Hydrogels derived from lithocholic acid (LCA), other bile acids, and their salts are promising materials for drug delivery, cellular immobilization, and other applications. We have found that ammonium salts of LCA are particularly useful for probing the mechanism of hydrogelation and for understanding the relationship between molecular organization in gels and crystals. The well-defined amphiphilic steroidal structure of the lithocholate anion favors a consistent pattern of association under different conditions. However, the nature of the resulting aggregates can be controlled by systematically varying the ammonium counterions, giving rise to hydrogels, mixtures of fibrils and crystals, or only crystals under essentially identical conditions of assembly. By using tools for studying gels in tandem with methods of crystal engineering, we have developed a detailed understanding of the association of ammonium lithocholates. In particular, our work suggests how molecules of lithocholate are arranged in networked fibrils that give rise to hydrogelation, provides evidence that gelation and crystallization are intimately related in this system, and helps explain in molecular detail why certain salts give rise to gels and others favor crystallization.

Hydrogels of bile acids and their salts are promising materials for drug delivery, cellular immobilization, and other applications. However, these hydrogels are poorly understood at the molecular level, and further study is needed to allow improved materials to be created by design. We have used NMR spectroscopy to probe hydrogels formed from mixtures of formic acid and sodium deoxycholate (NaDC), a common bile acid salt. By assaying the ratio of deoxycholate molecules that are immobilized as part of the fibrillar network of the hydrogels and those that can diffuse, we have found that 65% remain free under typical conditions. The network appears to be composed of both the acid and salt forms of deoxycholate, possibly because a degree of charge inhibits excessive aggregation and precipitation of the fibrils. Spin–spin relaxation times provided a molecular-level estimate of the temperature of gel–sol transition (42 °C), which is virtually the same as the value determined by analyzing macroscopic parameters. Saturation transfer difference (STD) NMR spectroscopy established that formic acid, which is present mainly as formate, is not immobilized as part of the gelating network. In contrast, HDO interacts with the network, which presumably has a surface with exposed hydrophilic groups that form hydrogen bonds with water. Moreover, the STD NMR experiments revealed that the network is a dynamic entity, with molecules of deoxycholate associating and dissociating reversibly. This exchange appears to occur preferentially by contact of the hydrophobic edges or faces of free molecules of deoxycholate with those of molecules immobilized as components of the network. In addition, DOSY experiments revealed that gelation has little effect on the diffusion of free NaDC and HDO.

Hydrogels formed from aqueous solutions of bile acids and their salts are biocompatible materials that promise to be useful in drug delivery, cellular immobilization, and other applications. These materials are considered to result from self-association of the components to give networks of fibrils; however, the molecular structure of the fibrils has not yet been established with certainty. Previous work has shown that ammonium salts of lithocholic acid can form both crystals and hydrogels under the same conditions. Structural analyses of these salts by single-crystal X-ray diffraction revealed that lithocholate anions are invariably arranged in similar ways, leading to the suggestion that the fibrils causing hydrogelation have closely related structures. This hypothesis has now been strengthened by additional studies of the behavior of ammonium salts of lithocholic acid and other bile acids. In this new work, both crystallization and fibril-induced gelation are again observed, and the crystals tend to have fibril-like acicular morphologies that reflect rapid growth by edge-to-edge association of bile anions. When the ammonium cations are small, the crystals have closely related structures. The observation that simple ammonium salts of many bile acids consistently favor the same pattern of molecular organization in crystalline solids reinforces the hypothesis that the fibrils responsible for hydrogelation have analogous internal structures.

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