Development of a method for industrial production of plga nanoparticles with quality by design (QBD) approach

The lack of knowledge and research for the industrial production of nanoparticles is a major factor preventing these carriers from entering the pharmaceutical market. Although PLGA nanoparticles, which are accepted as the gold standard by the FDA, which are biocompatible and prominent with their biodegradability advantages, have many conventional production methods, these methods are not suitable for industrial scale production. The emulsion-solvent evaporation process, which is one of the most common methods used, is not a suitable method for large scales due to the step of slowly dropping the organic phase into the water phase with the syringe. Microfluidizer technology working with the principle of high pressure homogenizer is suitable devices for the industrial production of 'self-assembly' systems. Microfluidizer saves development phases in pilot production and offers scale-up guarantee thanks to linear volumetric scaling. Microfluidizer technology produces narrow particle size distribution results, providing greater stability, longer shelf life and efficient raw material utilization. In this study, while the formulation parameters were optimized by quality by design approach, PLGA nanoparticles were produced on a pilot scale with the help of Microfluidizer device. Launched by the FDA, Quality by Design is an approach based on predetermined goals and providing control from the first stage of the product to the final stage when it is commercialized. Statistical experiment designs (Design of Experiments, DoE) form the basis of the QbD approach. With the central composite design, device and formulation factors were determined and an experimental matrix was created for 60 formulations. After the polynomial equations related to the factors and responses were created, the PLGA nano drug delivery system was optimized in terms of average particle size, zeta potential and PdI with the Minitab 17 software. The desired limits are determined as mean particle size, zeta potential and minimum standard deviations for PdI. Thanks to these answers, optimized PLGA amount, T80 amount, pressure level and transition levels were determined. For the validation of the model, the desirability index, which is frequently used in the industry, was used. The composite desirability value was obtained as 0.955, thus it was shown that the model and the optimized values reached the target well. PLGA nanoparticles were obtained with injectable (less than 200 nm), stable (zeta potential-greater than 20 mv) and a narrow PdI value (less than 0.2). Keywords: Microfluidizer, quality by design, pilot scale, PLGA, central composite design