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Background/Objectives: Hydroxypropyl methylcellulose (HPMC) is one of the most commonly used hydrophilic polymers in formulations of matrix tablets for controlled release applications. However, HPMC attracts moisture and poses issues with drug stability in formulations containing moisture-sensitive drugs. Methods: Herein, the moisture sorption behavior of excipients and drug stability using aspirin as the model drug in matrix tablets were evaluated, using HPMC and the newly developed mannitol-coated HPMC, under accelerated stability conditions (40 °C, 75% relative humidity) with open and closed dishes. Results: Tablets prepared with mannitol-coated HPMC showed a slower drug degradation rate compared to tablets prepared with directly compressible HPMC. Initial moisture content and hygroscopicity were stronger predictors of drug stability compared to water activity when comparing samples without similar moisture content. In the early stage (day 0 to 30), the aspirin degradation rate was similar in both open and closed conditions, as moisture content is the main degradation contributor. In the later stage (day 30 to 90), aspirin degradation was faster under closed conditions than under open conditions, likely due to autocatalytic effects caused by the volatile acidic by-product entrapped in the closed environment. Conclusions: The findings from this study reinforced the importance of judicious excipient selection based on the understanding of excipient–moisture interactions to maximize the chemical stability of moisture-sensitive drugs. Mannitol-coated HPMC is a promising addition to the formulator's toolbox for the formulation of controlled release dosage forms by direct compression. [ABSTRACT FROM AUTHOR]

[Display omitted] One of the most common forms of controlled release technology for oral drug delivery comprises an active ingredient dispersed in a hydrophilic matrix forming polymer such as hydroxypropyl methylcellulose (HPMC), which is tableted via direct compression. However, HPMC may pose problems in direct compression due to its poor flowability. Hence, mannitol syrup was spray-coated over fluidized HPMC particles to produce co-processed HPMC–mannitol at ratios of 20:80, 50:50, and 70:30. Particles of pure HPMC, co-processed HPMC–mannitol, and their respective physical mixtures were evaluated for powder flowability, compression profiles, and controlled release performance. It was found that co-processed HPMC–mannitol consisted of particles with improved flow compared to pure HPMC particles. Sufficiently strong tablets of >2 MPa could be produced at moderate to high compression forces of 150–200 MPa. The dissolution profile could be tuned to obtain desired release profiles by altering HPMC–mannitol ratios. Co-processed HPMC–mannitol offers an interesting addition to the formulator's toolbox in the design of controlled release formulations for direct compression. [ABSTRACT FROM AUTHOR]