Abstract

Product development using quality by design is a proactive and risk-based approach that shifts the manufacturing process from empirical to science-based. Risk assessment was performed to identify and analyse risk areas for the manufacture of captopril pellets. Twelve experimental runs were performed using a Plackett-Burman screening design. Pareto plots revealed the effect of formulation and process variables on the responses monitored and facilitated the identification of the most critical parameters for optimization of the formulation. A response surface methodology approach in conjunction with a central composite design was used to optimize the Eudragit® RL 30D (15-30 ml), microcrystalline cellulose (20-40 % w/w), sodium starch glycolate (2-5 % w/w) and spheronizer speed (650-1050 rpm). The amount of Eudragit® RL 30D had a significant effect on % yield, cumulative % captopril released and content. The % cellulose had a moderate effect on particle size and % yield. The signal to noise ratio was found to be adequate and therefore the model could be used to navigate the design space. The lower and upper limits for Eudragit® RL 30D, % w/w cellulose, % w/w disintegrant and spheronizer speed were established as 20-22 ml, 32-34 % w/w, 3.7 -4.1 % w/w, 928-1050 rpm, respectively. In vitro release of captopril from the optimized, lower and upper limit design space formulations ranged between 59.60-76.01, 95.68-110.34 and 101.12-111.84 %, respectively. In conclusion, a risk-based quality by design approach and design of experiments was successfully used to establish a design space for captopril pellets manufactured by extrusion-spheronization while monitoring targeted outputs for safe and effective use.