The present study was aimed at enhancing the entrapment efficiency of highly water soluble Isoniazid (INH) nanoparticles using the biodegradable polymers, Poly-ε-caprolactone (PCL) by varying the different formulation parameters such as polymer ratio, amount of drug loading (w/w), solvent selection, electrolyte addition and pH in the formulation. The PCL loaded INH were prepared by water-in-oil-in-water double emulsion technique. The prepared nanoparticles were characterized by atomic forced microscopy (AFM), differential scanning calorimetry (DSC) and for in vitro drug release study. Fourier transform infrared spectroscopy (FTIR) study, differential scanning calorimetry analysis and in vitro release kinetics study. The percentage entrapment can be enhanced up to 63 by changing different formulation parameters.