Understanding Solute-Hydrotrope Aggregation in Aqueous Solutions: A Molecular Dynamics Approach.

Hydrotropy is a phenomenon where an amphiphilic molecule (i.e., the hydrotrope) is able to enhance the aqueous solubility of a hydrophobic solute.

Structural and Dynamic Heterogeneity of Deep Eutectic Solvents Composed of Choline Chloride and Ortho-Phenol Derivatives.

Structural, thermal, and dynamic properties of four deep eutectic solvents comprising choline chloride paired with phenolic derivative hydrogen-bond donors were probed using experiments and molecular simulations. The hydrogen-bond donors include phenol, catechol, -chlorophenol, and o-cresol, in a 3:1 mixture with the hydrogen-bond acceptor choline chloride. Density, viscosity, and pulsed-field gradient NMR diffusivity measurements were conducted over a range of temperatures.

Assessing Melting and Solid-Solid Transition Properties of Choline Chloride via Molecular Dynamics Simulations.

Choline chloride (ChCl) is used extensively as a hydrogen bond donor in deep eutectic solvents (DESs). However, determining its melting properties experimentally is challenging due to decomposition upon melting, leading to widely varying literature values. Accurate melting properties are crucial for understanding the solid-liquid phase behavior of ChCl-containing DESs.

Combining High-Throughput Experiments and Active Learning to Characterize Deep Eutectic Solvents.

The high tunability of deep eutectic solvents (DESs) stems from the ease of changing their precursors and relative compositions. However, measuring the physicochemical properties across large composition and temperature ranges, necessary to properly design target-specific DESs, is tedious and error-prone and represents a bottleneck in the advancement and scalability of DES-based applications. As such, active learning (AL) methodologies based on Gaussian processes (GPs) were developed in this work to minimize the experimental effort necessary to characterize DESs.

Designing type V deep eutectic solvents with antimalarial pharmaceutical ingredients.

This work studies the formation of deep eutectic solvents formed by one active pharmaceutical ingredient (quinine, pyrimethamine, or 2-phenylimidazopyridine) and a second component potentially acting as an excipient (betaine, choline chloride, tetramethylammonium chloride, thymol, menthol, gallic acid, vanillin, acetovanillone, 4-hydroxybenzaldehyde, syringaldehyde, propyl gallate, propylparaben, or butylated hydroxyanisole), aiming to address challenges regarding drug solubility, bioavailability, and permeability. A preliminary screening was carried out using the thermodynamic model COSMO-RS, narrowing down the search to three promising excipients (thymol, propyl gallate, and butylated hydroxyanisole). Nine solid-liquid equilibrium (SLE) phase diagrams were experimentally measured combining the three model drugs with the screened excipients, and using a combination of a visual melting method and differential scanning calorimetry.

Stochastic machine learning via sigma profiles to build a digital chemical space.

This work establishes a different paradigm on digital molecular spaces and their efficient navigation by exploiting sigma profiles. To do so, the remarkable capability of Gaussian processes (GPs), a type of stochastic machine learning model, to correlate and predict physicochemical properties from sigma profiles is demonstrated, outperforming state-of-the-art neural networks previously published. The amount of chemical information encoded in sigma profiles eases the learning burden of machine learning models, permitting the training of GPs on small datasets which, due to their negligible computational cost and ease of implementation, are ideal models to be combined with optimization tools such as gradient search or Bayesian optimization (BO).

Role of Deep Eutectic Solvent Precursors as Hydrotropes: Unveiling Synergism/Antagonism for Enhanced Kraft Lignin Dissolution.

Lignin holds significant potential as a feedstock for generating valuable aromatic compounds, fuels, and functional materials. However, achieving this potential requires the development of effective dissolution methods. Previous works have demonstrated the remarkable capability of hydrotropes to enhance the aqueous solubility of lignin, an amphiphilic macromolecule.

Boosting Graph Neural Networks with Molecular Mechanics: A Case Study of Sigma Profile Prediction.

Sigma profiles are quantum-chemistry-derived molecular descriptors that encode the polarity of molecules. They have shown great performance when used as a feature in machine learning applications. To accelerate the development of these models and the construction of large sigma profile databases, this work proposes a graph convolutional network (GCN) architecture to predict sigma profiles from molecule structures.

The path towards type V deep eutectic solvents: inductive effects and steric hindrance in the system -butanol + perfluoro -butanol.

The solid-liquid phase behaviour of two tertiary alcohols, perfluoro--butanol and -butanol, was studied here using experimental (ITC, DSC and density measurements) and theoretical (MD simulations) approaches. The phase diagram of the binary mixture reveals highly negative deviations from ideality at low concentrations, as well as the formation of co-crystals and is characterized by two eutectic points, a congruent melting point and a peritectic reaction corresponding to TBH : TBF stoichiometries of 2 : 1 and 1 : 1 respectively. Excess molar enthalpies and volumes were calculated, showing negative and positive deviations from ideality, respectively.

Modeling the Solubility of Monoterpenoids with Hybrid and Predictive Thermodynamic Tools.

The Abraham and NRTL-SAC semipredictive models were employed to represent the solubility of (-)-borneol, (1R)-(+)-camphor, l-(-)-menthol, and thymol in water and organic solvents, using data measured in this work and collected from the literature. A reduced set of solubility data was used to estimate the model parameters of the solutes, and global average relative deviations (ARDs) of 27% for the Abraham model and 15% for the NRTL-SAC model were obtained. The predictive capability of these models was tested by estimating the solubilities in solvents not included in the correlation step.

Everything You Wanted to Know about Deep Eutectic Solvents but Were Afraid to Be Told.

Are deep eutectic solvents (DESs) a promising alternative to conventional solvents? Perhaps, but their development is hindered by a plethora of misconceptions. These are carefully analyzed here, beginning with the very meaning of DESs, which has strayed far beyond its original scope of eutectic mixtures of Lewis or Brønsted acids and bases. Instead, a definition that is grounded on thermodynamic principles and distinguishes between eutectic and deep eutectic is encouraged, and the types of precursors that can be used to prepare DESs are reviewed.

Extensive characterization of choline chloride and its solid-liquid equilibrium with water.

The importance of choline chloride (ChCl) is recognized due to its widespread use in the formulation of deep eutectic solvents. The controlled addition of water in deep eutectic solvents has been proposed to overcome some of the major drawbacks of these solvents, namely their high hygroscopicities and viscosities. Recently, aqueous solutions of ChCl at specific mole ratios have been presented as a novel, low viscous deep eutectic solvent.

Liquefying Flavonoids with Terpenoids through Deep Eutectic Solvent Formation.

The formation of deep eutectic solvents (DES) is tied to negative deviations to ideality caused by the establishment of stronger interactions in the mixture than in the pure DES precursors. This work tested thymol and menthol as hydrogen bond donors when combined with different flavonoids. Negative deviations from ideality were observed upon mixing thymol with either flavone or flavanone, two parent flavonoids that only have hydrogen bond acceptor (HBA) groups, thus forming non-ionic DES (Type V).

Sigma profiles in deep learning: towards a universal molecular descriptor.

This work showcases the remarkable ability of sigma profiles to function as molecular descriptors in deep learning. The sigma profiles of 1432 compounds are used to train convolutional neural networks that accurately correlate and predict a wide range of physicochemical properties. The architectures developed are then exploited to include temperature as an additional feature.

The impact of size and shape in the performance of hydrotropes: a case-study of alkanediols.

Inspired by the recently proposed cooperative mechanism of hydrotropy, where water molecules mediate the aggregation of hydrotrope around the solute, this work studies the impact of apolar volume and polar group position on the performance of hydrotropes. To do so, the ability of two different families of alkanediols (1,2-alkanediols and 1,-alkanediols) to increase the aqueous solubility of syringic acid is initially investigated. Interestingly, it is observed that in the dilute region (low hydrotrope concentration), the relative position of the hydroxyl groups of the alkanediols does not impact their performance.

Differences on the impact of water on the deep eutectic solvents betaine/urea and choline/urea.

The differences on the impact of water on the intermolecular interactions present in the deep eutectic solvents betaine/urea and choline/urea are investigated in this work by measuring the solid-liquid phase diagrams of these mixtures with different amounts of added water. These data are analyzed in terms of ternary systems, rather than the usual pseudo-binary approach, and are used to calculate activity coefficients, which provide precious insight into how water affects the interactions of these systems. It is found that the addition of water greatly enhances the intermolecular interactions of betaine/urea near its eutectic composition, hinting at the formation of a 1:1:1 betaine/urea/water aggregate.

Cholinium-based ionic liquids as bioinspired hydrotropes to tackle solubility challenges in drug formulation.

Hydrotropy is a well-established strategy to enhance the aqueous solubility of hydrophobic drugs, facilitating their formulation for oral and dermal delivery. However, most hydrotropes studied so far possess toxicity issues and are inefficient, with large amounts being needed to achieve significant solubility increases. Inspired by recent developments in the understanding of the mechanism of hydrotropy that reveal ionic liquids as powerful hydrotropes, in the present work the use of cholinium vanillate, cholinium gallate, and cholinium salicylate to enhance the aqueous solubility of two model drugs, ibuprofen and naproxen, is investigated.

The impact of the counterion in the performance of ionic hydrotropes.

The efficiency of an ionic hydrotrope is shown to increase with the hydrophobicity of its counterion, challenging the common view that ionic hydrotropes should possess a small, densely charged counterion such as sodium or chloride.

The role of ionic vs. non-ionic excipients in APIs-based eutectic systems.

Aiming to contribute to drug pre-formulation, new eutectic mixtures were developed. Thymol, coumarin, or quaternary ammonium chlorides as excipients, were combined with the active pharmaceutical ingredients (APIs) acetylsalicylic acid, acetaminophen, ibuprofen, ketoprofen, or lidocaine. Their solid-liquid equilibrium (SLE) binary phase diagrams were measured to study eventual phase separation between the compounds, preventing manufacturing problems, and to study the molecular interactions between the APIs and ionic or non-ionic excipients.

Understanding the Formation of Deep Eutectic Solvents: Betaine as a Universal Hydrogen Bond Acceptor.

The mechanism of formation of betaine-based deep eutectic solvents (DES) is presented for the first time. Due to its polarity unbalance, it was found that betaine displays strong negative deviations from ideality when mixed with a variety of different organic substances. These results pave the way for a comprehensive design of novel deep eutectic solvents.

Unveiling the mechanism of hydrotropy: evidence for water-mediated aggregation of hydrotropes around the solute.

A recent proposal attributes the origin of hydrotropy to the water-mediated aggregation of hydrotrope molecules around the solute. Experimental evidence for this phenomenon is reported for the first time in this work, using H-NMR. A new computational technique to quantify apolarity is introduced and is used to show that apolarity of both solute and hydrotrope is the driving force of hydrotropy.

Liquefying Compounds by Forming Deep Eutectic Solvents: A Case Study for Organic Acids and Alcohols.

The criterion to distinguish a simple eutectic mixture from a deep eutectic solvent (DES) lies in the deviations to thermodynamic ideality presented by the components in the system. In this work, the current knowledge of the molecular interactions in types III and V DES is explored to liquefy a set of three fatty acids and three fatty alcohols, here used as model compounds for carboxyl and hydroxyl containing solid compounds. This work shows that thymol, a stronger than usual hydrogen bond donor, is able to form deep eutectic solvents of type V with the fatty alcohols studied.

The Role of Charge Transfer in the Formation of Type I Deep Eutectic Solvent-Analogous Ionic Liquid Mixtures.

It was recently shown that tetramethylammonium chloride presented negative deviations to ideality when mixed with tetraethylammonium chloride or tetrapropylammonium chloride, leading to a strong decrease of the melting points of these salt mixtures, in a behavior akin to that observed in the formation of deep eutectic solvents. To better rationalize this unexpected melting point depression between two structurally similar compounds devoid of dominant hydrogen bonding capability, new solid-liquid equilibria data for tetramethylammonium-based systems were measured and analyzed in this work. Molecular dynamics was used to show that the strong negative deviations from ideality presented by these systems arise from a synergetic share of the chloride ions.

What a difference a methyl group makes - probing choline-urea molecular interactions through urea structure modification.

There is a lack of fundamental knowledge on deep eutectic solvents, even for the most extensively studied mixtures, such as the mixture of cholinium chloride and urea, which prevents a judicious choice of components to prepare new solvents. The objective of this work is to study and understand the fundamental interactions between cholinium chloride and urea that lead to the experimentally observed melting temperature depression. To do so, the structure of urea was strategically and progressively modified, in order to block certain interaction centres, and the solid-liquid equilibrium data of each new binary system was experimentally measured.

Phenolic hydrogen bond donors in the formation of non-ionic deep eutectic solvents: the quest for type V DES.

Mixtures of non-ionic compounds have been reported as DES but most are just ideal mixtures. In the thymol-menthol system, an abnormal strong interaction was identified stemming from the acidity difference of the phenolic and aliphatic hydroxyl groups. This type of interaction is found to be the key to prepare non-ionic DES, that may be classified as type V.