Structural Evaluation of the Choline and Geranic Acid/Water Complex by SAXS and NMR Analyses

Recently, choline and geranic acid (CAGE), an ionic liquid (IL), has been recognized to be a superior biocompatible material for oral and transdermal drug delivery systems (DDS). When CAGE is administered, CAGE would be exposed to various types of physiological fluids, such as intestinal and intradermal fluids. However, the effect of physiological fluids on the structure of CAGE remains unclear. In the present study, molecular structures of CAGE with different ratios of water were investigated using small-angle X-ray scattering (SAXS) and nuclear magnetic resonance (NMR). The SAXS pattern of CAGE showed an IL-specific broad peak derived from nanoscale aggregation until 17 vol % water. Meanwhile, narrow peaks were observed in samples with 25-50 vol % water, showing a transition to the lamellar phase. With more than 67 vol % water, CAGE was found to exist as micelles in water. The ¹H NMR spectra indicated that protons of H₂O, OH in choline (CH), and COOH in geranic acid (GA) were observed as only one peak up to 17 vol % water. This peak shifted to a high magnetic field, and the integral values increased with the water content, speculating that water is localized close to the COOH and OH groups to allow proton exchange. The ¹³C NMR spectra showed that peaks related to the carboxyl group shifted with adding water. Moreover, only GA peaks were observed in the lamellar phase through ¹³C cross-polarization magic-angle spinning NMR, suggesting that the main rigid component of the lamellar phase was GA. Taken together, this study suggested that CAGE still maintained its IL structure up to 17 vol % water, then transitioned to the lamellar phase with 25-50 vol % water, and finally changed to the micellar phase with more than 67 vol % water. This information would be useful in the formulation and development of DDS using CAGE.