Propranolol resolution using enantioselective biphasic systems

The commercialization of chiral drugs is an increasing concern in the pharmacological field since the differences in the pharmacological activities of enantiomers may result in serious problems in the treatment of diseases using racemates. The resolution of chiral drugs is important for the development of safer and more active pharmaceuticals. This work aims to develop an enantioseparation platform for the resolution of propranolol (R/S-PRP) resorting to esters of tartaric acid and chiral ionic liquids (CILs) as chiral selectors in biphasic systems. More specifically, the efficiency of enantioselective liquid–liquid extraction (ELLE) systems, both aqueous and non-aqueous biphasic systems, are here studied, aiming to do a direct comparison between these two types of systems for the resolution of R/S-PRP. Studies were carried to evaluate the proper phase forming components of ELLE, R/S-PRP:chiral selector ratio, the potential of CIL over esters of tartaric acid, and the most suitable alkyl chain length for the esters of tartaric acid. It was found that the selected organic phase formers of ELLE, 1,2-dichloroethane and ethyl acetate, greatly impact the potential of the enantiorecognition of the system. The most efficient biphasic system identified was composed of 1,2-dichloroethane- water, and dipentyl-L-tartrate and boric acid as chiral selectors, with a enantioselectivity of 2.54. This system was further employed for the resolution of R/S-PRP in centrifugal partition chromatography, to assess its scalability potential, being shown that it was possible to increase the purity of R-PRP from 59% to 75%.publishe

Solubility of H2S in ammonium-based ionic liquids

This work is inserted in a research program that consists mainly in the experimental and theoretical study of gas/liquid solubility in ionic liquids (ILs). In this study the experimental data of hydrogen sulfide solubility in ammonium-based ionic liquids, namely 2-hydroxyethylammonium acetate [2-HEA][Ace], bis(2-hydroxyethyl)ammonium acetate [B-2-HEA][Ace] and 2-hydroxyethyldiethylammonium hydrogen diacetate [2-HEDEA][H(Ace)2], were determined using a volumetric method in the 298 K to 318 K temperature range and at atmospheric pressure. The ionic liquids are functionalized with the OH group in the ammonium-based cations, in order to study the influence of hydroxyl group in the formation of hydrogen bonds between the IL-IL and IL-gas. The data gathered is modelled with the Cubic Plus Association Equation of State (CPA EoS), considering the association schemes four-sites (4C) for hydrogen sulfide and two-sites (2B) for the ILs ([2-HEA][Ace], [B-2-HEA][Ace] and [2-HEDEA][H(Ace)2]).publishe

A selective journey: enantioselective biphasic systems for the resolution of propranolol

Enantiomers may have different biological properties, leading to complications when using racemates for the treatment of diseases. Considering the difficulty in the synthesis of pure enantiomers, the synthesis of racemates followed by their chiral resolution is deemed as a simpler and cheaper alternative. Enantioselective liquid-liquid extraction (ELLE) is a promising separation process. ELLE is composed of two immiscible phases that enable the optimization of enantioseparation through the addition of a chiral selector, such as chiral ionic liquids (CIL) or tartaric acid derivatives. Upon their introduction in ELLE, these chiral selectors may help increase the selectivity of the system, contributing to high performant extraction/separation approaches. In this work, CILs and tartaric acid derivatives were used in biphasic systems as chiral selectors, aiming to separate R/S-propranolol (R/S-PRP) enantiomers. The most promising system was applied in centrifugal partition chromatography to further improve the enantiomeric purification rates.publishe

Design of a liquid-liquid extraction platform for the resolution of chiral pharmaceuticals

Enantiomers have different pharmacological properties, which can hinder the treatment of pathologies using racemic drugs. Racemates represent around 90 % of the commercialized chiral drugs, raising concerns by the FDA (Food and Drug Administration of United States) and EMA (European Medicines Agency). Therefore, the commercialization of the therapeutically active isomer should be preferential. Obtaining the pure enantiomer relies on direct synthesis or resolution of the existing racemates. Resolution is often considered a simpler and cheaper alternative. Enantioselective liquid-liquid extraction (LLE) is a promising separation process that can be operated in a continuous mode. LLE are composed of two tunable immiscible phases that allow the optimization of enantioseparation by the addition of a chiral selector, which is responsible for the chiral recognition. If the two immiscible phases are composed mainly of water, then the system is an aqueous biphasic system (ABS). Since the majority component of ABS is water, they are considered green, economical and reliable systems. A major advantage of LLE is that it can comprise both enantiomeric recognition and solvent extraction on a single technique. Ionic liquids are alternative solvents with great structural diversity, allowing the design of task-specific solvents, including chiral ionic liquids (CILs). The introduction of CILs in LLE may contribute to high performant extraction/separation systems. Another promising class of green chiral selectors is the tartaric acid esters family which in conjugation with boric acid appear as promising adjuvants for the LLE systems. In this work, two different approaches were explored for the purification of propranolol enantiomers using LLE and ABS. In the first one, CILs and tartaric acid esters were used in LLE systems as chiral selectors, and in the second one, CILs and tartaric acid esters were used as chiral selectors in polymer-polymer-based ABS. The best outcome was scaled-up resorting to centrifugal partition chromatography (CPC).publishe

Selection of hydrotropes for enhancing the solubility of artemisinin in aqueous solutions

Artemisinin is an antimalarial substance very sparingly soluble in water. In the attempt to identify environmental-friendly and non-toxic aqueous-based solvents to extract it from Artemisia annua L., the solubility of artemisinin in aqueous solutions of different hydrotropes was measured at 303.2 K, for hydrotrope concentrations up to 5 M. The ability of the studied hydrotropes for enhancing the artemisinin solubility increases in the following order: Na[N(CN)2] < Na[SCN] < [Chol][Van] < [Chol][Gal] < [N4,4,4,4]Cl < [Chol][Sal] < [P4,4,4,4]Cl < Na[Sal], with Na[Sal] allowing an increase in the solubility of 750 fold compared to pure water. The COSMO-RS model and experimental Kamlet-Taft solvatochromic parameters were applied to connect the solubility enhancement with solvent properties. At low hydrotrope concentration, the solubility increases with the decreasing of the difference between the Apolar Factors of the hydrotrope and artemisinin, while for higher hydrotrope concentration, the hydrogen-bond acceptor character of the hydrotrope seems to have an impact on the solubility enhancement. Even if some mechanistic understanding is still to unfold, quantitatively the empirical correlations of solubility enhancement with the hydrotrope concentration and the solvatochromic parameters show very high accuracy. In particular, 93% of the change on the artemisinin solubility enhancement could be explained using the hydrotrope concentration and two combined solvatochromic parameters (αβ and π∗2) as explaining variables.This work was developed within the scope of the projects CICECOAveiro Institute of Materials, UIDB/50011/2020 & UIDP/50011/2020, CIMO-Mountain Research Center, UIDB/00690/2020, and Green Health (Norte-01-0145-FEDER-000042) all financed by national funds through the FCT/MEC and when appropriate co-financed by FEDER under the PT2020 and NORTE 2020 Partnership Agreement. Isabela Sales and Silvana Mattedi thanks the finantial support from CAPES and CNPq/ Brazil (CAPES: Proc. 88881.189075/2018-01 and 88887.494428/2020- 00. CNPq: Grant 303089/2019-9 and Proc.438036/2018-2).info:eu-repo/semantics/publishedVersio

Synthesis and characterization of chiral ionic liquids based on quinine, l-proline and l-valine for enantiomeric recognition

The separation of enantiomers remains a major challenge for the pharmaceutical industry. In this work, eight chiral ionic liquids (CILs) directly derived from the ‘chiral pool’ were synthesized and characterized in order to develop enantioselective systems, for the chiral resolution. According to their chiral cations, three different groups of CILs were prepared, namely based on quinine, L-proline and L-valine, and their enantiomeric recognition ability evaluated. For that purpose the diastereomeric interactions between a racemic mixture of Mosher's acid sodium salt and each CIL were studied using 19 F NMR spectroscopy. The remarkable chemical shift dispersion induced by some CILs demonstrates their potential application in chiral resolution. Additionally the optical rotation, thermophysical properties and ecotoxicity against the marine bacteria Aliivibrio fischeri of these chiral ionic liquids were addressed.publishe

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.publishe

Odd–even effect in the formation and extraction performance of Ionic-Liquid-Based aqueous biphasic systems

Ionic-liquid-based aqueous biphasic systems (IL-based ABS) have been extensively investigated in the separation of high-value biomolecules. However, the understanding of the molecular-level mechanisms ruling phase separation and extraction performance of these systems is crucial to successfully design effective separation processes. In this work, IL-based ABS composed of K2HPO4 and cholinium carboxylate ILs ([Ch][CnCO2] with n = 1 to 7, comprising anions with odd and even alkyl chain length) were investigated. The respective ternary phase diagrams, including binodal curves, tie-lengths, tie-line lengths and critical points, as well as the Setschenow salting-out coefficients (ks) that is a quantitative measure of the two-phase formation ability, were determined at 298 K. The extraction performance of these systems was then evaluated for four amino acids (L-tryptophan, L-phenylalanine, L-tyrosine, L-3,4-dihydroxyphenylalanine/L-dopa). It was found that ILs composed of anions with even alkyl chains display slightly higher ks values, meaning that these ILs are more easily salted-out or more easily phase separate to form ABS. On the other hand, ABS formed by ILs with anions comprising odd alkyl chains lead to slightly higher partition coefficients of amino acids. Beyond the neat ILs odd-even effect resulting from their nanostructuration, being this a well-known phenomenon occurring in a series of their thermophysical properties, it is here shown the existence of an odd-even effect displayed by the IL anion aliphatic moiety in aqueous solution, visible both in the two-phase formation ability and extraction performance of ABS. These findings contribute to elucidate the molecular-level mechanisms governing ABS formation and partitioning of biomolecules, ultimately allowing the design of effective separation platforms.publishe

Enhancing artemisinin solubility in aqueous solutions: searching for hydrotropes based on ionic liquids

Artemisinin is a sesquiterpenoid lactone peroxide, known for its potent antimalarial activity that can be extracted from Artemisia annua L. This compound is only sparingly soluble in water, making its extraction using environmental-friendly and non-toxic aqueous solvents difficult. In the attempt to overcome this limitation, hydrotropes, which are a class of compounds that can assist in increasing the solubility of hydrophobic solutes in water, were investigated in this work. In particular, the hydrotropic capability of ionic liquids (ILs) on the aqueous solubility of artemisinin was studied. The effects of IL concentration and anion nature of 1-butyl-3-methylimidazolium-based ILs on the solubility of artemisinin at 303.2 K in water were evaluated. It is here shown the excellent capacity of ILs containing thiocyanate or dicyanamide anions to enhance the solubility of artemisinin in aqueous media, with a magnitude comparable to that obtained with the best organic solvents. Furthermore, solvatochromic parameters of the ILs aqueous solutions were also measured and combined with COSMO-RS and the cooperative hydrotropy model to establish relations between the artemisinin solubility enhancement and the solvent characteristics. The solubility enhancement of artemisinin is favored by the apolarity of the medium and the lower hydrogen-bond acceptor character of the hydrotrope.This work was developed within the scope of the projects CICECO-Aveiro Institute of Materials, UIDB/50011/2020 & UIDP/50011/2020, CIMO-Mountain Research Center, UIDB/00690/2020, all financed by national funds through the FCT/MEC and when appropriate co-financed by FEDER under the PT2020 Partnership Agreement. Isabela Sales and Silvana Mattedi thanks the finantial support from CAPES and CNPq/Brazil (CAPES: Proc. 88881.189075/2018-01 and 88887.494428/2020-00. CNPq: Grant 303089/2019-9 and Proc.438036/2018-2).info:eu-repo/semantics/publishedVersio

Synthesis and characterization of analogues of glycine-betaine ionic liquids and their use in the formation of aqueous biphasic systems

A series of novel analogues of glycine-betaine ionic liquids (AGB-ILs), viz. 1-(4-ethoxy-4-oxobutyl)-1-methylpyrrolidin-1-ium, N,N,N-tri(n-butyl)(4-ethoxy-4-oxobutyl)-1-phosphonium and N,N,N-trialkyl(4-ethoxy-4-oxobutyl)-1-aminium cations with ethyl, n-propyl and n-butyl alkyl chains, combined with the bromide anion, have been synthesized and characterized. Their synthesis and characterization by spectroscopic methods and elemental analysis is here reported. These ILs were further characterized in what concerns their thermal properties and ecotoxicity against Allvibrio fischeri, and compared with the commercial tetra(n-butyl)ammonium and tetra(n-butyl)phosphonium bromide. The novel AGB-ILs described in this work have low melting points, below 100 °C, display high degradation temperatures (180–310 °C), and low toxicity as shown by being harmless or practically harmless towards the marine bacteria Allvibrio fischeri. Finally, the ability of the synthesized AGB-ILs to form aqueous biphasic systems with potassium citrate/citric acid (at pH 7) was evaluated, and the respective ternary phase diagrams were determined. It is shown that the increase of the cation alkyl chain length facilitates the creation of ABS, and that phosphonium-based ILs present a slightly better separation performance in presence of aqueous solutions of the citrate-based salt.publishe