Hesperetin Nanoparticle Powder as a Potential Antioxidant Nutraceutical Ingredient: Fabrication, Characterization, and Comparative Dissolution in Vegetarian and Non-Vegetarian Capsules

<b>Background/Objectives:</b> Hesperetin (HSP) is a bioactive flavonoid known for its strong antioxidant and anti-inflammatory properties. However, its low water solubility (1.36 ± 0.30 μg/mL) and poor oral bioavailability (~20%) greatly hinder its potential in nutraceutical applications. <b>Methods:</b> Using the solvent dispersion method, nanoparticles composed of HSP, hydroxypropyl-β-cyclodextrin (HPBCD), and polyvinylpyrrolidone K30 (PVPK30) were prepared and collectively termed HHPNP. Characterization involved particle size measurement, FTIR, XRD, SEM, and TEM. Antioxidant activity was evaluated using DPPH and ABTS⁺ radical scavenging assays. In vitro dissolution testing was performed at pH 1.2 and pH 6.8 to compare HHPNP with physical mixtures, and release behavior was assessed using both gelatin (non-vegetarian) and HPMC (vegetarian) capsules. <b>Results:</b> The optimal formulation (1:15:12) produced uniformly distributed spherical nanoparticles with a mean size of 14.87 ± 0.49 nm and achieved an 827-fold increase in water solubility compared with raw HSP. FTIR analysis indicated hydrogen bond formation, and XRD confirmed a complete transition from a crystalline to an amorphous state. In aqueous environments, HHPNP demonstrated markedly improved antioxidant activity, with DPPH and ABTS⁺ radical scavenging comparable to HSP solutions prepared in methanol. In vitro dissolution testing revealed rapid release at both pH 1.2 (>65% in 10 min) and at pH 6.8 (70% in 5 min). In contrast, physical mixtures only released 10-30% over two hours. T50% values at pH 1.2 were 17.8 min (gelatin) and 16.8 min (HPMC). At pH 6.8, T50% values were 17.6 min (gelatin) and 7.5 min (HPMC). Both capsule types matched the HHPNP in release at 120 min, and these comparable profiles indicate the formulation's stability and adaptability across capsule variants. <b>Conclusions:</b> This nanoparticle-based delivery system, leveraging molecular inclusion and amorphization, significantly enhanced the solubility, bioactivity, and release efficiency of HSP, offering a potent platform for oral flavonoid-based dietary supplements.