Montmorillonite (Mt) has been extensively applied in drug delivery systems owing to its high cation exchange capacity, large specific surface area, and biocompatibility. However, its strong hydrophilicity and interlayer water molecules significantly restrict the efficient loading of hydrophobic drugs (e.g., ibuprofen (IBU)). Organic modification using surfactants can enhance Mt's hydrophobicity, where cationic types dominate as mainstream modifiers due to their efficient ion-exchange characteristics, capable of expanding interlayer spacing and optimizing drug compatibility. Nevertheless, anionic surfactants rely on anion-dipole interaction adsorption, while nonionic surfactants, despite advantages in low toxicity and biodegradability, exhibit inferior binding efficiency with limited research on related drug carriers. Recently, green nonionic alkyl polyglucosides have attracted considerable attention for their environmental friendliness, superior interfacial activity, and biosafety. This study employed dodecyl glucoside (DPG) to fabricate DPG-Mt composite carriers through wet ball-milling intercalation modification. It systematically investigated the intercalation mechanisms between nonionic surfactants and Mt, along with drug-loading performance and release behaviors, aiming to overcome limitations of conventional ionic modifiers and elucidate the efficiency-enhancing principles of nonionic modification in drug delivery systems. This research not only provides novel strategies for developing safe and stable Mt-based drug delivery systems but also advances technological innovation in green pharmaceutics, demonstrating significant theoretical and practical implications.

This study employed green and safe nonionic DPG to prepare a safe and biocompatible DPG-Mt based pharmaceutical formulation through intercalation modification of natural Mt using a wet ball-milling technique. The synthesized DPG-Mt was systematically characterized for its morphology, crystal structure, functional groups, thermal stability, and colloidal properties using scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), Raman spectroscopy (RS), thermogravimetric analysis (TGA), BET surface area analysis, and Malvern laser particle size analysis. By investigating the effects of various DPG content on the structure and properties of DPG-Mt, the mechanistic role of DPG in modifying Mt was elucidated, and the adsorption capacity of DPG-Mt for the anti-inflammatory drug, IBU was evaluated. Finally, simulated drug release experiments were conducted to examine the IBU release behavior from drug-loaded DPG-Mt, while cytotoxicity assays were performed to assess its biocompatibility, thereby validating its potential for biomedical applications.

The characterization results of DPG-Mt revealed that the wet ball-milling process did not disrupt or exfoliate the layered structure of Mt. Instead, under the compressive, impact, and frictional forces of mechanical ball-milling, the particle size of Mt was significantly reduced. DPG overcame the weak electrostatic forces, van der Waals interactions, and hydrogen bonding between stacked Mt layers, adsorbing and intercalating into its interlayer spaces, thereby expanding the interlayer spacing of DPG-Mt. Specifically, the interlayer spacings of 1.0DPG-Mt, 2.0DPG-Mt, and 3.0DPG-Mt increased to 1.47 nm (2θ = 6.0°), 1.55 nm (2θ = 5.7°), and 1.52 nm (2θ = 5.8°), respectively. Raman spectroscopy and BET surface area analysis demonstrated that nonionic DPG did not form chemical bonds with DPG-Mt but was physically intercalated into the interlayers via hydrogen bonding and electrostatic interactions. The BET surface area of Na-Mt increased from 62.6 m²/g to 72.0 m²/g under mechanical ball-milling, likely due to the fragmentation of large Mt particles during the modification process. However, the adsorption and intercalation of DPG into DPG-Mt partially obstructed pore channels, leading to a reduction in pore volume and average pore size from 0.337 mL/g and 4.61 nm to 0.245 mL/g and 2.15 nm, respectively.

Concurrently, after organic modification, the particle size of DPG-Mt decreased from 984.0 nm (PDI = 0.34) to 605.0 nm (PDI=0.31), while its zeta potential increased from -39.7 mV to -22.5 mV. These results indicated that the adsorption and intercalation of DPG not only inhibited particle aggregation but also reduced surface charge density. Furthermore, the interfacial tension (IFT) of the DPG-Mt aqueous suspension significantly decreased from 72.75 × 10^-3 N·m^-1 to 41.12 × 10^-3 N·m^-1 after modification. This phenomenon can be attributed to the hydrophobic dodecyl chains of intercalated DPG, which weakened the hydrophilicity of DPG-Mt and enhanced its interfacial activity. Adsorption experiments to IBU demonstrated that organic modification increased the saturated adsorption capacity (Q_m) of Mt for IBU from 35.336 mg/g to 46.083 mg/g, with IBU adsorption on DPG-Mt favoring a multilayer mechanism. In vitro drug release and cytotoxicity analyses revealed that both Mt and DPG-Mt exhibited sustained release of IBU over 480 min. Notably, the biocompatible DPG-modified Mt (DPG-Mt) displayed superior biocompatibility, underscoring the synergistic benefits of organic modification in optimizing drug delivery performance while maintaining biosafety.

The wet ball-milling process exerted compressive, impact, and frictional forces on Mt, leading to reduced particle size, increased specific surface area, and enhanced colloidal interfacial activity of DPG-Mt. The organic modification of Mt by DPG occurred via physical intercalation, where DPG was physically embedded into the interlayer spaces of Mt under mechanical forces. This not only expanded the interlayer spacing and improved the thermal stability of the intercalated DPG but also effectively altered the strong polarity of Mt, thereby enhancing its affinity for the hydrophobic IBU. Consequently, the saturated adsorption capacity of Mt for IBU increased from 35.336 mg/g to 46.083 mg/g. Owing to the superior adsorption performance of DPG-Mt to IBU, DPG-Mt exhibited sustained drug release over 480 min, demonstrating favorable sustained-release performance, with the released IBU amounting to 76% of the total dosage. Cytotoxicity tests further confirmed that the organic modification of Mt with DPG conferred excellent cytocompatibility to DPG-Mt. Given its high drug adsorption capacity, excellent sustained-release properties, and outstanding cytocompatibility, DPG-Mt demonstrates significant potential as a hydrophobic anti-inflammatory drug formulation for biomedical applications.