FORMULATION AND OPTIMIZATION OF CHLORTHALIDONE LOADED NANO-PARTICLES BY ANTISOLVENT PRECIPITATION USING BOX-BEHNKEN DESIGN

Chlorthalidone is a long-acting diuretic recommended for treatment of oedema associated with congestive heart failure. It is oral active diuretic mainly acting on distal convoluted tubule of nephron. Chlorthalidone is poorly soluble in water at room temperature. Nanoparticles have great potential as a carrier and can improve the solubility of poorly water-soluble drugs like chlorthalidone. The aim of the present study was to formulate and optimize the chlorthalidone nanoparticles using Box-Behnken factorial design approach. Effect of three independent variables (concentration of polymer, amount of surfactant and ultrasonication frequency) on two dependent variables such as particle size and dissolution of the drug was studied. The nanoparticles of chlorthalidone were formulated by anti-solvent precipitation-ultrasonication-freeze drying technology to improve its solubility and dissolution. The samples were characterized using Horiba nanoparticles analyzer, Zeta potential analyzer, Differential Scanning Calorimetry (DSC), Fourier Transform Infrared Spectroscopy (FTIR), Powder X-ray Diffraction (PXRD), and Field Emission Scanning Electron Microscopy (FESEM). The average particle size of 342.5 nm with a Polydispersibility index 0.158 was confirmed by dynamic light scattering. Differential scanning calorimetry and powder X-ray diffraction revealed reduced crystallinity of chlorthalidone. Freeze-dried nanoparticles were observed as spherical shape under field emission scanning electron microscopy. The value of zeta potential was -15.5 mV. In-vitro dissolution study by dialysis bag investigated improvement of dissolution rate. The stability of the developed nanoparticle was confirmed by the accelerated stability study of developed nanoparticles. These results showed an increase in the saturation solubility and drug release of chlorthalidone due to particle size reduction and amorphous nature of the drug.