Purpose <p>This study investigates the intermolecular interactions between Bisoprolol fumarate (1) and Candesartan cilexetil (2) to characterize the physicochemical compatibility of their binary system, providing a scientific framework for stable fixed-dose combinations.</p> Methods <p>A multidisciplinary approach was employed, integrating thermal (DSC) and spectroscopic (FTIR) analyses with Response Surface Methodology (RSM) to explore binary behavior. Computational analysis, including Density Functional Theory (DFT) and Hirshfeld surface analyses, was used to characterize intermolecular interactions. A rapid HPLC method (3-minute run time) was developed and validated for simultaneous quantification. Forced degradation studies were conducted under thermal and hydrolytic stress.</p> Results <p>DSC revealed the disappearance of (2)’s melting endotherm and a shift in (1)’s melting peak, while FTIR confirmed that interactions are non-covalent in nature, resulting in the establishment of stable intermolecular hydrogen bonding throughout the binary system. However, forced degradation studies showed significant chemical sensitivity under thermal and hydrolytic stress, particularly in alkaline media. Computational analysis suggested the formation of a stable binary system stabilized by hydrogen bonding, π–π stacking, and van der Waals forces. The HPLC method proved highly specific and precise, ensuring reliable quantification.</p> Conclusion <p>This integrated approach demonstrates that while (1) and (2) maintain physical compatibility and structural consistency upon initial mixing, their chemical vulnerability under stress necessitates advanced formulation strategies. The study highlights the synergy between experimental and computational tools in assessing drug-drug compatibility.</p>