(411g) Advanced Designs for Choline-Based Ionogels of Tuneable Physicochemical and Rheological Properties

Ionogels are captivating materials offering high transparency, electroconductivity, and thermal and structural stability.^1,2 Conventionally, ionogels are comprised of ionic liquids (ILs), consisting of cations and anions, confined within polymer networks. Typically, ionogels require complex chemistry, show high viscosity, poor biocompatibility, and low biodegradability.² In this work, we develop a rational formulation design approach for facile construction of novel thermoresponsive ionogel formulations, addressing the issues of conventional ionogels for pharmaceutical applications.¹ The ionogels were comprised of biocompatible choline-based ILs, silk fibroin, and traditional pharmaceutical excipients, including tween 20, histidine, trehalose, sucrose, glycerol, and polyvinylpyrrolidone (PVP). We utilized the ILs, choline acetate ([Cho][OAc]), choline dihydrogen phosphate ([Cho][DHP]), and choline chloride ([Cho][Cl]). These ILs have previously been shown to lower formulation viscosity, increase gel strength, tune the gelation properties of diverse systems, and improve drug solubility and storage stability.^3,4 We found that formulations lacking IL failed to show gels formation; yet formulations including IL resulted in ionogel formation. Visual tests, transmission electron microscopy, and confocal reflection microscopy, demonstrated the formation of distinct ionogels, also improving the solubility of the poorly soluble antiepileptic drug, phenobarbital. Overall, [Cho][DHP] and [Cho][OAc]-ionogel formulations exhibited relatively lower hydrodynamic diameter (D_h) and more negative zeta potential values compared to the [Cho][Cl]-ionogel formulations. Furthermore, formulations lacking IL exhibited relatively higher D_h and polydispersity index values and less negative zeta potential values. This indicated that inclusion of IL reduced aggregation propensity, and likely, improved system structural stability. Under 25 °C storage, overall, the [Cho][DHP]-ionogels and [Cho][OAc]-ionogels formed relatively rapidly, shortest following 1 day. The [Cho][Cl]-ionogels required longer formation periods, extended to 32 days. Addition of PVP to each formulation reduced the Ionogel formation period to 14 days. Rheological measurements at 25 °C showed the formation of diverse ionogels of strengths between 18 and 642 Pa. Of the systems examined, [Cho][Cl]-ionogels exhibited the lowest strengths. Furthermore, addition of PVP increased the strengths of the ionogels. This was most prominent for [Cho][OAc]-ionogels and [Cho][DHP]-ionogels also including glycerol. These exhibited maximum storage modulus (G′) values of 167 and 642 Pa, respectively. Additionally, we found that formulations showing lower G′ values also required longer ionogel formation time, and disaccharide identity was interchangeable. Finally, heating the fresh aqueous formulations including IL, from 25 to 60 °C, resulted in the formation of thermoresponsive ionogels between 35 and 41 °C. Addition of PVP resulted in the formation of ionogels between 44 and 49 °C. Conversely, formulations lacking IL presented as cloudy solutions upon heating. Based on the experimental findings and density functional theory calculations, we propose that the dihydrogen phosphate anions act as hydrogen bond donors and acceptors, facilitating a network of strong intermolecular hydrogen bonding interactions. This explains the rapid [Cho][DHP]-ionogel formation period. Accordingly, since the acetate anions act solely as hydrogen bond acceptors, relatively weak ionogels formed. Moreover, inclusion of the chloride anions resulted in the weakest intermolecular hydrogen bonding interactions explaining the delayed formation of [Cho][Cl]-ionogels. We suggest that the addition of glycerol and PVP to the formulations resulted in strong intermolecular hydrogen bonding and macromolecular crowding, contributing to ionogels of greater strength, structural and energetic stability. As increasingly advanced ionogel designs are explored, applying our rational development strategy enables the production of ionogels which can be formulated for precise control of multiple unique ionogel features. We believe, these could potentially fill niche pharmaceutical applications.

References

1. Shmool, T.A.; Martin, L.K.; Jirkas, A.; Constantinou, A.P.; Vadukul, D.M.; Aprile, F.A.; Georgiou, T.K.; Hallett, J.P. Unveiling the Rational Development of Stimuli-Responsive Silk Fibroin-Based Ionogel Formulations. Chem. Mater. 2023, 35, 5798–5808.

2. Kopilovic, B.; e Silva, F.A.; Pedro, A.Q.; Coutinho, J.A.P.; Freire, M.G. Ionogels for Biomedical Applications. In Nanotechnology for Biomedical Applications; Gopi, S., Balakrishnan, P., Mubarak, N.M., Eds.; Materials Horizons: From Nature to Nanomaterials; Springer: Singapore, 2022; pp 391–425.

3. Shmool, T.A.; Constantinou, A.P.; Jirkas, A.; Zhao, C.; Georgiou, T.K.; Hallett, J.P. Next Generation Strategy for Tuning the Thermoresponsive Properties of Micellar and Hydrogel Drug Delivery Vehicles Using Ionic Liquids. Polym. Chem. 2022, 13, 2340–2350.

4. Nahar, Y.; Horne, J.; Truong, V.; Bissember, A.C.; Thickett, S.C. Preparation of Thermoresponsive Hydrogels Via Polymerizable Deep Eutectic Monomer Solvents. Polym. Chem. 2021, 12, 254–264.