This paper presents a complex analytical study on the distribution, solubility, amorphization, and compatibility of diltiazem within the composition of Eudragit RS 100-based particles of microspongeous type. For this purpose, a methodology combining attenuated total reflectance Fourier transform infrared (ATR-FTIR) absorption spectroscopy, differential scanning calorimetry (DSC), scanning electron microscopy with energy-dispersive X-ray microanalysis (SEM-EDX), and in vitro dissolution study is proposed. The correct interpretation of the FTIR and drug-dissolution results was guaranteed by the implementation of two contrasting reference models: physical drug-polymer mixtures and casting-obtained, molecularly dispersed drug-polymer composites (solid dispersions). The spectral behavior of the drug-polymer composites in the carbonyl frequency (νCO) region was used as a quality marker for the degree of their interaction/mutual solubility. A spectral-pattern similarity between the particles and the solid dispersions indicated the molecular-type dispersion of the former. The comparative drug-desorption study and the qualitative observations over the DSC and SEM-EDX results confirmed the successful synthesis of a homogeneous coamorphous -type formulation with excellent drug-loading capacity and "controlled" dissolution profile. Among them, the drug-delivery particles with 25% diltiazem content (M-25) were recognized as the most promising, with the highest population of drug molecules in the polymer bulk and the most suitable desorption profile. Furthermore, an economical and effective analytical algorithm was developed for the comprehensive physicochemical characterization of complex delivery systems of this kind.