Multivariate optimization of formulation and process variables influencing physico-mechanical characteristics of site-specific release isoniazid pellets

In the present study, isoniazid was formulated as site-specific release pellets with high drug loading (65%, w/w) using extrusion-spheronization followed by aqueous coating of Sureteric® (35% weight gain). A statistical experimental strategy was developed to optimize simultaneously the effect of the two formulation variables and one process variable on the critical physico-mechanical properties of the core pellets of isoniazid. Amount of granulating fluid and amount of binder were selected as formulation variables and spheronization speed as a process variable. A 23 full factorial experimental design was employed for the present study. Pellets were characterized for physico-mechanical properties viz. usable yield, pellet size, pellips, porosity, abrasion resistance, mechanical crushing force, residual moisture and dissolution efficiency. Graphical and mathematical analysis of the results allowed the identification and quantification of the formulation and process variables active on the selected responses. A polynomial equation fitted to the data was used to predict the responses in the optimal region. The optimum formulation and process parameters were found to be 44.24% (w/w) of granulating fluid, 2.13% (w/w) of binder and spheronization speed of 1000 rpm. Optimized formulation showed usable yield 84.95%, particle size 1021.32 μm, pellips 0.945, porosity 46.11%, and abrasion resistance 0.485%. However, mechanical crushing force, residual moisture and dissolution efficiency were not significantly affected by the selected independent variables. These results demonstrate the importance of, amount of water, binder and spheronization speed, on physico-mechanical characteristics of the isoniazid core pellets with high drug loading.