Statistical optimization of a method to generate alginate microparticles by co-axial air microcapillary atomization and ionic gelation

Polysaccharides, such as alginate and chitosan, are widely used as base biomaterials in drug delivery systems due to their abundance, biocompatibility, biodegradability and low immunogenicity, and the ease with which they generate microcarriers by mild methods, mainly the ionic gelation technique. However, the limiting step is the generation of drops of polymer in the micrometer scale, being the atomization processes the most convenient. In this article, a custom-made device based on a co-axial air flow and capillary HPLC tubing was used to adapt the oil-free droplet microfluidics method and generate fine sprays with D[4,3] mean sizes from 39 to 104 μm and size distributions with Span values between 1.22 and 2.96, with the droplets being stabilized by the ionic gelation reaction using calcium chloride. This synthesis method was statistically optimized by a two-step design of experiments-based approach consisting of a screening process, using fractional designs, and a response surface methodology with central composite designs. The fitted model for size distribution (span) depends on three factors (alginate concentration, air flow rate and the distance between the nozzle and the hardener solution), while the mean size of particles depends only on the alginate concentration and the air flow rate. Moreover, the best conditions to minimize the size distribution and to obtain the minimum and maximum expected values for the D[4,3] mean size were determined.