Active Pharmaceutical Ingredient-Ionic Liquids (API-ILs): Nanostructure of the Glassy State Studied by Electron Paramagnetic Resonance Spectroscopy

Abstract

Active Pharmaceutical Ingredient-Ionic Liquids (API-ILs) draw increasing interest as a particular class of ILs that possess unusual physicochemical properties along with simultaneous potentials for pharmaceutical applications. Although nanostructuring phenomena were actively investigated in common ILs, their studies in API-ILs are scarce so far. In this work, using the complex methodology of Electron Paramagnetic Resonance (EPR) and dissolved spin probes, we investigate nanostructuring phenomena in a series of API-ILs: [Cnmim][Ibu], [Cnmim][Gly], and [Cnmim][Sal] with n = 2, 4, and 6, respectively. We reveal similar trends for API-ILs and common ILs, as well as peculiarities inherent to the studied API-ILs. Unusual behavior observed for [Cnmim][Ibu] has been assigned to the presence of a non-polar fragment in the [Ibu]− anion, which leads to the formation of more complex nanostructures around the radical compared to common ILs. Understanding general trends in the formation of such self-organized molecular structures is of fundamental interest and importance for applying API-ILs.

Effects of Zwitterions on Structural Anomalies in Ionic Liquid Glasses Studied by EPR

“…To observe and investigate structural anomalies in IL glasses, we employed the combination of continuous wave (CW) and pulse EPR techniques, as was used in a series of our previous works [39][40][41][42][43][44][45][46][47]56]. The pulse EPR study relies on the methodology of stochastic molecular librations, previously developed and broadly applied by Dzuba et.al.…”

“…A recent series of IL studies using pulse electron paramagnetic resonance (EPR) spectroscopy revealed peculiar molecular dynamics in the glassy state near the glass transition temperature (T g ) [39][40][41][42][43][44][45][46]. Such "structural anomaly" was first found in imidazolium-based ILs, and was later observed for other ILs, phthalates, alkyl alcohols, and alkyl benzenes [44].…”

“…Using metal-organic frameworks as crystalline nanocontainers, we studied the influence of space restrictions on the occurrence and character of structural anomalies [42]. Finally, we studied the peculiarities of nanostructuring in Active Pharmaceutical Ingredient-Ionic Liquids [45].…”

Ionic Liquids: New Forms of Active Pharmaceutical Ingredients with Unique, Tunable Properties

“…API-ILs nanostructure can be evaluated in the same manner as for other ILs: via collection of Continuous Wave Electron Paramagnetic Resonance (CW EPR) spectra of the compounds with dissolved N1 and TEMPO–D 18 spin probes. This has been recently shown for API-ILs for the first time, in an elegant study designed to understand interionic arrangement of the API-IL ions, through elucidation of H-bonding between the radicals and IL ions . The most interesting observations were noticed for ibuprofenate-based ILs with 1-alkyl-3-methyl­imidazolium cations with shorter (ethyl), approximately the same (butyl), or longer (hexyl) alkyl substituents than the ibuprofenate anion which has an isobutyl alkyl substituent.…”

“…This has been recently shown for API-ILs for the first time, in an elegant study designed to understand interionic arrangement of the API-IL ions, through elucidation of H-bonding between the radicals and IL ions. 305 The most interesting observations were noticed for ibuprofenate-based ILs with 1-alkyl-3methylimidazolium cations with shorter (ethyl), approximately the same (butyl), or longer (hexyl) alkyl substituents than the ibuprofenate anion which has an isobutyl alkyl substituent. When the cation had a shorter alkyl chain ([1-ethyl-3-methylimidazolium][ibuprofenate]), the micelles around the spin probe were formed by alkyl moieties of the anion, whereas when the cation had longer alkyl substituents ([1-hexyl-3-methylimidazolium][ibuprofenate]) than the radical probe was surrounded by alkyl chains of the cations.…”