Polypeptide-k is an antidiabetic phytochemical isolated from dried and ripened seeds of Momordica charantia. The peptide has not been able to find much clinical use despite its established therapeutic effect. This is mainly attributed to its poor aqueous solubility. Present study presents the formulation of solid dispersion containing polypeptide-k to enhance its aqueous solubility. The study was carried out by employing the optimization approach using spray drying technique. Variables were evaluated using Box Behnken design. These include trehalose to drug ratio, tween-80 to drug ratio, inlet air temperature and feed flow rate. Responses measured were moisture content, solubility, product yield and angle of repose. Data analysis by ANOVA test indicated that ratio of trehalose to PPK significantly affected product flow properties and yield, whereas ratio of tween-80 to PPK was found to significantly affect moisture content, solubility and flow properties of the resultant formulation. Inlet air temperature significantly influenced moisture content while feed flow significantly affected moisture content and product yield. The optimized batch of formulation exhibited higher solubility in water as well as various aqueous buffers as compared to pure polypeptide-k. Through PXRD and SEM, it was inferred that enhanced solubility was due to reduced particle size and increased surface area of polypeptide-k present in the formulation.