Liquid Equilibrium Research Articles

Overview and thermodynamic modelling of deep eutectic solvents as co-solvents to enhance drug solubilities in water

The poor water solubility of active pharmaceutical ingredients (APIs) is a major challenge in the pharmaceutical industry. Co-solvents are sometimes added to enhance drug dissolution. A novel group of co-solvents, the Deep Eutectic Solvents (DES), have gained interest in the pharmaceutical field due to their good solvent power, biodegradability, sustainability, non-toxicity, and low cost. In this study, we first provide an overview of all the literature solubility studies involving a drug or API + water + DES, which can be a valuable list to some researchers. Then, we analyze these systems with focus on each individual drug/API and provide statistical information on each. A similar analysis is carried out with focus on the individual DESs. An investigation of the numeric values of the water-solubility enhancement by the different DESs for various drugs indicates that DESs are indeed effective co-solvents, with varying degrees of solubility enhancement, even up to 15-fold. This is strongly encouraging, indicating the need for further studies to find the most promising DESs for solubility enhancement. However, time-consuming and costly trial and error should be prevented by first screening, using theoretical-based or thermodynamic-based models. Based on this conclusion, the second part of the study is concerned with investigating and suggesting accurate thermodynamic approaches to tackle the phase equilibrium modeling of such systems. For this purpose, a large data bank was collected, consisting of 2009 solubility data of 25 different drugs/APIs mixed with water and 31 different DESs as co-solvents at various DES concentrations, over wide ranges of temperatures at atmospheric pressure. This data bank includes 107 DES + water + drug/API systems in total. The solubility data were then modeled according to the solid–liquid equilibrium framework, using the local composition activity coefficient models of NRTL, and UNIQUAC. The results showed acceptable behavior with respect to the experimental values and trends for all of the investigated systems, with AARD% values of 9.65 % and 14.08 % for the NRTL and UNIQUAC models, respectively. In general, the lower errors of NRTL, as well as its simpler calculation process and the requirement of fewer component parameters, suggest the priority of NRTL over UNIQUAC for use in this field.

Characterization of choline chloride‐based deep eutectic solvent for anthocyanin extraction via aqueous two‐phase system: Physicochemical properties and liquid–liquid equilibrium phase diagram

AbstractThe purpose of this research is to characterize and explore the feasibility of deep eutectic solvent‐based aqueous two‐phase system (DES‐ATPS) for its potential application in the extraction and purification of anthocyanins. Various combinations and molar ratios of DES using choline chloride as hydrogen bond acceptor (HBA) and butanediol (BDO), ethylene glycol (EG), and lactic acid (LA) as hydrogen bond donor (HBD) were synthesized, screened, and investigated on its physicochemical properties. The binodal phase diagrams were developed as basis for the ATPS development. It was noted that LA‐based natural deep eutectic solvents (NADES) were highly polar and likely to enhance the solubility of anthocyanin in DES. Regardless, the simple molecular structure and low viscosity of EG‐ and BDO‐based DES enhanced the solubility of anthocyanin and recorded a monomeric anthocyanin content ranging from 10.52 ± 0.78 mg cyanidin‐3‐glucoside/g at 40°C and 10.78 ± 0.84 mg cyanidin‐3‐glucoside/g at 30°C, respectively. Lastly, the liquid–liquid equilibrium binodal curves were developed and ChCl:1,3‐BDO (1:4) and ChCl:1,4‐BDO (1:4) exhibited excellent phase‐forming ability, thus concluding its excellent potential for anthocyanin extraction through ATPS.

Vapor-liquid phase equilibria behavior prediction of binary mixtures using machine learning

Basic thermodynamic data plays an important role in chemical applications. However, the traditional acquisition of thermodynamic data through experiments is laborious. Thermodynamic data prediction is considered as an alternative to the experiments, especially when qualitative analysis is needed prior to experimental studies. In this work, we report a successful machine-learning based approach to predict the fundamental thermodynamics characteristics of vapor–liquid equilibrium (VLE). A new dataset of the VLE experimental data of 210 binary mixtures with screened descriptors was constructed. The obtained results show that the VLE characteristics of the target system can be fully revealed by machine learning methods and random forest has more excellent predictive ability on the VLE behavior than the neural network. This work provides a new approach to the prediction of VLE data and useful information for the mechanistic study on the VLE phenomenon.

Prediction of Vapor Liquid Equilibrium of Binary CO2-Contained Mixtures for Carbon Capture and Sequestration using Artificial Intelligence

Prediction of Vapor Liquid Equilibrium of Binary CO2-Contained Mixtures for Carbon Capture and Sequestration using Artificial Intelligence

A Numerical Study of Vapor–Liquid Equilibrium in Binary Refrigerant Mixtures Based on 2,3,3,3-Tetrafluoroprop-1-ene

The binary refrigerant mixtures containing 2,3,3,3-Tetrafluoroprop-1-ene are considered as excellent substitutes for traditional refrigerants. Weak hydrogen bonds exist in hydrofluorocarbons and hydrofluoroolefins. However, for several recently published binary refrigerant mixtures, there is no Vapor–Liquid Equilibrium calculation study considering hydrogen-bonding associations. This work presents a calculation work of the saturated properties of nine pure refrigerants using the Cubic-Plus-Association Equation of State, considering the hydrogen-bonding association in refrigerant fluids. The average relative deviations of the saturated vapor pressure, liquid, and vapor density are less than 1.0%, 1.5%, and 3.5%, respectively. The Vapor–Liquid Equilibrium of ten binary refrigerant mixtures containing 2,3,3,3-Tetrafluoroprop-1-ene is also calculated using the Cubic-Plus-Association Equation of State with the van der Waals mixing rule. The average relative deviations of the liquid-phase and vapor-phase mole fractions are less than 1.0% and 2.0%, respectively. Moreover, the Vapor–Liquid Equilibrium data and the model’s adaptability are analyzed and discussed.

Research on solubility behavior of iminostilbene in twelve mono-solvents: Measurement, modeling, molecular simulation and thermodynamic properties

Iminostilbene (IMB) is an important pharmaceutical intermediate that can be used to prepare the antiepileptic drug omazepine. The measurement of solid–liquid equilibrium solubility parameters in various solvents can be employed for crystallization and separation processes of IMB. In this research, mole-fraction solubility of IMB in twelve individual organic solvents namely: “methyl acetate (MeAC), ethyl acetate (EtAC), n-propyl acetate (NPAC), isopropyl acetate (IPAC), n-butyl acetate (NBAC), isobutyl acetate (IBAC), N-methylpyrrolidone (NMP), acetone (DMK), N,N-dimethylformamide (DMF), acetonitrile (MeCN), N,N- dimethylacetamide (DMAC) and 1,4-dioxane (Diox)” was critically evaluated ranged from 278.15/288.15 K to 323.15 K at 0.1 MPa using laser monitoring method. Experimental solubility data had a general uptrend with the incremental temperature. Simultaneously, IMB solubility in selected mono-solvents showed an obvious order from high to low of: NMP > DMAC > DMF > Diox > DMK > NBAC > NPAC > EtAC > IBAC > IPAC > MeAC > MeCN. In order to explore dissolution behavior, Hirshfeld surface as well as molecular electrostatic potential surface (MEPs) were employed to analyze intermolecular interaction, and result indicated hydrogen bonding was easily formed on >NH group and its opposite position CHCH group. Meanwhile, Hansen solubility parameters (HSPs) were used to investigate solubility order, the result of which suggested that dispersion interaction could be the main factor influenced on solubility order in homologous solvents. Moreover, four activity coefficient models (Margules, UNIQUAC, NRTL, NRTL-SAC model) as well as a combined equation (Jouyban model) were applied for correlation of solubility data with twelve solvents. UNIQUAC model provided the highest regression accuracy among five models in terms of average relative deviation (ARD) lower than 1.178 % and root mean square deviation (RMSD) not higher than 1.176 ‰. Furthermore, based on UNIQUAC equation, thermodynamic properties including dissolution and mixing process were strictly evaluated for further research on solubility behavior. The results demonstrated that both of mixing and dissolution behaviors were spontaneous and entropically driven.

Investigation on solid–liquid equilibrium behavior of 4-cyanobenzoic acid in fourteen mono-solvents: Determination, correlation, molecular simulation and thermodynamic analysis

4-Cyanobenzoic acid (4-CyBZA) is an important pharmaceutical intermediate, and the research on solubility behavior of 4-CyBZA in organic solvents is very necessary for its crystallization and separation processes. Therefore, this study aimed at exploring dissolution behavior of 4-CyBZA in several pure solvents via experiment, calculation, and simulation process. In this study, mole-fraction solubility values of 4-CyBZA in fourteen common solvents including four low alcohols (methanol (MeOH), ethanol (EtOH), n-propanol (NPOH), n-butanol (NBOH)), four acetates (methyl acetate (MeAC), ethyl acetate (EtAC), n-propyl acetate (NPAC), n-butyl acetate (NBAC)), two alcohol ethers (2-ethoxyethanol (EGEE), 2-methoxyethanol (EGME)) as well as four common heteroatom/heterocyclic solvents (acetonitrile (MeCN), N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), 1,4-dioxane (Diox)) were critically measured by using laser monitoring method from 278.15/288.15 K to 323.15 K under 100 kPa. Interestingly, experimental results indicated that an increase in temperature facilitated the dissolution of 4-CyBZA in selected 14 solvents. At the same time, the solubility curve underwent a crossover phenomenon. At 298.15 K, the common order of 4-CyBZA solubility was: DMF > EGME > EGEE > NMP > Diox > MeOH > MeAC > EtOH > EtAC > NPAC > NPOH > NBOH > NBAC > MeCN. The Hansen solubility parameter (HSP) was introduced to analyze solubility behavior via molecular similarity between 4-CyBZA and chosen solvents. Molecular modeling including Hirshfeld surface (HS) analysis and molecular electrostatic potential surface (MEPS) were employed to understand internal interactions within 4-CyBZA crystals. Moreover, solubility was fitted by Margules model, NRTL model, NRTL-SAC model, UNIQUAC model as well as a combined model (Jouyban model). Results showed that NRTL and NRTL-SAC model were more suitable for correlating 4-CyBZA solubility with absolute temperature. Furthermore, given the high accuracy of the NRTL model, dissolution thermodynamic characteristics of 4-CyBZA in chosen solvents were analyzed by NRTL model, which revealed that the dissolving process and mixing process were spontaneous and entropy-driven.

Insight into the aggregation and phase behavior for aqueous solution of ethylene glycol monobutyl ether with self-assembly induced optical and electrical properties

Ethylene glycol monobutyl ether (EGMBE) is a polar small molecule with amphiphilic characteristics, which can form various aggregates in aqueous solution. The solubility of EGMBE decreases as the temperature increasing with a lower critical solution temperature (LCST). The influence of temperature and salinity on aggregation behavior and solubility of EGMBE were thoroughly investigated in this paper. The phase transition temperatures of EGMBE aqueous solutions with different concentrations were determined and compared with literature. The completed phase diagram of the ternary system (water + NaCl + EGMBE) was constructed. The measured liquid-liquid equilibrium (LLE) data can be well fitted to the commonly used empirical equations Othmer–Tobias, Bancroft and Setschenow. The dynamic light scattering (DLS) measurement shows that the particle size of EGMBE aggregates increases with increasing concentration, reaching its maximum at EGMBE mass fraction of about 30 %. Increasing temperature and inorganic salt concentration can both promote the increase of particle size, especially when approaching the phase separation point, the particle size increases sharply, and the corresponding viscosity of EGMBE solution abnormally increases with increasing temperature. The Tyndall effect of EGMBE solution was also observed to be most significant at mass fraction around 30 %. It is interesting to note that the conductivity of EGMBE solution increases with increasing concentration, reaching its maximum value when the EGMBE mass fraction is about 30 %, though EGMBE is not conductive. The investigation of pyrene fluorescence probes and surface/interfacial tension also demonstrated the aggregation and surface adsorption of EGMBE.

Separation of methyl ethyl ketone - methanol azeotrope by ionic liquids: Thermodynamic and molecular mechanism

In this work, three ionic liquids (ILs) based on acetate, namely tetraethylammonium acetate ([N2222][Ac]), 1-hexyl-2,3-dimethylimidazolium acetate ([HMMIM][Ac]), and tributylmethylammonium acetate ([N4441][Ac]) were selected to separate the methyl ethyl ketone - methanol azeotrope. The vapor–liquid equilibrium (VLE) data of the binary system (methyl ethyl ketone + methanol) and the ternary systems (methyl ethyl ketone + methanol + IL) were measured at 101.3 kPa. It was found that all the experimental data were thermodynamically consistent and the three ionic liquids could effectively eliminate the azeotropic phenomenon at a specific concentration. The separation ability of the three ionic liquids is [N2222][Ac] > [HMMIM][Ac] > [N4441][Ac]. The NRTL model was used to correlate the VLE data and was found to have an excellent quality of fit. Moreover, the quantum chemical calculations, COSMO-RS model, and FT-IR analysis were used synergistically to provide microscopic insights into the separation mechanism of ionic liquids.

Isothermal vapor-liquid equilibrium measurements and PC-SAFT, PR78, and CPA phase behavior modeling of n-tricosane + SC CO2 mixtures

This study reports the isothermal VLE (PTxy) data of n-tricosane (heavy n-alkane, n-C23H48) in supercritical (SC) CO2 at two selected temperatures of (323 and 343) K over the pressure range from (1.66 to 34.88) MPa. The measurements were made using a high-temperature and high-pressure VLE optical cell. The combined expanded uncertainty of the temperature, pressure, and phase concentration measurements at 0.95 confidence level with a coverage factor of k = 2 is estimated to be 0.2 K, 0.22 %, and 3.5 %, respectively. The measured VLE data has been used to estimate the critical parameters (TC, PC, xC) of the binary n-tricosane + CO2 mixture. The derived L-G critical properties data of the binary n-tricosane + CO2 mixture are: TC = 323.15 K, PC = 34.02 MPa, xC=0.060 mole fraction of n-tricosane; and TC = 343.15 K, PC = 40.14 MPa, xC=0.071 mole fraction of n-tricosane. The measured solubility data for the mixture has been used to estimate the physical meaning Krichevskii parameter ∂P∂xTCVC∞=-75.93MPa. Based on the derived Krichevskii parameter the thermodynamic (partial molar volumes, V¯2∞,H¯2∞,C¯P2∞) and structural (cluster size,Nexc∞) properties of the infinite dilution mixture of n-tricosane + CO2 near the critical point (CP) of pure solvent (CO2) have been calculated. The measured vapor – liquid equilibrium data for n-tricosane + CO2 was modeled using three equations of state (PC-SAFT, PR78, and CPA). The best prediction option with PC-SAFT was obtained with kij=0.12, while kij=0 was the best using PR78 and CPA EoS.

Liquid-liquid equilibrium data for the ternary (nonan-2-one + dihydroxy benzenes + water) systems at 298.15, 313.15, 323.15 and 333.15 K

Nonan-2-one is a novel solvent with extremely low solubility in water to extract dihydroxy benzene from coal gasification wastewater. In this work, the liquid–liquid equilibrium (LLE) data for the ternary (nonan-2-one + benzene-1,2-diol/benzene-1,3-diol/benzene-1,4-diol + water) systems were determined at 298.15, 313.15, 323.15 and 333.15 K under 101.3 kPa. According to calculation, distribution coefficients show that nonan-2-one can offer good extraction performance and selectivity parameters. The NRTL and UNIQUAC models were used to correlate the experimental data and the binary interaction parameters were obtained. The root mean square deviation values of the two models are similar and lower than 0.021, which means the two models can estimate the LLE data accurately. Nonan-2-one is an efficient extractant for separating dihydroxy benzenes from wastewater.

Vacuum distillation: A sustainable separation and purification approach for extracting valuable metals from In–Zn, In–Sn, and In–Sn–Zn waste alloys

The vacuum distillation (VD) method was studied for extraction of valuable metals from In–Zn, In–Sn, and In–Sn–Zn waste alloys. The VD studies were carried out between 773 K and 1073 K, at 5 Pa, and for 60 min for the In–Zn alloys. The In content in the residues was greater than 99.999 wt%, and the Zn content in the volatiles was the highest at 99.8962 wt%. For the In-Sn alloys, the VD experiments were carried out from 1323 K to 1573 K at 5 Pa for 540 min for the In–Sn alloys. The Sn content in the residues exceeded 99.9963 wt%, whereas the In content in the volatiles was 99.86 wt%. Further, the In–Sn–Zn VD was carried out between 773 K and 1073 K at 5 Pa for 90 min. The Zn content of the residues decreased from 6.0 wt% to 0.0009 wt%, while the Zn content of the volatiles was 99.79 wt%. Using the M-MIVM and vapor–liquid equilibrium (VLE) theories, the VLE data was predicted and the related phase diagrams for the binary and ternary alloys were displayed. The remarkable similarity between theoretical and experimental VLE phase diagrams demonstrates the reliability of the M-MIVM for In-based alloys.

Effects of electric field on vapor–liquid equilibrium of binary mixture

Effects of electric field on vapor–liquid equilibrium of binary mixture

Modelling the thermodynamic properties of the mixture of water and polyethylene glycol (PEG) with the SAFT-[formula omitted] Mie group-contribution approach

The SAFT-γ Mie group-contribution (GC) equation of state (EoS) is employed to describe the thermodynamic properties of aqueous mixtures of polyethylene glycol (PEG), a polyether of great industrial and scientific interest. This prototypical system is chosen due to the intrinsic complexity of hydrogen-bonding polymers, and represents a critical test of the theory. Water is modelled as a single Mie segment with four association sites and PEG as a linear heteronuclear chain of three types of segments: the associating hydroxymethyl end group (CH2OH); the associating oxygen (cO); and the modified methylene group (CH2OE), which incorporates the effects that the proximity of an electronegative atom has on the electronic environment of the methylene group. The SAFT-γ Mie model parameters characterizing the newly-defined group interactions are estimated to reproduce the liquid–liquid equilibrium (LLE) closed-loop miscibility gaps observed in the orthobaric phase diagram of PEG + water mixtures. The resulting model allows one to predict miscibility gaps in a temperature range between 350 K and 600 K, capturing both the UCST and the LCST within a 2% error with a close description of the overall phase behaviour. The predictive capability of the model is assessed by comparing the calculations with the experimental density of pure PEG, the enthalpy of mixing, and vapour–liquid equilibrium properties of PEG + water mixtures, with a good overall agreement. By coupling the present SAFT model with a recent thermodynamic model describing solubility in semi-crystalline polymers, the solubility of water in PEG below its melting point is semi-quantitatively captured both in the low- and high-humidity regimes. In particular, deliquescence – the melting of semi-crystalline PEG at high relative humidity – is predicted by simply accounting for the melting enthalpy of PEG crystals.

Liquid–Liquid Equilibrium for the Binary Mixtures of Butyl l-Lactate + Water and Butyl Lactate + Water at 74.6 kPa

Liquid–Liquid Equilibrium for the Binary Mixtures of Butyl <scp>l</scp>-Lactate + Water and Butyl Lactate + Water at 74.6 kPa

Assessment of the performance of mesityl oxide extraction from water with n-alkanols: A study on liquid–liquid equilibrium, thermodynamic modeling, and simulation analysis

Mesityl oxide (MO) is a crucial organic synthesis intermediate and a popular high boiling point solvent. However, during its production process, wastewater containing MO is easily generated. To recover MO from wastewater, four alkanols with different carbon chain lengths (C6-C9) were chosen as extractants for the separation of MO from water. Liquid-liquid equilibrium (LLE) data for the ternary mixture of extractants + MO + water was experimentally measured at 303.2 K and 101.3 kPa. The separation factor (S) and distribution coefficient (D) were used to evaluate the extraction performance of the four extractants in separating MO from water. The results showed that 1-nonanol exhibited higher S and D values compared to other extractants, indicating its suitability as an effective extractant. The NRTL and UNIQUAC models were used to correlate the experimental data and determine the regression parameters. According to the mixing surface analysis based on the Gibbs energy topology, the binary interaction parameters are found to be consistent with the measured data. The UNIFAC model was used for predicting LLE data and comparing the results with the experimental data. The root mean square deviation (RMSD) was lower than 0.0077, 0.0075, and 0.0211 in these three models, respectively. In addition, differences in extractant extraction effects were analyzed by intermolecular interactions (σ-Profile, interaction energy, and hydrogen bond length).

Study of Methanol Extraction from Saturated Alkanes: Solvent Screening, Liquid–Liquid Equilibrium Measurement, and Thermodynamic Simulation

Study of Methanol Extraction from Saturated Alkanes: Solvent Screening, Liquid–Liquid Equilibrium Measurement, and Thermodynamic Simulation

VLE measurement of binary systems 1-butyl-3-methylimidazolium-based ionic liquids and ethanol or water

Experimental vapor–liquid equilibrium (VLE) data for binary systems of ethanol or water with four ionic liquids (ILs) comprising 1-butyl-3-methylimidazolium cation and different anions were measured at atmospheric pressure within a broad region of IL concentrations, IL mole fraction ranging between 0 and 0.7 or even 0.87. Siwoloboff procedure of vapor–liquid phase transition temperature measurement was applied to estimate VLE of the binary mixtures. Obtained t–x data were fitted assuming ideal vapor and non-ideal liquid phase behavior, using the original NRTL equation to calculate component activity coefficients. VLE description results are presented in form of equilibrium diagrams and as the variation of activity coefficients with mixture composition. Quality of the VLE data fitting was assessed based on root mean square deviations and mean deviations in temperature. Some experimental binary t–x data sets were compared to those available in literature (measured in much narrower concentration range) or predicted from ternary VLE data. The selection of ILs in this study was related to the separation of ethanol−water mixture by extractive distillation. Principal IL selection criterium was its ability to affect the ethanol–water relative volatility. Thermodynamic description of the VLE data of IL-containing systems within a wide concentration range is an essential building block of the mathematical model of separation devices, especially in case of regeneration equipment where concentrated IL is present.

Nonlinear liquid-liquid chromatography: Modeling a binary mixture separation

In liquid-liquid chromatography (LLC), mixture components are separated due to their different distribution between the phases of a biphasic liquid system composed of three or four solvents. LLC separations are typically modeled assuming that only the solutes distribute between the two liquid phases and their distribution can be described with a concentration-independent distribution constant. With increasing solute concentration, the physicochemical properties of the biphasic system change, and the distribution of the solutes becomes a function of their concentration. However, the experimental determination of liquid-liquid equilibria in multicomponent systems is time-intensive, and its prediction using thermodynamic models is often not sufficiently accurate for process design purposes. Thus, in this work, we propose a simple approach to model and simulate LLC separations in the nonlinear (concentration-dependent) range of the solutes’ distribution equilibria, namely cannabidiol (CBD) and cannabigerol (CBG). Using the inverse method, the distribution equilibrium equation parameters were estimated from pulse injection experiments of single solutes at concentrations ranging from 1 to 100 mg/mL and 1–50 mg/mL for CBD and CBG, respectively. The obtained parameters were then successfully used to predict the elution profiles of binary mixtures of different compositions at 40 mg/mL total cannabinoid concentration. The approach was demonstrated and validated for CBD and CBG as model compounds and n-hexane/methanol/water 10/7.5/2.5 (v/v/v) as the biphasic solvent system. It should be noted that the applicability of the proposed approach is system-dependent, and hence, it should be evaluated for each separation task individually.

Cobalt and nickel separation in aqueous two-phase systems with polyethylene glycol 20,000 and sodium electrolytes

The separation of Co(II) and Ni(II) in aqueous two-phase systems (ATPSs) formed by the polymer polyethylene glycol 20,000 and several sodium electrolytes, coupled with the organic extractant 1-nitroso-2-naphthol was studied. First, the liquid-liquid equilibrium experiments were carried out to describe the phase diagrams of the ATPS. Then, the metal separation efficiency was evaluated considering several factors. It was observed that pH had a great influence on the selective metal chelation. When lowering the pH to 2 and 1 in the system with sodium sulfate, it was possible to suppress the Ni extraction under 5%. These results showed that the differences in the metal chelate stabilities could displace the equilibrium reaction with Ni(II) for selective extraction. In addition, experimental results showed that the interactions between metal cations and the salt anions also determined the separation efficiency. For the system with sodium sulfate (Na2SO4), Ni(II) extraction was suppressed at pH 2, but when sodium citrate (Na3C6H5O7) was used, the suppression occurred at pH lower than 0.5, while sodium tartrate (Na2C4H4O6) and sodium hydrogen phosphate (Na2HPO4) were not suitable for selective extraction. High separation factors of 11,080, 1136, and 3300 were obtained for the aqueous systems with Na2SO4 at pH 2, and pH 1, and Na3C6H5O7 at pH 0.5, respectively. Finally, the extraction at higher metal ion concentrations was tested. When the concentration of 1N2N was 1000 mg/kg, the maximum amount of extracted Co reached about 85 mg/kg within 15 min, which corresponds to complete extraction considering a metal:1N2N ratio of 1:4.