Phospholipid-based formulations provide a key technology to formulate poorly water-soluble drugs. A recent interest has been in using phospholipids with a high content of monoacyl phosphatidylcholine (monoacyl PC) due to its ability to form mixed micelles of mono- and di-acylphospholipids upon aqueous dispersion. The present work focused on binary drug- monoacyl PC systems (at about equimolar ratio) with respect to screening of solid dispersion feasibility. It was tested whether or not a molecular rule of thumb can predict the desirable absence of drug crystallinity in the products. Subsequently, molecular simulations were performed to gain a better understanding of molecular association between drugs and monoacyl PC. Finally, the glass-forming ability (GFA) of pure drugs was considered with respect to solid dispersion formation. All products were obtained from a solvent-evaporation process and subsequent analysis of potential drug crystallinity was measured with X-ray powder diffraction and differential scanning calorimetry. Molecular simulations were making use of a Monte Carlo algorithm and molecular properties relevant for GFA were calculated. As a result, the dataset of 28 drugs confirmed an earlier proposed empirical rule that enthalpy of fusion and logP were important for solid dispersion formation, while some relevance was also evidenced for drug energies of frontal orbitals. Interestingly, the Monte Carlo simulations revealed several likely associations between drug and phospholipid rather than a well-defined single complex formation. However, drug-excipient interactions were still pivotal, since GFA of pure drug could not predict solid dispersion formation. These findings led to important molecular insights into binary solid dispersions of drug and monoacyl PC, which can guide formulators in early drug product development.