Exploratory In Silico Evaluation of Microencapsulation Matrices for Indomethacin

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin (ID), may produce gastrointestinal adverse effects associated with cyclooxygenase-1 (COX-1) inhibition, motivating the investigation of microencapsulation strategies for modulating drug release. However, protein-based encapsulating materials remain comparatively underexplored using molecular simulation relative to synthetic polymers. In this study, the interaction tendencies of ID with cottonseed flour protein (CFP) and maltodextrin (MD) as potential encapsulating matrices were explored in silico using molecular dynamics simulations under NPT and NVT ensembles, cohesive energy density and Hildebrand solubility parameter (δ) calculations, the Flory–Huggins interaction parameter (χ), and mixing energy (Emix). The protein cohesive properties exhibited substantial force-field dependence, while the absolute χ values obtained for the binary systems were considerably higher than those reported for comparable drug–excipient systems, limiting their quantitative interpretation as predictors of miscibility. Nevertheless, within the same computational framework, CFP–ID exhibited lower χ and Emix values than MD–ID, indicating comparatively less unfavorable calculated interactions. As a complementary analysis independent of the formulation assessment, molecular docking of free ID against COX-1 and COX-2 showed a relative computational trend qualitatively consistent with published enzyme-inhibition data. Overall, the results support the use of the present workflow as an exploratory computational pre-screening approach and identify CFP as the candidate warranting further investigation among the two encapsulating materials evaluated, subject to experimental validation.