Utilization of supercritical CO2 gas antisolvent (GAS) for production of Capecitabine nanoparticles as anti-cancer drug: Analysis and optimization of the process conditions

• Capecitabine (CPT) nanoparticles were produced by GAS technique for the first time. • Experimental design based on Box–Behnken was employed to optimize the GAS process. • Prepared nanoparticles (CPT) were characterized by the SEM, DLS, FTIR, DSC and XRD. • A great reduction (243.3 nm) was observed compared to the original particles (65μm). • Optimum temperature, pressure and CPT concentration in DMSO are specified as 308 K, 160 bar and 15 mg/mL, respectively. Reducing the size of pharmaceutical particles is an approved way to enhance solubility and bioavailability of a drug, leading to a decrease in the drug dose and its side effects. In this research, nanoparticles of Capecitabine (CPT), an anti-cancer drug, were produced using the gas anti-solvent supercritical (GAS) process. Also, Box–Behnken design (BBD) method was applied to optimize the process condition. Accordingly, the GAS process was performed at different pressures of 120, 140 and 160 bar, temperatures of 308, 318 and 328 K, and solute concentrations of 15, 45 and 75 mg/mL. Based on the size of the precipitated CPT particles, the optimum condition was specified as the pressure of 160 bar, the temperature of 318 K and the initial CPT concentration of 45 mg/mL. Physical identification analysis including differential scanning calorimetry (DSC), X-ray diffraction (XRD), scanning electron microscopy (SEM), dynamic light scattering (DLS), Fourier transform infrared spectrometry (FTIR) and high pressure liquid chromatography (HPLC) analyses were employed to characterize the produced CPT nanoparticles. Significant size reduction of drug particles from 25 μm on average (original) to about 243.3 nm and uniform structure of obtained nanoparticles with a narrow size distribution indicate the effectiveness of the GAS process. Results of the physical analysis confirm the purity of CPT structure with no changes during the GAS process. Also, according to the results of DSC and XRD, the crystallinity of CPT nanoparticles was lower than that of the original sample, leading to higher solubility. Improved CPT solubility was also confirmed by comparison of the dissolution rate of the original and obtained CPT samples in optimum conditions.