Green mechanochemical design of a tulobuterol–ketoprofen binary system: solid-state intermolecular interactions, solubility enhancement, and modulated membrane permeation

To develop a solvent-free binary formulation of tulobuterol (Tulo) and ketoprofen (KTF) and evaluate its solid-state properties, solubility enhancement, and controlled transdermal delivery potential. A KTF/Tulo (1/1 molar ratio) ground mixture (GM) was prepared using mechanochemical co-grinding. Solid-state characterization was performed using differential scanning calorimetry, powder X-ray diffraction (PXRD), Fourier-transform infrared spectroscopy (FT-IR), and scanning electron microscopy. Molecular interactions were investigated via nuclear Overhauser effect spectroscopy and diffusion-ordered spectroscopy nuclear magnetic resonance (NMR) analyses. Solubility studies were conducted to assess improvements in aqueous solubility. Silicone membrane permeation and membrane retention studies were performed to evaluate transdermal release behavior. The KTF/Tulo GM exhibited substantial morphological changes and the loss of characteristic melting peaks, halo-pattern PXRD profiles, and FT-IR peak shifts. This indicated the formation of a novel low-crystallinity binary complex. NMR analyses confirmed intermolecular proximity and altered molecular association mediated by acid–base interactions and hydrogen bonding. The GM markedly enhanced KTF and Tulo solubility by 10–17 fold and 8–10 fold, respectively, compared with that of the pure compounds. Although Tulo alone showed high membrane permeation, the physical mixture and GM markedly suppressed transmembrane permeation. The enhanced membrane retention suggested altered membrane association behavior, which may influence drug release and permeation characteristics. The KTF/Tulo (1/1) binary system simultaneously improved drug solubility and enabled controlled transdermal delivery via reduced permeation and enhanced membrane retention. Overall, this solvent-free binary formulation represents a promising green chemistry-based strategy for multifunctional transdermal pharmaceutical systems containing pharmacologically distinct active ingredients. Mechanochemical grinding formed a solvent-free KTF/Tulo binary system. Solid-state analyses confirmed reduced crystallinity and intermolecular interactions. KTF/Tulo binary system significantly enhanced the solubility of both drugs. Binary formulation suppressed membrane permeation and improved retention. This system shows promising potential for controlled transdermal dual-drug delivery.