The research focuses on optimizing the production of hydrogel microspheres using droplet microfluidics for pharmaceutical and bioengineering applications. A semiempirical method has been developed to predict the dynamic interfacial tension at the interface of ion-cross-linked sodium alginate microsphere-sunf lower oil modified with glacial acetic acid and Tween 80 surfactant. These microspheres are produced in a smallscale coaxial device that is manufactured using affordable DLP/LCD 3D printing technology with a transparent photopolymer. The method was tested to design the minireactor in the device, which allows for the production of fully cross-linked microspheres that are ready for use at the output of the reactor without additional cross-linking steps in the microsphere collector. The mathematical expression for estimating the interfacial tension at the moment of formation of a hydrogel microsphere includes the Reynolds number for a two-phase liquid, the Ohnesorge number, and the surface tension at the liquid−air interface for continuous medium flow (modified oil). The reliability of the prediction is confirmed for continuous medium and dispersed phase flow rates of 0.8−3.2 and 0.01−0.08 mL/min, respectively. The evolution of the interfacial tension from the moment the microspheres formed and the estimated ultimate interfacial tension in a cross-linked hydrogel−modified oil system contributed to the reliable determination of the linear size of a minireactor. The ultimate interfacial tension of 76.5 ± 0.3 mN/m was determined using the Young−Laplace equation, which is based on measuring the surface free energy of the hydrogel as soft matter using the Owens-Wendt method. Additionally, the equilibrium static contact angle of the fully cross-linked hydrogel surface wetted with oil is measured using the sessile drop method. From a practical perspective, a method for optimizing and streamlining the high-tech manufacturing of cross-linked polymer microspheres and mini-and microchannel devices for use in bioengineering and pharmaceutical applications is suggested.