Impact of the Cross-Linking Agent on the Physicochemical Performance of Alginate Hydrogels and the Release Rate of Immobilized Metronidazole

In this study, alginate hydrogels (A) cross-linked with a mixture of calcium and europium ions (Ca+Eu)A were developed for the first time as potential carriers for the targeted delivery and sustained release of drugs to specific regions of the gastrointestinal tract. Comparative studies were conducted to investigate the effect of the cross-linking agent (Ca2+, Eu3+, or their mixture) on the physicochemical properties of alginate hydrogels and the release kinetics of metronidazole in media simulating different gastrointestinal environments. Rheological analysis demonstrated that (Ca+Eu)A hydrogels form mechanically robust, highly cross-linked networks. The hydrogels exhibited negligible swelling in an acidic medium (swelling ratio, SR ≈ 1–1.5 g/g); however, in PBS, calcium alginate (CaA) hydrogels swelled 7–8 times more (SR ≈ 42.5 g/g) than hydrogels cross-linked with Eu3+ ions or a Ca2+/Eu3+ mixture (SR = 5–8 g/g). Metronidazole was released 1.5–2 times faster from calcium-cross-linked hydrogels than from hydrogels cross-linked with Eu3+ ions or the mixed Ca2+/Eu3+ system, whereas (Ca+Eu)A hydrogels exhibited a more sustained and uniform release profile. These results demonstrate that the drug release kinetics can be tuned by adjusting the Ca2+/Eu3+ ratio during alginate cross-linking. Consequently, such hydrogels represent a promising platform for the targeted delivery and controlled release of therapeutic agents, particularly antibiotics, to specific regions of the gastrointestinal tract.