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.

The kinetics of the hydrolysis and polycondensation reactions of saccharides have made the subject of numerous studies, due to their importance in several industrial sectors. The present work, presents a novel kinetic modeling framework that is specifically well-suited to reacting systems under strict moisture control that favor the polycondensation reactions towards the formation of high-degree polysaccharides. The proposed model is based on an extended and generalized kinetic scheme, including also the presence of polyols, and is formulated using two different numerical approaches, namely a deterministic one in terms of the method of moments and a stochastic kinetic Monte Carlo approach. Accordingly, the most significant advantages and drawbacks of each technique are clearly demonstrated and the most fitted one (i.e., the Monte Carlo method) is implemented for the modeling of the system under different conditions, for which experimental data were available. Through these comparisons it is shown that the model can successfully follow the evolution of the reactions up to the formation of polysaccharides of very high degrees of polymerization.