Unravelling the nature of citric acid:<scp>l</scp>-arginine:water mixtures: the bifunctional role of water

Roda, Ana; Santos, Filipa; Chua, Yeong Zen; Kumar, Aarti; Tam, Hoang; Paiva, Alexandre; Duarte, Ana Rita C.; Held, Christoph

doi:10.1039/d0cp04992a

Cited by 24 publications

(7 citation statements)

References 58 publications

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“…NMR spectroscopy was performed for the identification of hydrogen-bonding interactions between the components of the LTTMs, the predominant type of interactions responsible for their formation. The NMR spectra of the C:A:W ( Figure S2 in Supplementary material ) were previously reported by the authors [ 29 ], where the results supported the presence of an altered hydrogen-bonding network in the ternary mixture. Regarding G:S and pure components, their H 1 NMR spectra were here analysed.…”

Section: Resultssupporting

confidence: 79%

“…DSC is often used in the characterization of LTTMs, as they are commonly defined as mixtures with low-temperature transitions, either glass transition temperatures (T g ) and/or melting temperatures (T m ). The DSC results for the C:A:W system were previously reported by us (see Figure S1 in supplementary material ) [ 29 ]. From those results, although a melting peak around −13 °C was detected for this system, it was attributed to the free water component of the mixture.…”

Section: Resultsmentioning

confidence: 55%

“…Liquid systems with a molar ratio of 2:1 glycerol:sorbitol (G:S) and 1:1:7 citric acid:L-arginine:H 2 O (C:A:W) [ 29 ] were prepared. Briefly, the components were mixed in their respective ratio and submitted to heating and stirring until a translucid liquid was obtained.…”

Section: Methodsmentioning

confidence: 99%

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Therapeutic Liquid Formulations Based on Low Transition Temperature Mixtures for the Incorporation of Anti-Inflammatory Drugs

2021

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Most nonsteroidal anti-inflammatory drugs (NSAIDs) present poor aqueous solubility, impairing their efficiency in physiological media. In this context, Low Transition Temperature Mixtures (LTTMs) are a promising platform to overcome drugs’ poor solubility, forming therapeutic liquid formulations. In this work, the LTTMs of citric acid:L-arginine:water (C:A:W) and glycerol:sorbitol (G:S) were studied in terms of their features and assessed in terms of their ability to increase the solubility of six NSAIDs in physiological media. The physicochemical properties of LTTMs were characterized by state-of-art techniques commonly used for these systems. The cytotoxicity of G:S was also evaluated in L929 mouse fibroblasts and the viscosity, polarity, and pH properties of the studied mixtures were related to the solubility of NSAIDs. The pH and polarity were the parameters that most influenced the drugs’ solubility. Ibuprofen, naproxen, ketoprofen, indomethacin, and flurbiprofen did not present any solubility improvement in the formulations tested. However, concentrated mixtures of C:A:W or G:S in the physiologic-mimicked media (PBS) rendered a celecoxib solubility 4 and 5 times higher than PBS, respectively. These therapeutic liquid formulations of celecoxib in C:A:W or G:S can be a promising tool to increase celecoxib’s therapeutic efficiency in local applications.

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Section: Resultssupporting

confidence: 79%

Section: Resultsmentioning

confidence: 55%

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Therapeutic Liquid Formulations Based on Low Transition Temperature Mixtures for the Incorporation of Anti-Inflammatory Drugs

2021

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“…Thus, while the melting point depression is closely linked with the hydrogen bond (HB) network formed between the components, a comprehensive picture of the relationship between structure, molecular interactions, and the properties of the DES remains elusive. Furthermore, the presence of water, either as a component to form a DES or to tailor properties such as the viscosity, raised several questions about these solvents: − is there a water ratio at which a transition from a binary to a ternary (where water is the third component) DES occurs? Is there a well-defined crossover between a DES and an aqueous solution?…”

Section: Introductionmentioning

confidence: 99%

Structure and Dynamic Properties of a Glycerol–Betaine Deep Eutectic Solvent: When Does a DES Become an Aqueous Solution?

Monteiro

Paiva

Duarte

et al. 2022

ACS Sustainable Chem. Eng.

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Deep eutectic solvents (DESs) are an emerging class of green solvents with a wide spectrum of potential applications whose properties may be further tailored through the addition of water. Here, we study, through molecular dynamics, the influence of water on the properties of a betaine–glycerol–water (B:G:W) DES (1:2:ζ; ζ = 0 to 100), aiming at getting insight into the structural and dynamic crossover between a DES and an aqueous solution. The density, shear viscosity, and diffusion coefficients are found to exhibit a non-linear dependence of ζ, similar to that observed for the solvation layers’ composition. Each Gly and Bet are replaced, respectively, by ∼3 and ∼5 water molecules, with the highest rates of depletion being found for Gly around Bet and Gly around Gly. Above ζ = 7 (70 mol %; 29.5 wt %), a major structural transformation occurs, with the complete disruption of the second Bet-Gly solvation layer and the formation of a new second layer at a shorter distance, accompanied by a sudden change in the rate of increase of the components’ diffusion. Nonetheless, opposite to other DES, our results indicate a smooth crossover between a DES and an aqueous solution.

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“…However, adding more than 50% of water to the system could lead to a disruption of the hydrogen bonds and dilution of the components, creating a solution (Dai et al, 2015;Craveiro et al, 2016). In previous studies, the possibility of pH itself affect the solubility of other components in the mixture was explored and it was observed that the slight variation of pH did not affect the solubility of these eutectic mixtures and due to that, the pH was not considered in molecular dynamics (MD) studies (Santos et al, 2018;Roda et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Molecular Dynamics Studies of Therapeutic Liquid Mixtures and Their Binding to Mycobacteria

Monteiro

Santos²,

Paiva³

et al. 2021

Front. Pharmacol.

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Tuberculosis is an highly contagious disease still considered by the WHO as one of most infectious diseases worldwide. The therapeutic approach, used to prevent and treat tuberculosis targets the Mycobacterium tuberculosis complex, comprises a combination of drugs administrated for long periods of time, which, in many cases, could cause several adverse effects and, consequently, low compliance of the patient to the treatment and drug-resistance. Therefore, therapeutic liquid mixtures formulated with anti-tuberculosis drugs and/or adjuvants in tuberculosis therapy are an interesting approach to prevent toxic effects and resistance to anti-tuberculosis drugs. The herein formulated therapeutic liquid mixtures, including ethambutol, arginine, citric acid and water under different molar ratios, were studied through a molecular dynamics approach to understand how ethambutol and arginine could be stabilized by the presence of citric acid and/or water in the mixture. To gain insights on how the uptake of these mixtures into the mycobacteria cell may occur and how a mycobacterial ABC transporter could contribute to this transport, multiple simultaneous ligand docking was performed. Interactions between citric acid and ethambutol involving the carboxyl and hydroxyl groups of citric acid with the amines of ethambutol were identified as the most critical ones. Water molecules present in the mixture provides the necessary network of hydrogen bonds that stabilize the mixture. Molecular docking additionally provided an interesting hypothesis on how the different mixture components may favor binding of ethambutol to an ABC importer. The data presented in this work helps to better understand these mixtures as well as to provide cues on the mechanisms that allow them to cross the mycobacterial cell membrane.

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Unravelling the nature of citric acid:l-arginine:water mixtures: the bifunctional role of water

Abstract: DES? Solution? Either a DES or other type of non-ideal solution, the studied systems are non-ideal mixtures. Their liquefaction is mediated by water through the formation of charged species and cross interactions between the mixture constituents.

Cited by 24 publications

References 58 publications

Therapeutic Liquid Formulations Based on Low Transition Temperature Mixtures for the Incorporation of Anti-Inflammatory Drugs

Therapeutic Liquid Formulations Based on Low Transition Temperature Mixtures for the Incorporation of Anti-Inflammatory Drugs

Structure and Dynamic Properties of a Glycerol–Betaine Deep Eutectic Solvent: When Does a DES Become an Aqueous Solution?

Molecular Dynamics Studies of Therapeutic Liquid Mixtures and Their Binding to Mycobacteria

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