(592g) Self-Assembly Induced Solubilization of Drug-like Molecules in Nanostructured Ionic Liquids

Dissolution is a fundamental process that is vital for chemistry and biological science. Unfortunately, many drug molecules exhibit poor solubility due to their high molecular weights and structural complexity, which leads to low bioavailability and substantially hinders the development of efficient separation methods and drug delivery systems. To date, a wide variety of solubilization strategies have been developed to improve drug molecule solubility. These include molecular modification, mixed solvents, micelles and microemulsions, cosolvent, deep eutectic solvents, and ionic liquids (ILs). Although substantial progress has been made, the solubility of relatively large molecules with both H-bond and hydrophobic segments is still limited. Aim of the present work is to overcome this limitation, a novel and versatile approach, which is referred to as a self-assembly induced (SAI) solubilization strategy is developed using nanostructured ILs, for the dissolution of sparingly soluble drug-like molecules with both H-bond and hydrophobic segments. First, the drug-like molecules form an amphiphilic complex with the nanostructured ILs via H-bond interactions, and then, the complex undergoes secondary self-assembly in the nanostructured ILs to form a highly ordered aggregate structure, such as a liquid crystal (LC), at room temperature. With this strategy, the enhancement of solubilization could transcend the limit of the conventional interaction-adjustment mode, resulting in extremely high solubilities of various drug-like molecules being achieved. For example, the molar solubilities of cholesterol and stigmasterol were as high as 0.91 and 0.93 at 50 °C, which are 5-8000-fold higher than their solubilities in organic solvents, micelles, microemulsions, and common ILs; the solubilities of naproxen, folic acid, hydrocortisone, vitamin D₃, and indomethacin, are also the highest level reported in the literature. Small angle X-ray scattering (SAXS), polarized optical microscopy (POM), wide angle X-ray diffraction (WAXRD) and infrared (IR) spectroscopy measurements were employed to investigate the nanoscale organizations in these long-chain carboxylate ILs (LCC-ILs) and the dissolution mechanism. In addition to the ultra-high solubility, the SAI solubilization strategy using nanostructured ILs has two distinctive features. First, differing from the classic microemulsion solubilization method that uses surfactants, solvents, and other excipients, only one LCC-IL was employed in this strategy due to the unique properties of these nanostructured ILs. Secondly, the SAI solubilization strategy is highly reversible. It is a physical dissolution process based on reversible H-bond self-assembly rather than covalent modification. In addition, the solubilities of these seven drug molecules in water/[P₄₄₄₄][C₁₅H₃₁COO] and phosphate-buffered saline (PBS)/[P₄₄₄₄][C₁₅H₃₁COO] mixtures are still 2-35-fold higher than in common microemulsions under similar conditions and is 2-4 orders of magnitude higher than in pure water even at low IL concentration. Our work shows that both mesoscopic aggregation and H-bond interactions play pivotal roles in the self-assembly induced dissolution behavior. Based on its excellent performance and unique chemistry, we believe that the SAI solubilization strategy will inspire more applications of nanostructured ILs for advanced separation and novel drug delivery systems.

References

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Acknowledgements

The research was supported by the National Natural Science Foundation of China (21222601, 21476192, and 21436010), the Zhejiang Provincial Natural Science Foundation of China (LR13B060001), and Huabin Xing was supported by the Young Top-Notch Talent of Ten Thousand Talent Program of China..