João M. M. Araújo

Aqueous biphasic systems: a boost brought about by using ionic liquids

During the past decade, ionic-liquid-based Aqueous Biphasic Systems (ABS) have been the focus of a significant amount of research. Based on a compilation and analysis of the data hitherto reported, this critical review provides a judicious assessment of the available literature on the subject. We evaluate the quality of the data and establish the main drawbacks found in the literature. We discuss the main issues which govern the phase behaviour of ionic-liquid-based ABS, and we highlight future challenges to the field. In particular, the effect of the ionic liquid structure and the various types of salting-out agents (inorganic or organic salts, amino acids and carbohydrates) on the phase equilibria of ABS is discussed, as well as the influence of secondary parameters such as temperature and pH. More recent approaches using ionic liquids as additives or as replacements for common salts in polymer-based ABS are also presented and discussed to emphasize the expanding number of aqueous two-phase systems that can actually be obtained. Finally, we address two of the main applications of ionic liquid-based ABS: extraction of biomolecules and other added-value compounds, and their use as alternative approaches for removing and recovering ionic liquids from aqueous media.

Ionic liquid-based aqueous biphasic system for lipase extraction

A successful process to extract lipolytic enzymes based on an aqueous biphasic system (ABS), which uses both ionic liquids (ILs) and a high charge-density inorganic salt (K2CO3), is proposed in this work. The activity of a model Thermomyces lanuginosuslipase (TlL) in some of the most common hydrophilic ILs, based on the 1-alkyl-3-methylimidazolium cation, combined with chloride, alkylsulfate, alkylsulfonate and acetate, was investigated. Several operating conditions influencing lipase activity and ABS formation were investigated. Parameters such as temperature, pH, deactivation kinetics and water content were evaluated in order to propose a viable extraction process. A deeper analysis in terms of enzyme deactivation kinetics was carried out, and the data were modelled through a series-type deactivation equation. ATR-FTIR studies aimed at identifying the TlL structure in selected ILs have also provided an insight into the enzyme deactivation behaviour.

Aqueous biphasic systems: a benign route using cholinium-based ionic liquids

Ionic-liquid-based aqueous biphasic systems (ABS) have been the focus of a significant amount of research in the last decade. However, only (moderately) toxic and poorly biodegradable ionic liquids have been explored hitherto. Focusing on the development of more benign and sustainable approaches, a novel class of ABS using cholinium-based ionic liquids is proposed. For the first time, it is shown that a large assortment of cholinium-based ionic liquids is capable of undergoing liquid–liquid demixing in the presence of aqueous solutions with strong salting-out species. In order to assess the applicability of these systems for separation purposes, the partitioning of two antibiotics and/or their hydrochloride forms was also investigated. Cholinium-based ABS are shown to be improved routes for the extraction of pharmaceuticals, achieving complete extractions in a single-step by way of the proper tailoring of the phase forming components and their concentrations in the aqueous media.

Inorganic salts in purely ionic liquid media: the development of High Ionicity Ionic Liquids (HIILs).

This work explores the possibility of increasing the ionicity of ionic liquids via the solubilization of inorganic salts in their midst. The resulting purely ionic media-distinct ionic liquid plus inorganic salt mixtures-are liquid in an extensive concentration range and can be aptly denominated High Ionicity Ionic Liquids (HIILs).

Evaluation of solubility and partition properties of ampicillin-based ionic liquids

In order to overcome the problems associated with low water solubility, and consequently low bioavailability of active pharmaceutical ingredients (APIs), herein we explore a modular ionic liquid synthetic strategy for improved APIs. Ionic liquids containing L-ampicillin as active pharmaceutical ingredient anion were prepared using the methodology developed in our previous work, using organic cations selected from substituted ammonium, phosphonium, pyridinium and methylimidazolium salts, with the intent of enhancing the solubility and bioavailability of L-ampicillin forms. In order to evaluate important properties of the synthesized API-ILs, the water solubility at 25 °C and 37 °C (body temperature) as well as octanol-water partition coefficients (Kows) and HDPC micelles partition at 25 °C were measured. Critical micelle concentrations (CMCs) in water at 25 °C and 37 °C of the pharmaceutical ionic liquids bearing cations with surfactant properties were also determined from ionic conductivity measurements.

A thermophysical and structural characterization of ionic liquids with alkyl and perfluoroalkyl side chains

This work represents an essential step towards the understanding of the dynamics and thermodynamic characteristics of a novel family of ionic liquids, namely fluorinated ionic liquids based on the combination of 1-alkyl-3-methylimidazolium cations with perfluoroalkylsulfonates or perfluoroalkylcarboxylates anions. The so far scarce information about these fluids constitutes a limiting factor for their potential applications. In this work, we provide detailed evidence on the influence of hydrogenated and fluorinated alkyl chain lengths in the final characteristics of the fluorinated ionic liquids. Different properties, namely, melting point, decomposition temperature, density, dynamic viscosity, ionic conductivity and refractive index, were determined and the experimental results were discussed taking into account the influence of the length of the hydrogenated and fluorinated alkyl chains. Molecular dynamic simulations were also performed to study the nanoscale structure of these novel compounds.

Cholinium-based ionic liquids with pharmaceutically active anions

Novel ionic liquids (ILs) containing cholinium as a benign cation combined with anions based on five active pharmaceutical ingredients (APIs), namely, nalidixic acid, niflumic acid, 4-amino-salicylic acid, pyrazinoic acid and picolinic acid, were prepared via a simple and sustainable two-step anion exchange reaction. The solubility of the prepared pharmaceutically active ILs (API-ILs) in both water and simulated biological fluids at 25 °C and 37 °C, as well as the solubility of the parent APIs, were measured. Further, in vitro cytotoxicity levels for both cholinium-based API-ILs and parent APIs were established using two different human cells lines, namely Caco-2 colon carcinoma cells and HepG2 hepatocellular carcinoma cells. Herein, the dual nature of ILs is exploited by combining the cheap, available and essential nutrient cholinium cation with pharmaceutically active anions, upgrading the chemical, physical and biopharmaceutical properties, particularly melting point, aqueous solubility and the potential to penetrate cell membranes of the parent APIs, without impair their cytotoxicity response which prompt opportunities for creating further advances in pharmaceutical challenges.

Aggregation Behavior and Total Miscibility of Fluorinated Ionic Liquids in Water

In this work, novel and nontoxic fluorinated ionic liquids (FILs) that are totally miscible in water and could be used in biological applications, where fluorocarbon compounds present a handicap because their aqueous solubility (water and biological fluids) is in most cases too low, have been investigated. The self-aggregation behavior of perfluorosulfonate-functionalized ionic liquids in aqueous solutions has been characterized using conductometric titration, isothermal titration calorimetry (ITC), surface tension measurements, dynamic light scattering (DLS), viscosity and density measurements, and transmission electron microscopy (TEM). Aggregation and interfacial parameters have been computed by conductimetry, calorimetry, and surface tension measurements in order to study various thermodynamic and surface properties that demonstrate that the aggregation process is entropy-driven and that the aggregation process is less spontaneous than the adsorption process. The novel perfluorosulfonate-functionalized ILs studied in this work show improved surface activity and aggregation behavior, forming distinct self-assembled structures.

Chiral separation by two-column, semi-continuous, open-loop simulated moving-bed chromatography.

A two-column version of a multicolumn, semi-continuous, open-loop chromatograph for chiral separation is presented and validated experimentally. The heart of the process is a flexible node design and cyclic flow-rate modulation that succeed at keeping the mass-transfer zone inside the system without resorting to any recycling technique. One advantage of this streamlined design is the simplicity of its physical realization: regardless of the number of columns, it only requires two pumps to supply feed and desorbent into the system, while the flow rates of liquid withdrawn from the system are controlled by material balance using simple two-way valves. A rigorous model-based optimization approach is employed in the optimal cycle design to generate a solution that is physically realizable in the experimental apparatus. The optimized scheme for two-column operation supplies fresh feed into the system where the composition of the circulating fluid is closest to that of the feedstock fluid, and recovers the purified products, extract and raffinate, alternately at the downstream end of the unit while desorbent is supplied into the upstream end of the system. The feasibility and effectiveness of the two-column process are verified experimentally on the separation of reboxetine racemate, a norepinephrine re-uptake inhibitor, under overloaded conditions. Our set-up employs an automated on-line enantiomeric analysis system, comprising an analytical HPLC set-up with two UV detectors to monitor the composition profile at the downstream end of one of the columns; this monitoring system does not use a polarimeter.

Hydrogen-Bonding and the Dissolution Mechanism of Uracil in an Acetate Ionic Liquid: New Insights from NMR Spectroscopy and Quantum Chemical Calculations

The dissolution of uracil-a pyrimidine nucleic acid base-in the ionic liquid 1-ethyl-3-methylimidazolium acetate ([C2mim][CH3COO]) has been investigated by methods of (1)H and (13)C NMR spectroscopy, (1)H-(1)H NOESY NMR spectroscopy, and quantum chemical calculations. The uracil-[C2mim][CH3COO] interactions that define the dissolution mechanism comprise the hydrogen bonds between the oxygen atoms of the acetate anion and the hydrogen atoms of the N1-H and N3-H groups of uracil and also the hydrogen bonds between the most acidic aromatic hydrogen atom (H2) of the imidazolium cation and the oxygen atoms of the carbonyl groups of uracil. The bifunctional solvation nature of the ionic liquid can be inferred from the presence of interactions between both ions of the ionic liquid and the uracil molecule. The location of such interaction sites was revealed using NMR data ((1)H and (13)C chemical shifts both in the IL and in the uracil molecule), complemented by DFT calculations. NOESY experiments provided additional evidence concerning the cation-uracil interactions.