Purpose <p>The solubility of a crystalline drug in a polymer is commonly determined by measuring melting point depression with differential scanning calorimetry (DSC). The accuracy of this measurement depends on rapid dissolution of the drug into the molten polymer during the DSC heating scan. A preferred method of accelerating this dissolution process is to preblend the drug and polymer by cryo-milling. However, cryo-milling may be unsuitable for water-sensitive drugs or polymers such as poly(lactic-co-glycolic acid) (PLGA). The purpose of this study was to develop a PLGA-specific melting point depression method that did not require a cryo-milling operation.</p> Methods <p>A three-step DSC method was used to measure the solubility of a small-molecule drug, voriconazole, in amorphous PLGA (Resomer ® RG 502H). First, drug/PLGA powder mixtures of multiple drug loadings were melted and rapidly cooled to form glassy solid solutions. Second, these solid solutions were heated above their T_g until the drug crystallized. Third, these crystallized samples were slowly heated to measure melting point depression (i.e., solubility temperatures).</p> Results <p>The crystallization procedure generated the desired drug polymorph and likely generated small, well-mixed crystalline drug particles, as the drug dissolved rapidly into the molten polymer during melting point depression scans. Drug/PLGA solubility temperatures were determined with confidence between 40 – 100% drug loading. The solubility curve was extrapolated to lower drug loadings using the Flory–Huggins model.</p> Conclusion <p>This technique can assist product development of high-drug-loaded PLGA products, particularly those manufactured by melt extrusion.</p> Graphical Abstract <p></p>