MHY498 Nanosuspensions for Improved Topical Drug Delivery: Understanding of Its Solubility Behavior in DEGME + Water Mixtures and Preparation of Nanosuspension Using Box–Behnken Design

<b>Background/Objectives</b>: MHY498, a tyrosinase inhibitor, exhibits poor water solubility, which limits its topical delivery. Despite the importance of solubility data in rational formulation design, comprehensive information on its solubility behavior in various solvents and across a range of temperatures remains limited. Thus, this study aimed to systematically evaluate the solubility characteristics of MHY498 and to develop a nanosuspension formulation using an antisolvent precipitation approach to facilitate the development of an optimized topical formulation. <b>Methods</b>: In this study, we measured the solubility of MHY498 in various monosolvents and diethylene glycol monoethyl ether (DEGME) + water solvent mixtures at 293.15-313.15 K using a solid-liquid equilibrium technique. Based on these solubility data, MHY498 nanosuspensions were prepared via antisolvent precipitation guided by a Box-Behnken design matrix. In vitro skin permeability was also assessed using a Franz diffusion cell system to assess the topical delivery potential of the MHY498 nanosuspensions. <b>Results</b>: Among the investigated monosolvents, MHY498 exhibited the highest solubility in dimethylformamide, dimethylacetamide, DEGME, while the lowest solubility was observed in water. The solubility increased with temperature and DEGME content in solvent mixtures, and the experimental data were well described by thermodynamic and semi-empirical models, indicating an endothermic and spontaneous dissolution process. Solvent-solute interaction analysis revealed that hydrogen-bonding and nonspecific polarity interactions played key roles in enhancing MHY498 solubility. All nanosuspensions prepared within the design space exhibited particle sizes below 150 nm, and the optimized formulation achieved an average particle size of 28.1 nm. The optimized nanosuspension demonstrated a 3.3-fold increase in the cumulative permeated amounts compared with the conventional microsuspension. <b>Conclusions</b>: These findings demonstrate that a rational solvent selection strategy based on thermodynamic solubility analysis and antisolvent precipitation enables effective nanosuspension formulation of MHY498. The DEGME-water system was identified as a formulation-relevant solvent environment that supports both adequate drug solubilization and reproducible formation of nanosized particles. The resulting nanosuspension exhibited favorable particle size characteristics and enhanced formulation feasibility for topical applications. Therefore, it was shown that the developed nanosuspension system, established through a solubility-driven systematic approach, represents a promising strategy for improving topical delivery of MHY498.