. Compared to sodium CMS, the protonated CMS provided a longer release time which increases with the increase of PR. Over storage time, the highly protonated CMS showed a decrease in solubility and a progressive structural alteration due to hydrogen bonded carboxyl groups. Simultaneously, an acceleration of release rate of formulated drug was observed. The CMS(DS 0.11) with PR up to 50% showed relatively low sensitivity to dissolution medium pH and sustained release pattern almost independent of tablet preincubation in SGF and of drug loading (20% and 40%). The CMS(DS 0.20) was more sensitive to pH and showed an accelerated release rate in SIF. For the CMS formulations, a diffusion mechanism was suggested in SGF, whereas in SIF the release was mostly controlled by swelling and erosion.