A Design of Experiment Study of Nanoprecipitation and Nano Spray Drying as Processes to Prepare PLGA Nano- and Microparticles with Defined Sizes and Size Distributions.

Purpose: Aim of this study was to explore the potential of a design of experiments approach to nanoprecipitation (NPR) and nano spray drying (NSD) as processes for preparing poly (lactic-co-glycolic acid, PLGA) nano- and microparticles. In particular, we determined the feasible size range, critical factors influencing particle size, size distribution or yield, and the robustness towards variations of the batch size.

Methods: A fractional factorial design for response surface was applied to study the influence on continuous, categorical and discrete factors.

Results: NPR yielded nanoparticles (150-200 nm) with narrow size distribution (PDI < 0.15). Polymer concentration was the main factor in this process, which was found to be very robust to varying the batch size (0.625-50.0 ml). In contrast, NSD yielded microparticles (2-163 μm). The latter process appeared, however, to be influenced by various factors and, therefore, more difficult to control and less robust towards varying the batch size (5-40 ml). By a factorial design approach to NPR, we succeeded to derive an equation, which allowed the prediction of several optimal formulations with defined particle sizes and distributions.

Conclusion: DOE can help to understand innovative manufacturing processes for nano- and microparticulate drug delivery systems, as well as to optimize these processes regarding particle size, size distribution and yield. Such understanding of these processes is instrumental for their subsequent scale up and quality control as needed for preclinical and clinical test batches.