The use of design of experiments and green chemistry for the preparation of a taste-masked metronidazole-loaded cubosomal nanostructured oral gel.

Taste masking is critical when developing formulations for paediatric patients. Metronidazole (MTZ) was encapsulated in cubosomal gels to mask its bitter, metallic taste. A cubosomal gel using glyceryl monooleate, oleic acid, Poloxamer 407, and polyvinyl alcohol was developed and optimized using Box-Behnken and I-Optimal designs.The optimized nanocarrier particle size was 34.30 nm, Zeta potential -26.6 mV, polydispersity index 0.152, and entrapment efficiency 38.73%. TEM confirmed the formation of a cubic nanostructure, and FTIR was used to monitor stability. The <i>in vitro</i> release was biphasic, with 14% MTZ released within 5 minutes, followed by sustained release over 12 hours. Diffusion-controlled release was confirmed using Higuchi and Korsmeyer-Peppas models. Effective taste masking was determined using an electronic. The system exhibited satisfactory physicochemical stability at 22 °C, over 4 weeks, with PS, PDI, and ZP remaining within acceptable parameters. The EE decreased from 38.73% to 24.75%, indicating hydrophilic-driven MTZ leakage during storage.The cubosomal gel formulation effectively masks unpleasant taste, sustains MTZ release, and maintains acceptable physicochemical properties at 22 °C for four weeks. The EE requires further optimization. These results suggest that cubosomal encapsulation may be a taste-masking strategy for MTZ. Translation to periodontal applications will require evaluation of mucoadhesion, gingival retention, antimicrobial efficacy, and formulation behaviour in gingival crevicular fluid.