Integrated analytical characterization and multiscale modeling of supramolecular interactions in...

Poor aqueous solubility, limited physical stability of amorphous forms, and suboptimal systemic absorption remains major challenges for lipophilic small molecule drugs. In this study, lumefantrine (LMF) and curcumin (CUR) were engineered into stoichiometry-controlled coamorphous systems (CAMS) using an interaction-driven solid-state design strategy. Integrated analytical characterization using powder X-ray diffraction, differential scanning calorimetry, and attenuated total reflectance Fourier transform infrared spectroscopy confirmed the formation of homogeneous single-phase coamorphous matrices and established composition-dependent relationships between supramolecular organization, molecular mobility, and stability. Multiscale computational analyses integrating density functional theory, reduced density gradient analysis, and molecular dynamics simulations identified the dominant intermolecular interactions governing miscibility and stabilization within the CAMS. AI/ML models trained using interaction-derived molecular descriptors accurately predicted composition-dependent glass transition temperatures, showing close agreement with experimental measurements and simulation-derived estimates. Among the investigated systems, LC_12_CAM exhibited the most balanced supramolecular organization, integrating strong heteromolecular stabilization with controlled molecular mobility. This optimized architecture produced a ∼2-4-fold increase in apparent solubility relative to crystalline LMF and CUR and markedly improved dissolution performance, achieving >85-90% drug release within 6 h. The improved biopharmaceutical performance further translated into substantially enhanced systemic exposure of LMF in vivo and was accompanied by pronounced apoptosis-associated anticancer activity in A549 lung cancer cells. Accelerated stability studies confirmed sustained amorphous integrity of LC_12_CAM for six months, consistent with reduced moisture uptake observed in dynamic vapor sorption analysis. Collectively, these findings establish a stoichiometry-resolved structure-stability-performance framework for drug-drug CAMS and highlight the utility of integrated analytical characterization combined with multiscale predictive modeling for the rational design of stable, high-performing formulations of poorly soluble drugs.