Enhancing the Solubility and Antibacterial Efficacy of Sulfamethoxazole by Incorporating Functionalized PLGA and Graphene Oxide Nanoparticles into the Crystal Structure

<b>Background/Objectives</b>: The widespread use of sulfamethoxazole (SMX) has led to increasing antibiotic resistance, and there is a need for improved formulations to enhance its therapeutic effectiveness. In this study, we investigated the biocidal potential of SMX composite crystals incorporated with functionalized poly(lactic-co-glycolic acid) (<i>nf</i>PLGA) and nano-graphene oxide (nGO). <b>Methods</b>: The composites, namely SMX-<i>nf</i>PLGA and SMX-nGO, were synthesized via antisolvent precipitation and evaluated using Kirby-Bauer disk diffusion assays. <b>Results</b>: Incorporation of <i>nf</i>PLGA and nGO significantly improved SMX solubility, increasing it from 0.029 mg/mL to 0.058 mg/mL and 0.063 mg/mL, respectively. Additionally, the log partition coefficient (log P or K_w) also improved from 1.4 to 0.86 for nGO and 0.92 for <i>nf</i>PLGA composites. Both formulations exhibited improved antibacterial activity with distinct time-dependent bactericidal effects. Compared to pure SMX, the SMX-<i>nf</i>PLGA showed 60% and 53% greater bacterial inhibition at concentrations of 50 mg/mL and 100 mg/mL, respectively. Although SMX-nGO was slightly less potent, it still surpassed pure SMX, with 50% and 33% higher inhibition at the same concentrations. <b>Conclusions</b>: Importantly, neither <i>nf</i>PLGA nor nGO showed any biocidal effects, confirming that the observed enhancement was due to improved SMX solubility caused by their incorporation. These findings suggest that embedding solubility-enhancing nanoparticles into the existing crystal structure of the antibiotic is a promising strategy for enhancing the effectiveness.