Combining non-toxic biomaterials to obtain high effective hybrids is a promising approach in medicine and drug delivery. This study aims to combine the biomaterial with different swelling behavior to attain high controlled release. Hydroxyapatite (HA) nanoparticles do not possess swelling properties and are stable in different pH solutions. HA was used to prevent the unwanted sudden release in acidic media by modifying the swelling properties of chitosan-based hydrogels (CTS). CTS being soluble in acidic pHs causes drug release as it dissolves, resulting in burst release behavior. The experiments confirmed that the introduction of HA remarkably reduced the swelling ratio, which independent of the pH led to a decrease in the release amount (approximately 38–73%) and prevented the burst release. The metronidazole-loaded CTS/MMt/HA1 with low content HA showed a high sustained pH-responsive release. However, the metronidazole-loaded CTS/MMt/HA2 with high content of HA didn't show sustained release. Indeed, the release rate was sustained by modifying the HA content. The kinetic investigations indicated the release mechanisms were changed from dissolution in CTS/MMt to diffusion in CTS/MMt/HA by introducing HA, which is compatible with the swelling ratio reduction. As well as CTS/MMt, HA grafted samples showed high encapsulation efficiency (>96%) and pH-sensitive properties. The biocompatibility of Metronidazole-loaded nanocomposites was confirmed by the cytotoxicity tests on the human nasopharyngeal carcinoma L929 cells.
