Molecular and Spectroscopic Insights of a Choline Chloride Based Therapeutic Deep Eutectic Solvent

Abstract

In this study, atomic level interactions of a 1:1 choline chloride (ChCl)/acetylsalicylic acid (ASA) therapeutic deep eutectic solvent (THDES) has been investigated by combining the molecular dynamics (MD), density functional theory (DFT), and spectroscopic (Raman and IR) techniques. Atom−atom radial distribution functions (RDFs) based on MD simulation reveal that hydrogen bonds are formed between Cl − ••• HO Ch + and Cl − •••HO COOH of the THDES, where Cl − works as a bridge between ASA and Ch + . Cation−anion electrostatic attractions are disrupted by highly interconnected hydrogen bonds. Cluster conformers of the THDES are isolated from MD simulation and optimized using ωB97XD/6-311++G(d,p) level of theory, in which the strongest H bonds are found among OH Ch + ••• Cl − (2.37 Å) and Cl − •••HO COOH (2.40 Å). Charge transfer calculations, using CHEPLG and NBO analysis, disclose that the charge of Cl − is reduced in the cluster structures and transferred to Ch + and ASA. Further analyses are conducted using experimental and computed spectroscopic data. These confirm the formation of the THDES as peaks for −COOH, −COOR, and −OH functional groups of ASA and ChCl are either get broadened or disappeared in the spectra of the cluster conformers. Moreover, principal component analysis (PCA) assists to understand the feature of the simulated data and confirms the formation of the THDES. Solvent selectivity triangle (SST) of solvatochromic parameters also demonstrate that this THDES has some important properties similar to ionic liquids and common deep eutectic solvent.

Computer Simulations of Deep Eutectic Solvents. Challenges, Solutions, and Perspectives

“…Role of HBD can be played by acids, which can endow a DES with unique properties [51,201], [202], [203][204][205]. Fu et al [201] developed a DES based on acrylic acid and estimated the stability of the ChCl-acrylic acid complexes by QM calculations.…”

“…These DESs can be used to enhance the solubility of active ingredients, membrane transport, drug delivery, and bioavailability [206,207]. Saha et al [203] used combined DFT/MD simulations to study the possibility of developing DESs based on acetylsalicylic acid (aspirin), and Bonab et al [204,205] simulated DESs based on ChCl and phenyl propionic acid, which have a wide variety of uses including cosmetics, food additives, and pharmaceuticals [208]. The authors aimed to understand the physical mechanisms occurring at the eutectic composition point.…”

“…Thus, the smaller molecular size of ethaline compared to propeline and propaneline, allows these molecules to get closer to choline leading to a higher density of DES based on diatomic alcohols. The critical role of the H-bond network in DES formation was also recently demonstrated using MD simulations by Panda et al[200] who compared DESs based on tetrabutylammonium chloride and two different HBDs glycerol and ethylene glycol.Role of HBD can be played by acids, which can endow a DES with unique properties[51,201],[202],[203][204][205]. Fu et al[201] developed a DES based on acrylic acid and estimated the stability of the ChCl-acrylic acid complexes by QM calculations.…”

Deep Eutectic Solvents as Active Pharmaceutical Ingredient Delivery Systems in the Treatment of Metabolic Related Diseases

“…Choline chloride was widely used as a component in the synthesis of DESs (Alizadeh et al, 2020;Jeliński et al, 2019;Li & Lee, 2016;Mano et al, 2017;Morrison et al, 2009;Saha et al, 2020;Silva et al, 2019;Wikene et al, 2015;Zainal-Abidin et al, 2020) (Figure 1, Table 2). Choline chloride:glycolic acid, choline chloride:glycolic acid:oxalic acid, choline chloride:urea and choline chloride:malonic acid based DESs have been synthesized to increase solubility of low-soluble compounds including piroxicam, lidocaine, posaconazole, benzoic acid, danazol, griseofulvin, AMG517 and itraconazole (Morrison et al, 2009;Li & Lee, 2016).…”

“…Besides, choline chloride:malic acid and choline bicarbonate:vanillic acid, were also synthesized and applied as excellent carriers to increase the solubility of unstable drugs (Zakrewsky et al, 2016;Shekaari et al, 2017), which is beneficial to drug storage and delivery. Carboxylic compounds, including benzoic acid, phenylacetic acid, lauric acid, myristic acid, acetylsalicylic acid, stearic acid, mandelic acid and maleic acid were commonly selected as DES components due to their low toxicity and stable hydrogen bonding capacity (Makoś et al, 2018;Pereira et al, 2019;Saha et al, 2020) (Figure 1).…”