Journal Pre-proof

Enhanced distribution kinetics in liquid-liquid extraction by CO2 -expanded

solvents

Larissa P. Cunico, Mingzhe Sun, Yu Rui, Semhar Ghirmai, Markus

Enekvist, Simon Lundegard, Margareta Sandahl, Charlotta Turner

PII: S0896-8446(20)30125-X
DOI: https://doi.org/10.1016/j.supflu.2020.104874
Reference: SUPFLU 104874

To appear in: The Journal of Supercritical Fluids

Received Date: 5 November 2019

Revised Date: 19 March 2020
Accepted Date: 20 March 2020

Please cite this article as: Cunico LP, Sun M, Rui Y, Ghirmai S, Enekvist M, Lundegard S,
Sandahl M, Turner C, Enhanced distribution kinetics in liquid-liquid extraction by
CO2 -expanded solvents, The Journal of Supercritical Fluids (2020),
doi: https://doi.org/10.1016/j.supflu.2020.104874

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© 2020 Published by Elsevier.

Enhanced distribution kinetics in liquid-liquid extraction by CO2-expanded

solvents

Larissa P. Cunico†‡, Mingzhe Sun†‡, Yu Rui‡, Semhar Ghirmai‡, Markus Enekvist‡, Simon
Lundegard‡, Margareta Sandahl‡, Charlotta Turner*‡
†
Shared first authorship
‡
Lund University, Department of Chemistry, Centre for Analysis and Synthesis, P.O. Box 124,
SE-22100 Lund, Sweden
*
Corresponding author: charlotta.turner@chem.lu.se (Charlotta Turner)

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Graphical abstract

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Highlights

 First time CO2-expanded solvents are used in liquid-liquid extraction (CXLLE)

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 Novel distribution kinetic data for three pharmaceutical compounds in water samples
 Designed equipment with on-line GC and LC for phase equilibria and kinetics studies
 Fast distribution rate with CO2 added, enabling 2 to 3 times shorter extraction time
 Novel phase equilibria data for CO2 + octanol + water

Abstract

1
Liquid-liquid extraction (LLE) is a useful extraction technique for highly complex samples,

however, it suffers from being slow due to mass transfer limitations. Carbon dioxide expanded

liquids (CXL) is a good replacement of traditional organic solvents for extraction, and for the

first time, the use of CXL in LLE was evaluated. An equipment consisting of a high-pressure

view cell with on-line gas chromatography analysis was built and validated, and thereafter used

to obtain novel phase equilibria data of the CO2/n-octanol/water system. The system was con-

nected on-line to HPLC to study the potential of CO2-expanded liquid-liquid extraction

(CXLLE) of pharmaceutical contaminants in water. In comparison with traditional LLE per-

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formed under similar experimental conditions, the addition of CO2 as a viscosity-lowering en-

trainer significantly increased the speed of mass transfer. Changes in compound log D (octanol-

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water distribution ratio) values brought by the CO2 expansion also proved the possibility of

selectivity-tuning in CXLLE.
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Keywords: Distribution kinetics, CO2-expandend solvents, phase equilibria, liquid-liquid ex-
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traction.
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1 Introduction
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Liquid-liquid extraction (LLE) is one of the most utilized techniques for sample preparation in

various types of chemical analysis processes. Examples of its application include the extraction
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of contaminants from water [1], soil [2] and natural sediments [3]; recovery of products ob-

tained from fermentation [4] and accumulation kinetics of compounds in aquatic organisms [5].

LLE is a useful extraction technique, especially for very complex samples containing particles

or those that are semisolid/slurry type-of-samples. A well-known drawback of LLE is the oc-

currence of relatively severe mass transfer limitations, making LLE a slow technique depending

2
on how efficient stirring is provided. The distribution kinetics can take more than 10 hours to

achieve its equilibrium in some cases [3]. One way to minimize the duration of the process is

by simply increasing the extraction temperature, thereby decreasing the viscosity and corre-

spondingly enabling faster diffusion rates in the solvent. This approach can however not be

applied in the extraction of thermally labile compounds. In addition, intense stirring can be

applied to promote the formation of small droplets and facilitate faster mass transfer. However,

intense stirring has been proven to cause damage to molecules of high molecular weight in

some cases [6].

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In a supercritical fluid, the viscosity is gas-like even at low temperatures. Hence, fast diffu-

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sivities can be achieved in a supercritical fluid without increasing the temperature [7]. The re-

placement of a conventional organic solvent by liquid or supercritical CO2 (even with a co-
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solvent added) does not only reduce the environmental burden, but also enables faster mass

transfer and consequently higher sample throughput [8]. A liquid mixture of an organic solvent
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and compressed CO2 is often in the literature called a gas expanded liquid (GXL). Recent years
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have witnessed an intense exploration of the development and use of GXLs in various fields,

such as catalysis, separation and extraction [9]. Compared with traditional organic solvents,
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dissolving compressed CO2 in an organic solvent decreases the solvent’s polarizability, surface

tension and viscosity, of which the latter improves the mass transfer in the solvent [10]. Mean-
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while, CO2-expanded liquids (CXL) consisting of binary or ternary mixtures of compressed

CO2 and polar organic solvent(s), offers much higher solubility of relatively polar compounds
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than supercritical CO2/co-solvent mixtures used in supercritical fluid extraction (SFE). The

presence of CO2 also increases the acidity of water, which can be beneficial in some applica-

tions where compound ionization is minimized by lowering the pH [10].

Despite its great potential, publications describing the use of CXL in extraction has been scarce.

Only a few research papers have reported the use of CO2-expanded alcohol for the extraction

3
of solid sample matrices [11-13]. No published research has been conducted on the application

of CXL in LLE of aqueous samples (CXLLE) so far. One major obstacle for studying CXLLE

is the lack of phase composition data of systems composed of CO2-expanded organic solvent

and water. Regarding the important solvent system n-octanol/water (i.e. to obtaining log Doct/wat

data), there is surprisingly no data for ternary mixtures of CO2/n-octanol/water. As two solvents

should be immiscible (at least nearly) in order to perform any LLE operation, it is essential to

obtain phase composition data of the CO2 expanded organic solvent/water system.

In the present study, an equipment setup was built to conduct CXLLE with on-line chromato-

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graphic analysis. The system was validated and then used to obtain novel phase equilibria data

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of CO2/n-octanol/water under different conditions. The same ternary system was then used in

the study of the distribution kinetics of three pharmaceutical compounds commonly found as
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water contaminants; acetylsalicylic acid (aspirin), acetaminophen (paracetamol) and caffeine.

Comparative experiments of traditional LLE utilizing n-octanol/water were also conducted to

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demonstrate the effect of CO2 addition, as well as the effect of stirring.
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2 Materials and methods

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2.1 Chemicals

The target compounds in this study, acetylsalicylic acid (purity ≥ 99% from Sigma), acetamino-
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phen (purity ≥ 99%, from Sigma), and caffeine (purity ≥ 99%, from Merck) are listed in Ta-

ble 1. n-Octanol (purity of ≥ 99%) and n-decane (purity ≥ 99%) were purchased from Sigma -
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USA. CO2 (purity ≥ 99.9993%) was purchased from AGA - Sweden. For the GC calibration,

tetrahydrofuran (purity ≥ 99.9%) was purchased from Honeywell - Germany, ethanol (purity ≥

99.7%) was purchased from Solveco - Sweden, and n-heptane (purity ≥ 99%) was purchased

4
from Merck - Germany. Helium (purity ≥ 99.999%) was purchased from AGA. Hydrogen (pu-

rity ≥ 99.9995%) was purchased from AGA. Acetonitrile (purity ≥ 99.9%) was purchased from

Honeywell. Milli-Q water was used in all experiments. All purity figures are given in weight%.

Insert Table 1.

2.2 Phase equilibria measurements

The experiments were performed using a home-built view cell with variable volume of up to

20 mL (Fig. 1A). As the first step, known amounts of water and n-decane (or n-octanol) were

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placed in the view cell for equilibration under the set temperature and pressure. For the ternary

mixtures, CO2 was delivered into the view cell at the desired pressure and temperature using a

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syringe pump (model 260D, from Teledyne Isco -USA). The same syringe pump was used to

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provide pressure while enabling the movement of the piston, and thereby to maintain the set

pressure. Appropriate total amounts of the solvents were added to ensure that the recirculation
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line was filled and that the solvent in majority was saturated with the other two solvents. A

heating jacket connected to a controller was used for heating and keeping the temperature con-
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stant during the measurements. Stirring was provided by using a stir bar placed inside the view

cell and in contact with a magnetic stirrer. After the equilibration under the set conditions of
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pressure and temperature, the mixture in the view cell was then allowed to enter the recircula-

tion line connected to on-line gas chromatography (GC). An HPLC pump (model 515, from
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Waters – USA) was used for the recirculation. The selected phase was analyzed by rotating the
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view cell to submerge the recirculation inlet and outlet with only the corresponding phase.

A GC (model 3800, from Varian – USA) equipped with a Thermal Conductivity Detector

(TCD) was used to determine the concentration of n-octanol, water and CO2 in each of the

phases. A Flame Ionization Detector (FID) was also connected after the TCD in order to allow

the quantification of the small amount of n-octanol in the water phase. The GC was on-line

5
connected to the recirculation line with a four-port injection valve (VICI AG International –

Switzerland) equipped with an internal loop of 0.5 μL, (Injection valve 1 in Figure 1A). In this

work, a 3-meter retention gap was mounted on the Injection valve 1 and further connected to

the GC column with a fused quartz press-fit union. The inlet of the retention gap (part outside

the GC oven) was kept warm by heating it in a pre-heated (368 K) copper tube. In order to

allow the mixture in the rotor to be flushed by the carrier gas into the GC, the injection valve

was manually switched for each measurement. The capillary column used was a J&W

PoraPLOT Q-HT (25m x 0.32mm x 10μm) column from Agilent and the carrier gas used was

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helium at 1 mL/min. The GC method started at an oven temperature of 363 K with 3 min hold

time and ramped to 423 K at 283 K·min-1. After that, the oven temperature was increased to

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553 K at 313 K·min-1 giving a total analysis time of 17.25 min. The TCD temperature was set

to 473 K and the FID temperature was set to 553 K.

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Insert Figure 1.
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2.3 Distribution kinetics measurements
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5 mL n-octanol was pre-saturated with known amount of water or water + CO2 (amounts cal-

culated from phase equilibria data obtained in this work) in a view cell with variable volume
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(View cell 1 in Figure 1B), following the same procedure as described for the phase equilibria

measurements. This is done to create the n-octanol phase (expanded or unexpanded) ready to
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be used for extraction, i.e. being saturated with water. This avoids the phase transition to occur
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at the same time as the distribution of the target compounds between the phases. After equili-

bration of the phase under operation conditions (temperature and pressure), the n-octanol phase

was transferred to a second view cell holding the water phase (6 mL) that contains the target

compounds (View cell 2 in Figure 1B). This was done by opening the valve present in the line

connecting View cell 1 and View cell 2. After the n-octanol rich phase was transferred, the

6
valve between the two view cells was closed and the extraction started in View cell 2 under the

set operation conditions. The water phase was thereafter allowed to enter the recirculation line

connected to the View cell 2. An HPLC system (1100 Series, Agilent – USA) was used for

quantitative analysis of the compounds in the water phase with defined intervals of time. The

HPLC system was modified to allow on-line connection to the recirculation line and the view

cell via a manually operated 4-port 2-position injection valve (VICI AG International) with an

injection volume of 0.5 μL. Isocratic elution was applied using water/acetonitrile/acetic acid

(68/29/3, v/v/v) at 0.5 mL/min as mobile phase. An Agilent Eclipse Plus C18 (50*3mm, 1.8μm)

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column was used and UV-Vis detection of the compounds was performed at 254 nm.

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2.4 Calibration and validation

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For the GC calibration of n-octanol, n-heptane was used as diluent, while water was diluted

with THF. A syringe was used to fill the internal loop of the injection valve with calibration
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solution kept at ambient temperature and pressure. For the calibration of CO2, ethanol was used

as diluent and the measurements were done using a variable volume view cell to handle high
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pressures while operating with different amounts of CO2. Density data for the mixtures consid-

ered in this part of the work (n-octanol/n-heptane, water/THF and CO2/ethanol) were obtained
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from literature [14-19]. For lower amounts of CO2 in the mixtures with ethanol (molar fraction

of CO2 equal to 0.05, 0.1 and 0.5), it was not possible to find experimental data in the literature
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and the density values were therefore measured according to the method described in our pre-

vious work [20]. When higher concentrations of n-octanol were used, the response of the de-
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tectors was compromised due to memory effects caused by solvent residue remaining in the

retention gap. To solve this problem, an additional injection valve (VICI AG International) with

an injection loop volume of 2 μL was placed in the carrier gas line (Injection valve 2 in Fig-

ure 1A). Pure n-heptane was introduced into the system through the additional injection valve

7
acting as a washing solvent of the lines, which considerably improved the peak shape and peak

area repeatability for quantification of n-octanol.

For the validation of the home-built equipment setup, which was done before the determination

of compound distribution ratios in n-octanol-water (and CO2) system, vapor-liquid-liquid equi-

librium (VLLE) data for a ternary mixture containing CO2, n-decane and water was selected

from literature [21] and compared to obtained experimental data. In this part of the work, for

the GC calibration, n-decane was diluted with n-heptane. A syringe was also used to fill the

rotor of the injection valve with the solvent or mixture of solvents and injection was done at

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ambient temperature and pressure. The density information for the mixture of n-decane/n-hep-

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tane was obtained from literature [22, 23]. Two calibration curves were recorded, at low and at

high concentration ranges of n-decane for both detectors used (TCD and FID), respectively.
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The values showed good linearity for all the solvents with R2 ≥ 0.997 (see Figures S1-S4 in

the Supporting information, SI).

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2.5 Determination of distribution ratios
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The distribution ratio (presented in the form of log D) of the three analytes in an octanol/water

two-phase system with the addition of CO2 were determined from the distribution kinetics re-
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sults as described in section 2.3 using the following equation:

[𝑎𝑛𝑎𝑙𝑦𝑡𝑒]𝑖𝑜𝑛𝑖𝑧𝑒𝑑 +[𝑎𝑛𝑎𝑙𝑦𝑡𝑒]𝑢𝑛−𝑖𝑜𝑛𝑖𝑧𝑒𝑑
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log D = 𝑙𝑜𝑔 ( [𝑎𝑛𝑎𝑙𝑦𝑡𝑒]𝑜𝑐𝑡𝑎𝑛𝑜𝑙

𝑖𝑜𝑛𝑖𝑧𝑒𝑑 +[𝑎𝑛𝑎𝑙𝑦𝑡𝑒]𝑢𝑛−𝑖𝑜𝑛𝑖𝑧𝑒𝑑 )
𝑜𝑐𝑡𝑎𝑛𝑜𝑙
𝑤𝑎𝑡𝑒𝑟 𝑤𝑎𝑡𝑒𝑟
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In order to calculate the log D values, additional experiments were performed to estimate the

density and volume of the CO2-expanded n-octanol phase. View cell 2 shown in Figure 1B was

used in these experiments. Single CO2-expanded n-octanol phases corresponding to the equili-

brated octanol phases in the distribution kinetics measurements under different pressures were

created based on the results from the phase equilibria measurements (Table 2: Phase II, the

octanol-rich phase). A known amount of fluoranthene was pre-dissolved in 12 mL of n-octanol

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and added to the view cell. Fluoranthene was chosen as it has a strong retention on C18 HPLC

columns even when the mobile phase is composed of a high percentage of acetonitrile. There-

fore, possible peak deformation in HPLC analysis due to strong solvent effect and disturbance

of CO2 expansion on the analyte peak in HPLC were circumvented, so that accurate determi-

nation of the fluoranthene concentration was possible. Then the created single CO2-expanded

n-octanol phase containing fluoranthene was recirculated and injected into the HPLC. The same

Agilent Eclipse Plus C18 (50*3 mm, 1.8 μm) column was used for analysis. The analysis was

performed under isocratic elution (acetonitrile, 65 vol% in water). The flow rate was kept at 0.8

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mL/min. A calibration curve of fluoranthene was constructed through manual injections of flu-

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oranthene octanol solutions of a series of concentrations (Figure S5). The final volume and

density of the created single CO2-expanded n-octanol phase was then calculated based on the
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amount of fluoranthene added and its concentration determined by HPLC (Table S2). In the

distribution kinetics measurements (section 2.3), the equilibrium concentrations of the three
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target compounds in the water phase were acquired. Then, the equilibrium concentrations of
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the three compounds in the expanded n-octanol phase were calculated based on the known total

amounts of the three compounds added along with the determined volumes of the expanded n-

octanol phases at equilibrium during extractions. Finally, the log D values of the compounds
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were determined using the compound equilibrium concentrations in both phases (Table S3).
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3 Results and Discussion

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3.1 Phase equilibria measurements

Phase equilibrium data is important in the design of a LLE process as it shows the immiscibility

of the two liquid phases involved [24], which may change significantly upon the addition of

compressed CO2. Since a homebuilt equipment was used in our experiments, the system was

firstly validated by determining VLLE data for a well-known ternary mixture, that of CO2, n-

9
decane and water [21]. The phase equilibria measurements were done in triplicate and the stand-

ard deviation (STD) for each phase is shown in Table S1 (SI). As shown in the table, measured

data in this work is in close agreement with literature data [21].

In this study, the aim was to explore the n-octanol/water system for LLE, but with the differ-

ence that compressed liquid CO2 was added as a viscosity-lowering entrainer. The octanol/wa-

ter system has the benefit of lots of tabulated distribution constant data (log Koct/wat) for a vast

number of compounds [25, 26]. Hence, isothermal liquid-liquid equilibrium data was obtained

for the ternary mixture of CO2, n-octanol and water at 323 K and pressures of 70, 85 and 100

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bars. For the lower pressure considered in this work (70 bars), the measurements of the CO 2

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rich phase were not performed since this phase was at gas-like state of matter and could not

recirculate well in the line for the GC analysis in the current equipment setup. The molar frac-
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tion of CO2 (x1), n-octanol (x2) and water (x3) for the measured VLLE data can be seen in

Table 2.
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Insert Table 2.
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The amount of CO2 in the n-octanol rich phase increased with pressure, as expected. Roughly,

by going from 70 to 100 bars, the molar ratio of CO2 increased from 0.4 to 0.5 (at 323 K). The
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water content (molar ratio) in the n-octanol rich phase as measured in this study showed signif-

icantly lower values (roughly 0.08 to 0.10) as compared to in the literature without the addition
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of CO2 (0.2838-0.2871 at 323K) [27]. This might be the consequence of changes in solvent

properties of n-octanol when CO2 is added. The relative permittivity ("polarity") and hydrogen-
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bonding abilities are expected to decrease when adding CO2 to the n-octanol rich phase [28].

Not surprisingly, the molar ratio of water in the n-octanol rich phase decreases with the CO2

content (Table 2).

10
 3.2 Distribution kinetics measurements

To evaluate the potential of using a CO2-expanded organic solvent in LLE, the distribution

kinetics of three compounds was studied in this study: acetylsalicylic acid (aspirin), acetamino-

phen (paracetamol) and caffeine (Table 1). These compounds were selected because they have

different chemical properties, and they are relevant environmental pollutants.

The concentrations of the selected analytes were measured in the water phase during the distri-

bution process by in-line HPLC/UV analysis. As expected, the concentrations in water de-

creased until the equilibrium was reached. Based on the shapes of the curves during the begin-

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ning phase obtained by plotting the compound concentrations in the water phase versus time

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(Figures 2 to 4), a first order model was applied for describing the initial extraction kinetics.

dC
dt
= −kC -p (1)

where C is the concentration of the compound, t is extraction time in minutes and k is the rate
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constant.
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The horizontal dotted lines indicate compound equilibrium concentrations and the vertical dot-

ted lines displays the approximate time until the equilibrium was reached.
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Table 3 shows the distribution rate constants for the three compounds under different experi-

mental conditions. As expected, the addition of compressed CO2 significantly accelerated the
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extraction process of all three compounds under all conditions. This can be attributed mostly to

the significant viscosity decrement caused by the expansion of n-octanol with CO2, which sub-
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sequently enhanced the mass transfer of compounds between the two phases. Another trend that

can be observed is that extraction went faster with increasing pressure for acetylsalicylic acid

and caffeine when CO2 was added to the n-octanol phase. A higher pressure gives more CO2 in

the octanol phase, which decreases both viscosity and relative permittivity. However, the same

clear trend is not observed for acetaminophen. This could be explained by this compound´s

11
basic properties (pKa of 9.4 in aqueous solution), and the octanol-rich phase being acidic due

to the content of water and CO2. An increase in pressure causes a decrease in pH [29].

The distribution kinetic plots that are illustrated in Figures 2 to 4 show the effect of stirring

and addition of CO2 on distribution kinetics. When the pressure was set at 85 bars, without

stirring and no addition of CO2 it takes approximately 170 min until equilibrium is reached

(Figure 2A). When stirring is provided, then about 66 min are required (Figure 2B). By adding

CO2 without stirring, around 78 minutes is required to reach the equilibrium (Figure 3B). With

stirring, equilibrium is reached within less than 37 min (Figure 4B). It is evident that with the

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enhanced mass transfer brought by CO2-expanded extraction solvent, stirring can still be used

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to further speed up the extraction process.

Insert Table 3.

Insert Figure 2.
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Insert Figure 3.
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Insert Figure 4.
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3.3 Distribution ratio determination

The introduction of CO2 can lead to changes in the final distribution of compounds at equilib-
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rium, which is another interesting feature when using a CO2-expanded liquid in LLE. Figure 5
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shows the average log D values of compounds with and without CO2 addition (see Table S3,

SI for specific log D values under all experimental conditions). The addition of CO2 clearly

changed the distribution of all compounds between the two phases. This effect can be attributed

to two major causes. Firstly, altered compound solubilities in water due to increased acidity

with increasing pressure, which might be the case for acetaminophen (paracetamol) that has a

12
pKa of 9.3 and inherently will be more protonated (more water soluble) at lower pH (the frac-

tion αB=[B]aq/([B] aq +[BH+] aq) decreases with pH). Secondly, the compound solubility in

the organic phase will change with pressure, since the molar ratio of CO2 and water in n-octanol

is changing (Table 2), resulting in lower relative permittivity of the organic phase at higher

pressure. For both acetylsalicylic acid (aspirin) and caffeine there is a trend that the distribution

ratios are increasing with pressure. Both these compounds are neutral at the low pH expected

in the aqueous phase (<4). It can also be observed that the differences in distribution ratio for

the compounds become apparently larger with increasing pressure of the CO2-expanded liquid.

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This is an evidence that the extraction selectivity can be tuned by a pressure change in CXLLE,

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which is another advantage over traditional LLE besides faster equilibration kinetics.

Insert Figure 5.

3.4 Extraction curves

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Both the distribution ratio and the distribution kinetics affect the efficiency of the final extrac-

tion method. Since a batch system (static extraction) was used in this study, the extraction ki-
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netics slowed down and halted at equilibrium conditions. This means that a complete extraction

was not done here, which also was not the aim of this study. However, it is still interesting to
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visualize the extracted amount of analyte per time unit for each of the analyte using n-octanol

as extractant with or without the addition of CO2, see Figure 6. Clearly, observing the first data
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point after 7 min of extraction, the extraction rate is significantly larger when CO2 is added to
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the solvent as compared to when no CO2 is added. A comparison of Figures 5 and 6 interest-

ingly shows that although the distribution ratio of acetaminophen is larger without the addition

of CO2 (Fig. 5B), the extracted amount at equilibrium is equal regardless of adding CO2 or not

(Fig. 6B). This can be explained by the fact that the volume of the n-octanol-rich extracting

13
phase is larger with CO2 added than without (Table S2). This also means that an enrichment

can be obtained using CO2-addition, since after depressurization of the phase, CO2 is vaporized.

Insert Figure 6.

4 Conclusion

Liquid-liquid extraction utilizing CO2 expanded n-octanol as extractant was explored using a

home-built view cell system with on-line chromatographic analysis. The set-up was validated

and used to acquire novel phase equilibria data of the ternary CO2/n-octanol/water system. Ki-

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netics study of distribution of pharmaceutical water contaminants with CO2 expanded n-octanol

as organic solvent phase proved that extraction can be significantly accelerated by the addition

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of CO2, which can mainly be attributed to a viscosity decrease. Distribution rate constant was
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raised with up to 4 times compared with traditional LLE performed under similar conditions.

Consequently, time to reach equilibrium was shorted 2 to 3 times with the addition of CO2. This
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study also indicates that the selectivity of an extraction can be tuned by pressure changes in
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CXLLE, both due to a shift in distribution ratio and an effect of pH-change.

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Funding
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The authors would like to thank the Swedish Research Council Formas (2016-00604) and the

Swedish Foundation for Strategic Research (SSF, RBP 14-0052) for financial support of this
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work.

Declaration of interests
The authors declare that they have no known competing financial interests or personal relationships

14
that could have appeared to influence the work reported in this paper.

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Figures

A B

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Figure 1. Equipment setup used for A) phase equilibria measurements and B) distribution ki-

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netics measurements.

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 A B

Figure 2. Distribution kinetics without any CO2 added. A) Without stirring and B) with stir-

ring. Experiment conducted at 85 bars (for 70 and 100 bars, see Figures S6 and S7).

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 A B

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Figure 3. Distribution kinetics with CO2, without stirring. Experiments conducted at A) 70
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bars; B) 85 bars; and C) 100 bars
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 A B

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Figure 4. Distribution kinetics with CO2, with stirring. Experiments conducted at A) 70 bars;
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B) 85 bars; and C) 100 bars.

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 Caffeine Aspirin Paracetamol Caffeine
Log D No CO2 With CO2 Log D No CO2 With CO2 Log D Log D
No CO2 With CO2 No CO2 With CO2
0.3 1 0.4 0.3

0.2 0.9 0.3 0.2

0.1 0.8 0.2 0.1

0 0.7 0.1 0
bar 70 bar 85 bar 100 barA
Paracetamol
70 bar 85 bar 100 bar B
Caffeine
70 bar 85 bar 100 bar
Aspirin
70 bar 85 bar 100 bar

Log D No CO2 With CO2 Log D No CO2 With CO2 Log D No CO2 With CO2
0.4 0.3 1

0.3 0.2 0.9

0.2 0.1 0.8

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0.1 0 0.7
70 bar 85 bar 100 bar 70 bar 85 bar 100 bar 70 bar 85 bar 100 bar
C

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Figure 5. Average compound log D values of model compounds (A: acetylsalicylic acid; B:

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acetaminophen; C: caffeine) in an octanol/water system with and without addition of CO2.
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 Acetylsalicylic acid (mg) Acetaminophen (mg)
3,0 2,0
1,8
2,5 1,6
1,4
2,0
1,2
With CO2
1,5 With CO2 1,0
No CO2
No CO2 0,8
1,0
0,6
0,4
0,5
0,2
0,0 0,0
0 10 20 30 40 50 60 0 10 20 30 40 50 60
A Extraction time (min)
B Extraction time (min)

Caffeine (mg)
1,8
1,6
1,4
1,2

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1,0
0,8 With CO2

0,6 No CO2

0,4

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0,2
0,0
0 10 20 30 40 50 60
Extraction time (min)
C
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Figure 6. Extracted amount of A) acetylsalicylic acid; B) acetaminophen; and C) caffeine,
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with and without CO2 added, and with stirring. Experiment conducted at 85 bars.
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Tables
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Table 1. Chemical properties of the selected analytes

Compound Structure Molar mass (g/mol) pKa Log Kow

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Acetylsalicylic acid (aspirin) 180.16 3.5 1.19

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Acetaminophen (paracetamol) 151.16 9.4 0.46

Caffeine 194.19 14.0 -0.07

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Table 2. Experimental VLLE for CO2 (x1), n-octanol (x2), and water (x3) at 323 K, n=3.

(I: CO2-rich vapor phase; II: n-octanol-rich liquid phase; III: water-rich liquid phase)

Pressure (bars) Phase x1 (CO2) x2 (n-octanol) x3 (water)

I - - -

70 II 0.40 ± 0.01 0.492 ± 0.008 0.104 ± 0.002

III 0.0190 ± 0.0006 0.0040 ± 0.0001 0.9770 ± 0.0005

I 0.9960 ± 0.0002 0.0010 ± 0.0001 0.0030 ± 0.0001

85 II 0.424 ± 0.004 0.482 ± 0.002 0.094 ± 0.002

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III 0.020 ± 0.004 0.0040 ± 0.0006 0.976 ± 0.004

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I 0.996 ± 0.001 0.0030 ± 0.0001 0.001 ± 0.001

100 II 0.498 ± 0.008 0.422 ± 0.002 0.080 ± 0.009

III 0.023 ± 0.002

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0.0040 ± 0.0006 0.973 ± 0.003
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 Table 3. Distribution rate constants under all experimental conditions, as determined from the

water-rich phase.

Conditions /
Distribution rate constant k (*10-3 min-1)
Compounds

No CO2 No CO2 With CO2 No CO2

Stirring No Yes No Yes

Pressure (bars) 70 85 100 70 85 100 70 85 100 70 85 100

Acetylsalicylic acid 18 17 14 52 52 49 52 73 78 89 100 110

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Acetaminophen 8.3 7.5 7.3 32 32 32 42 43 44 64 67 69

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Caffeine 5.3 5.0 4.7 23 24 22 31 36 44 35 58 62

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