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

Abstract

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 1 H NMR spectra indicated that protons of H 2 O, 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 13 C 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 13 C 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.

Counteractive Effects of Choline Geranate (CAGE) ILs and Ethanol on Insulin’s Stability—A Leap Forward towards Oral Insulin Formulation

“…In addition, water-mediated H-bonding interactions with CAGE ILs and hydrophilic part ethanol are helpful to the various structural formations. The earlier report suggests that the structure of CAGE ILs transitioned from lamellar phase to micellar phase at more than 67 vol % of water [ 61 ]. Similarly, we also found that micellar formations are more favorable for the stabilization of the insulin dimer.…”

An overview of biomedical applications of choline geranate (CAGE): a major breakthrough in drug delivery

“…Thus, it is conrmed that CAGE maintains its structure with water up to 17 vol% and this information is useful to understand the drug delivery applications of CAGE. 15 Recently, surface tension and thermal expansion coefficients of various aqueous solutions of CAGE have been investigated, providing a new perspective on CAGE behavior; the liquidvapor interface, and its mechanism in a sophisticated way. This will inspire scientists to explore other applications of CAGE and related materials.…”

“…The most effective 1 : 2 ratio of CAGE has a viscosity 569 AE 19 mPa s, conductivity 13.79 AE 0.28 mS m À1 with diffusion coefficient 2.2 Â 10 À12 m 2 s À1 . 6 Moreover, CAGE has a molecular weight 440.32 g mL À1 with a density 0.989 : 0.001 g mL À1 at 25 C. 15,16…”

Novel Pharmaceutical Strategies for Enhancing Skin Penetration of Biomacromolecules

“…Moreover, the internal structure of ILs may alter when exposed to body fluid or water dilution. Taking CAGE as an example, a 25–50 vol% of water would transfer ILs into the lamellar phase, while further dilution would lead to micelle formation via aggregation of geranate anions’ hydrophobic chains [ 78 ]. However, current research works seldom discuss the influence of hydration state on the permeation enhancement of ILs.…”