The Flory-Huggins model interaction explained the compatibility and extent of polymer dissolution in selected solvent mixtures via Hansen Solubility Parameters (HSP). Metastable zone where nucleation of NPs would start was determined by the solvent mixture – polymer – water interaction. Simulation results explained that the combination of acetone-chloroform (0.20:0.80) was better than acetone-ethyl lactate (0.40:0.60) for PCL solvation while ethyl lactate-dimethyl sulfoxide (0.60:0.40) was better for PLA solvation as compared to ethyl lactate-acetone (0.80:0.20). Nanoprecipitation with aqueous to organic volume ratio of 10 was used to prepare the biodegradable PCL nanoparticles for experimental validation. The organic phase was 1 g L−1 PCL in solvents or solvent mixtures and the antisolvent was deionized (DI) water. Scanning Electron Microscope (SEM) and Atomic Force Microscope (AFM) were used to examine the morphology and size of nanoparticles formed. Results showed that the acetone-chloroform with volume fraction of 0.20 to 0.80 was the best solvent mixture for PCL in producing NPs with the mean size less than 100 nm. Solvent mixture proved by numerical simulation and experimental validation, able to enhance the affinity of polymer (PCL or PLA) for water to produce nanoparticles with much smaller size.