Three-Dimensional Response-Surface Models to Predict the Diameter of Electrospun Polycaprolactone Nanofibers: Application in the release of ferulic acid.

Controlling the diameter of electrospun polymeric nanofibers is essential for optimizing their performance in localized drug delivery applications. In this context, mathematical models able to use processing parameters to predict nanofiber dimensions remain limited. In this work, a series of polycaprolactone nanofibers synthesized across a wide diameter range (727-2925 nm) were initially fabricated by the electrospinning method to be subsequently evaluated for localized drug release applications. The nanofiber diameter was systematically varied by adjusting the flow rate and the solvent composition during nanofiber fabrication, while keeping the polymer mass constant. After that, three-dimensional response-surface models were developed, revealing a logarithmic dependence of the nanofiber diameter on the flow rate and an inverse dependence on the solvent ratio. Importantly, both the polymer mass flux through the Taylor cone and the solution viscosity were found to be derived variables, rather than independent, governed by the flow rate and solvent composition, respectively. To connect nanofiber fabrication with drug delivery performance, ferulic acid was selected as a model bioactive compound, and it was incorporated into the nanofibers at three loading levels (0.5, 2, and 6 wt %). Release studies, monitored by high-performance liquid chromatography and ultraviolet-visible spectroscopy, showed that the release behavior was strongly dependent on the ferulic acid content and on the electrospinning processing conditions, whereas no direct dependence on the nanofiber diameter alone was observed. Finally, a kinetic analysis using Higuchi, Peppas-Sahlin, and first-order models revealed that a purely diffusive mechanism does not apply. Instead, the release follows either a first-order or a Peppas-Sahlin model depending on the flow rate used during fabrication. These findings demonstrate that the processing parameters that govern nanofiber diameter also control the internal drug distribution and, consequently, the release kinetics, providing a unified framework for the rational design of electrospun drug delivery systems.