Structure-Property Relationships Governing Encapsulation and Release of Antibiotics from Calcium–Alginate Hydrogels

Understanding mass transport of structurally different drugs within ionically crosslinked hydrogel networks remains an important challenge in polymer-based delivery systems. In this study, hydrophilic amoxicillin (AMOX) and amphiphilic doxycycline (DOX) were encapsulated into calcium–alginate beads, respectively. A three-factor and three-level Box–Behnken design was utilized to examine the influences of alginate concentration (2–5%, w/v), CaCl2 concentration (1–3%, w/v), and gelation time (15–45 min) on encapsulation efficiency (EE). EE exhibited considerable variability for both AMOX (10–86%) and DOX (10–63%). Optimal EE values were achieved at almost 3.5% alginate and 3% CaCl2. The optimized gelation times differed between AMOX (45 min) and DOX (15 min), which is likely associated with differences in their physicochemical properties, although additional intermediate gelation times could further refine the optimal conditions. ANOVA identified CaCl2 concentration and the quadratic effect of alginate as the most influential parameters. Furthermore, both models demonstrated robust predictive capability (R2 > 0.98). In vitro release experiments demonstrated minimal drug diffusion in simulated gastric fluid (SGF) and significantly accelerated release in simulated intestinal fluid (SIF). These findings indicate a pH-responsive release behavior under simulated gastrointestinal conditions. The release profile was best represented by Higuchi and Korsmeyer–Peppas kinetic models. SEM and optical microscopy revealed uniform spherical beads with drug-dependent microstructural differences: hydrophilic AMOX produced smoother, wrinkled surfaces, whereas amphiphilic DOX induced localized cracking and heterogeneous microdomains. Furthermore, DLS and zeta potential measurements of the released fractions indicated nanoscale particle populations (≈190–225 nm) with moderate negative surface charge (≈−21 mV), suggesting stable colloidal dispersion during intestinal-phase release.