Accepted Manuscript

Hansen solubility parameters for selection of green extraction solvents

Andrea del Pilar Sánchez-Camargo, Mónica Bueno, Fabián Parada-Alfonso,

Alejandro Cifuentes, Elena Ibáñez

PII: S0165-9936(19)30124-4
DOI: https://doi.org/10.1016/j.trac.2019.05.046
Reference: TRAC 15544

To appear in: Trends in Analytical Chemistry

Received Date: 10 March 2019

Revised Date: 26 May 2019
Accepted Date: 28 May 2019

Please cite this article as: A.d.P. Sánchez-Camargo, M. Bueno, F. Parada-Alfonso, A. Cifuentes, E.
Ibáñez, Hansen solubility parameters for selection of green extraction solvents, Trends in Analytical
Chemistry, https://doi.org/10.1016/j.trac.2019.05.046.

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 ACCEPTED MANUSCRIPT

1 Hansen solubility parameters for selection of green extraction solvents

3 Andrea del Pilar Sánchez-Camargo1*, Mónica Bueno2, Fabián Parada-Alfonso1, Alejandro

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4 Cifuentes2, Elena Ibáñez2

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6 High Pressure Laboratory, Department of Chemistry, Faculty of Science, Universidad

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7 Nacional de Colombia, Carrera 30 #45-03, Bogotá D.C., 111321, Colombia.

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8 Laboratory of Foodomics, Institute of Food Science Research, CIAL, CSIC, Nicolás

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9 Cabrera 9, 28049 Madrid, Spain.
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10

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12
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13 Corresponding author:
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14 Dr. Andrea del Pilar Sánchez-Camargo, High Pressure Laboratory, Department of

15 Chemistry, Faculty of Science, Universidad Nacional de Colombia, Carrera 30 #45-03,

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16 Bogotá D.C., 111321, Colombia, e-mail: adsanchezc@unal.edu.co, Tel.: +57 1 3165000.

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17 Ext. 14480; fax: + 57 1 3165220

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18

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21 Abstract

22 Nowadays, green extraction processes are focused on the development of new strategies to

23 achieve sustainable separation processes, promoting the use of alternative solvents from

24 renewable sources. Green solvents have risen as an option that can replace petroleum based

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25 solvents, however, they should retain the same extraction properties and technological

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26 features. The choice of the solvent is a crucial step in the solvent-substitution process, so

27 Hansen solubility parameters (HSP) have been successfully used as a real decision-making

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28 tool. For the first time, this work aims to give an overview of HSP as solvent selection tool

29 for extraction of bioactive compounds from natural products. It includes a brief description

30
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about the emerging green solvents extraction, the HSP theory and an updated discussion of
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31 the most recent publications (from 2009 till January 2019). Finally, some concluding
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32 remarks about the importance of using this solvent selection approach in the near future are

33 included.
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34
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35 Keywords: Alternative solvents, bioactive compounds, green extraction, Hansen solubility

36 parameters, COSMO-RS.
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37
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38 1. INTRODUCTION

39 One of the emergent areas of green chemistry is perhaps the development of sustainable

40 solvents, as well as its proper selection and use for certain applications. The first and the

41 fifth of the 12 principles of green chemistry of Anastas and Warner [1] refer to prevent

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42 waste and avoid the use of solvent separation agents and other auxiliary chemicals

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43 (wherever possible) or their replacement by innocuous or more eco-friendly solvents

44 alternatives. In this sense, green solvents have risen attention as an option for the transition

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45 from the oil refinery to the biorefinery [2]. Recently, Schuur et al. [2] have classified the

46 green solvents for sustainable separation processes in five main solvent classes: a) aqueous

47
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solvent systems, b) ionic liquids (ILs), c) deep eutectic solvents (DESs), d) bio-based
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48 solvents (such ethanol, ethyl lactate, d-limonene,…etc.) and e) switchable solvent systems.
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49 Their final and appropriate selection must be carried out according to the solute and the

50 process conditions. In this regard, the solubility theory approach is based on the principle
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51 “like dissolves like” and it can be very advantageous to give a first approximation in
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52 extraction/dissolution processes, indicating the most suitable solvent for a given application

53 thus avoiding the selection of impractical experimental conditions [3]. The history of
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54 Hansen solubility parameters dates back to the year 1967, when in his doctoral thesis,

55 Charles Hansen developed a practical guide for the selection of solvents for coating
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56 systems [4]. His research was based on Hildebrand`s work, which could only be applied to
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57 relatively non-polar and non-hydrogen-bonding molecules. Aware of this, Hansen

58 improved it and in his approach developed a useful theory to describe the solubility of the

59 solvent, the polymer and the pigment by just three parameters: δD, δP and δH which

60 represented the Dispersive (van der Waals), Polar and Hydrogen-bonding aspects,
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61 respectively [4]. Nowadays, Hansen solubility parameters (HSP) are the workhorse

62 technique used in a wide range of solubility applications in diverse fields such as

63 pharmaceutical chemistry [5–8] materials science [9–12], molecular biology [13,14],

64 energy [15–18], agricultural and food science [19–22], dentistry [23], and arts and

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65 humanities [24], among others. In recent years, there has been an explosion of interest in

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66 HSP mainly due to its relevance on the development of sustainable formulations, the

67 progress in advanced material research and the use of safer solvents for extraction purposes.

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68 Likewise, the development of the software HSPiP at the end of 2008, which includes an

69 eBook and datasets, has made it much easier for the practical work to reach optimal

70
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formulations. The fact of selecting appropriate separation solvents by combining computer
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71 high throughput screening and experimental verification can save reagents, time and money

72 [25]. Figure 1 presents the annual number of publications about HSP including articles,
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73 conference papers, book chapters and reviews, covering the 1971-2018 period. The
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74 descriptor employed for the literature search was “Hansen solubility parameters” and it was
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75 performed using the Scopus search engine. Search for the descriptor was carried out in

76 article, abstract and keywords. For that period, 936 works have been published, being
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77 chemistry, material science and chemical engineering, the main subject areas where they

78 had been classified. In the last 10 years, there has been a notably increase on the research
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79 publications, going from 35 publications in 2008 to 125 publications in 2018. Until now, 21
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80 works have been scheduled to be published this year (2019).The present review work is

81 devoted to the paramount use of Hansen solubility parameters theory in the selection of

82 emerging safe alternative solvents that replace harmful and toxic petrochemical ones. These

83 theoretical estimations prior to the extraction experimental work help to save resources and

84 avoid unnecessary solvent wasting. In addition, COSMO-RS approach and the most recent
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85 applications of Hansen solubility parameters for green solvent extraction from natural

86 products considering those papers published from 2009-2019 (January) are presented.

87 Finally, a short discussion about the advances in tools for the “greenness” assessment for

88 extraction processes, the future trends and the importance of using Hansen solubility

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89 parameters on solvents selection is included.

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90 <Figure 1>

91

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92 2. EMERGING GREEN SOLVENTS FOR SUSTAINABLE EXTRACTION

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93 PROCESSES
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94 In the last decades, an evolution of extraction and sample-preparation processes towards

95 Green Analytical Chemistry tries not only to enhance extraction efficiencies but also to
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96 reduce environmental impact [26]. Interest in the search for alternative solvents that

97 substitute petroleum based solvents has increased. In general, the extraction of bioactive
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98 compounds requires the use of petroleum solvents such as dichloromethane, toluene,

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99 acetone, hexane, chloroform, etc. However, these solvents are classified as hazardous for
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100 the environment and health [27]. The use of greener solvents in combination with green

101 techniques, such as ultrasound-assisted processing, supercritical fluid extraction or

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102 microwave processing, has several benefits involving less time, a reduction in energy
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103 employed and in the water and CO2 footprint [27,28]. For this reason, researchers within

104 the CHEM21 consortium have created the CHEM21 selection guide trying to help others to

105 find the “greenest” solvent possible for their purposes. This guide ranked common and less

106 common solvents according to Safety, Health and Environment criteria [29]. Thus, solvents

107 were assigned to one of four categories: recommended, problematic, hazardous and highly
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108 hazardous. In this section, green recommended emerging solvents such bio-based solvents

109 (CO2, ethanol, terpenes, vegetable oils and organic ethers), ionic liquids (ILs) and natural

110 deep eutectic solvents (NADES) are briefly introduced. The solvating power of all of them

111 can be estimated employing Hansen solubility parameters. It worth mentioning that despite

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112 of their interesting features (non/low-toxic, eco-friendly, high selectivity to the desired

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113 compounds, among others), green emerging solvents for the extraction of bioactive

114 molecules have several technological limitations. Some authors have widely reviewed their

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115 advantages and disadvantages. The most relevant are compiled in Table 1 [25,30,31]. In

116 general, more advantages than limitations can be recognized; however, these last are mainly

117
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related to the high equipment and operational costs and the lack of scientific studies about
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118 their thermodynamics properties and extraction efficiencies.
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119 <Table 1 near here>

120 2.1. Bio-Based Solvents

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121 Bio-based solvents are biodegradable and non-toxic solvents that can be prepared from
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122 renewable sources and they often exhibit comparable properties to conventional solvents.

123 Examples of bio-based solvents include well known solvents such as ethanol or ethyl
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124 acetate and less common such as 2-methyltetrahydrofuran [32] or cyrene derivatives [33].
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125 These solvents can be prepared from biomass sources such as energy crops, forest products,
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126 aquatic biomass and waste materials by fermentation or chemical transformation processes.

127 The most used bio-based solvents can be classified in alcohols (ethanol, butan-1-ol, octan-

128 2-ol, propane-1,3-diol, butane-1,3-diol, glycol), esters (ethyl acetate, lactates), ethers (α-

129 valerolactone, 2-methyltetrahydrofurane) and CO2. Readers are encourage to carefully read

130 [31,34] for more details on bio-based solvents.

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131 2.1.1. Supercritical carbon dioxide

132 Supercritical fluids (SCFs) are commonly used for extraction or separation purposes in

133 supercritical fluid extraction (SFE) [35–38] or supercritical fluid chromatography (SFC)

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134 [39–42] respectively. Both techniques use the solvents at temperatures and pressures above

135 their critical points. If a substance approaches its critical temperature (Tc) and is pressurized

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136 above its critical pressure (Pc), the interface between gas and liquid phases diminish,

137 converging in only one phase – the supercritical fluid. What characterize a SCF are its

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138 physical properties, which are between those of a gas and those of a liquid. For example,

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139 the viscosity is similar to a gas and the density is similar to a liquid. The low viscosity leads
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140 to fast diffusivity, which is essential to achieve fast mass transfer in separation processes.

141 Carbon dioxide is by far the most widely used supercritical fluid due to its attractive
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142 properties. Supercritical CO2 is easily attainable (Tc = 31 °C, Pc = 7.4 MPa), inexpensive at

143 high purity, inertness, non-flammable, non-toxic, generally recognized as safe (GRAS) and
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144 environmentally friendly because is a recycled waste from many other processes.
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145 Moreover, extractions made with pure scCO2 provide solvent-free extracts because CO2 is

146 gaseous at room temperature and pressure. Due to its low polarity, scCO2 can be used to
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147 dissolve mainly nonpolar low-molecular-weight compounds. However, this is also its main
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148 drawback. To enhance its polarity, polar co-solvents (ethanol, ethyl acetate, water or d-
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149 limonene) are added in small amounts (1-10 %). In the last decade, compressed CO2 has

150 been added to organic solvents to obtain carbon dioxide expanded liquids (CXLs). As

151 explained by Jessop and Subramaniam [43], the properties of a gas expanded liquid (GXL)

152 are substantially different from those at atmospheric pressure. Therefore, CXLs can be

153 considered as switchable solvent that can be found half way from neat organic solvents to
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154 neat scCO2 by varying the CO2 composition, changing their physical-chemical properties

155 (see an excellent review article by Herrero et al.[44]).

156 2.2. Ionic Liquids

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157 Ionic liquids are salts that do not crystallize at room temperature and generally comprise

158 quaternary nitrogen cations. These solvents have attractive properties such as miscibility

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159 with water and organic solvents, nonflammability, chemical and thermal stability,

160 negligible vapor pressure, high ionic conductivity, tunable viscosity and wide

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161 electrochemical potential window. Thanks to these characteristics, ionic liquids have

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162 substituted traditional volatile or flammable organic solvents in electroanalytical
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163 applications, biocatalytic reactions chemical sensing, separations, extractions, among many

164 others [45–50]. Although the greenness of the ILs has been recognized, it is worth
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165 mentioning that not all ILs can be considered green; in fact, as described by Poole and

166 Lenca [51] “ILs environmental distribution and fate covers the complete gamut from a
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167 potential for low to high environmental impact”. Life-cycle studies including production,
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168 degradation and ecosystem have been identified as the most significant impacts for some

169 ILs: global warming, freshwater aquatic toxicity, and human toxicity potential [52]. In any
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170 case, their impact will also depend on the application, being limited on sample-preparation
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171 procedures.
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172

173 2.3. Natural Deep Eutectic Solvents (NADESs)

174 Deep Eutectic Solvents (DESs) emerged as an alternative to the “not so green” character of

175 ILs [53]. DESs are a mixture of two or more organic compounds, which may be solid or

176 liquid but together present a melting point lower than that of either individual component.
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177 Thus, temperature and component ratio are two major determinants in this type of eutectic

178 systems [54]. DES have similar characteristics to ILs (Table 2) and are inexpensive to

179 produce [55]. When DES are based on natural compounds such as organic acids, alcohols,

180 amino acids, sugars and choline derivatives, they are called Natural Deep Eutectic Solvents

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181 (NADES) [56]. NADES are obtained from a eutectic mixture of a natural hydrogen-bond

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182 acceptor, with a natural hydrogen bond donor molecule, interacting via intermolecular

183 forces (hydrogen bonding and Van der Waals interactions) but not through covalent or

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184 ionic bonds. Moreover, they have several advantages such as low cost, sustainability,

185 safety, simple preparation, biocompatibility in terms of high solubilizing capacity for

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natural compounds and biodegradability [57,58] that are encouraging research on their
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187 analytical applications: extraction and greening CO2 capture [59,60], organic synthesis and

188 catalysis [61,62], chromatography [63] and electrochemical detection [64].

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189 <Table 2 near here>

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190
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191 3. HANSEN SOLUBILITY PARAMETERS THEORY

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192 The basis of Hansen solubility parameters (HSP) [65] is the assumption that the total

193 cohesive energy (E) must be the sum of individual contributions from nonpolar (dispersion)
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194 interactions (Ed), polar (dipole-dipole and dipole-induced-dipole) interactions (Ep), and
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195 hydrogen-bonding or other specific association interactions (including Lewis acid-base

196 interactions) (Eh):

197
=
 +
 +
 (1)

198 Dividing the individual cohesive energy terms by the molar volume (V) gives Eq. 2.
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199 = + + (2)
   

200 The square of the total solubility parameter (δT2) is the sum of the squares of the Hansen

201 dispersion (δD2), polar (δP2) and hydrogen-bonding (δH2) contributions.

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202 δT2 = δD2 + δP2 + δH2 (3)

203 The distance between two molecules, a solute i and a solvent j, in Hansen three-

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204 dimensional space defined as “distance”, Ra (Eq. 4), depends on their respective partial

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205 solubility parameter components [65].

206 Ra = 4δDi − δDj + δPi − δPj + δHi − δHj (4)

207
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By a trial and error system, solvents tested are plotted in Hansen three-dimensional space
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208 creating the “solubility sphere”. Thus, this solubility sphere is defined as the region where
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209 solvent–solute combinations occur as a solution and the radius of the sphere is known as

210 “interaction radius” (R0). Thereby, the Relative Energy Difference (RED) is defined as
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211 follows:
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212 
 = (5)
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213 So, good solvents are comprised into the interior of the sphere or are at least on its surface

214 (RED ≤ 1), while a RED value higher than 1 indicates low affinity. Therefore, solubility
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215 requires that Ra has a smaller value than R0 [65]. Nevertheless, R0 can only be used when
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216 solubility experiments can be performed since it is based only on experimental data of the

217 observation of the interaction between studied solutes and well-known solvents.

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219 4. COSMO-RS
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220 In addition to HSP, there is another recent powerful approach employed to understand the

221 dissolving mechanism in liquids, called COSMO-RS (short for COnductor-like Screening

222 MOdel for Real Solvents). This approach has become very popular due to its algorithmic

223 simplicity, numerical stability and high accuracy (with far fewer approximations than HSP

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224 approach) for the prediction of solvation energies [66]. This method was developed and

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225 first published in 1995 by Klamt [67], which combines quantum-chemical considerations

226 (COSMOs) and statistical thermodynamics (RS) in order to predict thermodynamic

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227 properties without experimental data [66]. COSMO-RS includes a two-step procedure. As

228 an initial step, the molecule of interest is embedded into a virtual conductor ("dielectric

229
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continuum”), in order to induce a polarization charge density on its surface (Fig. 2a). Then,
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230 during the quantum chemical COSMO calculation, the molecule (i.e. tryacylglyceride -

231 TAG) converge to its energetically optimal state in the virtual conductor, mainly
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232 considering its geometry and electron density (Fig. 2b). In the second step, the statistical
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233 thermodynamic calculation uses the stored COSMO results to quantify the interaction
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234 energy of the pairwise interacting surface segments related to molecular interaction modes

235 (i.e. hydrogen bonding). From the 3D distribution of the polarization charges, the σ-profile
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236 is outlined on an histogram of the charge intensities around each molecule [68]. σ-profile

237 provided information about molecular polarity distribution. For instance, in the case of
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238 TAG, the region σ ± 0.01 e*A-2 is considered to be non-polar or weakly polar (Fig. 2c). On
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239 the other hand, the σ-potential (Fig. 2d) explains the affinity of the compound to interact

240 with the solvents with polarity and hydrogen bonds [69]. Similar to HSP, this interesting

241 tool can estimate the solubility between the compound and solvents in mixed state and to
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242 estimate many other thermodynamic properties of the system [69]. Recently, this method

243 has been focused on the assessment of ILs as green extraction solvents [70–72].

244

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245 5. RECENT APPLICATIONS OF HANSEN SOLUBITY PARAMETERS FOR

246 GREEN SOLVENT EXTRACTION FROM NATURAL PRODUCTS

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247

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248 As mentioned, nowadays, scientist and researchers are faced to an interesting challenge

249 looking for new answers towards the development of sustainable processes, which could

250
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maximize production while minimizing the environment impact. With this aim, they have
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251 been designing strategies based on the intensification and integration of emerging

252 processes, associating them to concepts such as biorefinery and green processes [73]. As
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253 defined by Chemat et al. [74], green extraction from natural product “is based on the
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254 discovery and design of extraction processes which will reduce energy consumption, allows
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255 use of alternative solvents and renewable natural products, and ensure a safe and high

256 quality extract/product”. The use of alternative solvents or agro-solvents issued from
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257 agricultural resources have consolidated the idea for seeking tools than can improve their

258 proper screening for each application, based on their solvent power properties [74,75]. For
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259 these reason, bio-solvents such as ethanol, α-limonene, methyl esters of fatty acids of
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260 vegetable oil, carbon dioxide or even ionic liquids already are included in the software

261 database of computational programs (i.e. HSPiP and COSMO-RS) as a first approximation

262 for the study of green solvent selection for extraction processes of bioactive compounds

263 from natural sources [76]. Figure 3 shows the milestones of the HSP strategy as a solvent

264 selection tool for selective extraction of target compounds. Taking into account concepts
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265 such as the principles of green chemistry, the use of renewable sources and the

266 sustainability, three milestones should be accomplished to develop the HSP strategy.

267 Firstly, for the predictive stage, the HSP estimation of the selected target compound(s)

268 present in the natural matrix is carried out. Then, the calculation of Ra and RED values for

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269 the selected target compound (s) and several bio-based solvents can indicate the most

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270 suitable solvents for a selective extraction. Secondly, for the experimental stage, the bio-

271 solvents selected in the previous screening stage are tested according to the green extraction

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272 method employed. Some variables such as extraction yield and target molecule recovery

273 are assessed, and in some cases its bioactivity is proved. In this stage, the results obtained

274
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by theoretical estimation and experimental assays are compared. Finally, considering the
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275 technological limitations related to the bio-solvent selected and the extraction technique

276 conditions, a protocol for a selective extraction of the target compound(s) is achieved. In
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277 Table 3 the most recent applications of solvent selection for green extraction processes
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278 employing HSP approach are presented. Time’s window researched comprises from 2009
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279 to January, 2019. From the best of our knowledge, between 2009 and 2014, there was no

280 research works published involving HSP for extraction purposes. As can be observed,
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281 conventional extraction methods such as solid-liquid extraction and Soxhlet have been

282 mainly employed for obtaining bioactive compounds. However, emerging technologies
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283 such as pressurized liquid extraction, supercritical fluid extraction, microwave assisted
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284 extraction (MAE), ultrasound assisted extraction (UAE) and CO2 expanded liquids have

285 been recently employed with success. In most cases, the use of the HSP approach is looking

286 for the replacement of petroleum based solvents by bio-based solvents such as CO2,

287 ethanol, vegetable oils, isopropanol, terpenes (d-limonene, p-cymene) and some ethers like

288 methyltetrahydrofuran (MeTHF) and cyclopentyl methyl ether (CPME). Despite of this,
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289 some research applications of the estimation of solubility parameters are developed to

290 improve the behavior of the bio-based solvents including, for instance, the use of a co-

291 solvent. Tirado et al. studied the best co-solvent to solubilize some fatty acids in

292 supercritical CO2. As a first approach, the miscibility prediction showed that mixtures of

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293 CO2 + benzene, CO2 + toluene or CO2 + cyclohexane were the best co-solvents for both

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294 oleic and linoleic acids. However, in the stage of the experimental validation of prediction,

295 they concluded that Hansen theory cannot predict properly the behavior of the solvents with

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296 ring structures [77]. They proposed that the stability of the ring is probably greater than the

297 one considered by the group contribution method used for the Hansen theory calculations.

298
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In this sense, excluding that type of co-solvent, supercritical mixtures with short-chain
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299 alcohols, with ethanol being the best, was corroborated experimentally [77].
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300 On the other hand, regarding the target molecules studied employing HSP theory, they can

301 be classified in: a) carotenoids [3,19,69,78], b) phenolic compounds [20,79,80], c)

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302 triacylglycerides and fatty acids from vegetable oils [69,75,77,81,82], d) terpenes [69,83–
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303 86], and e) xanthonoids [87], lactones [88] and steroids [89]. It is well known that algae and

304 microalgae have been usually studied as a good source of carotenoids. Currently,
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305 Phaeodactylum tricornutum (a marine diatom microalga) is used as biomass for the

306 commercial production of fucoxanthin, very appreciated for its several biological activities.
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307 In order to develop an efficient and selective extraction method, Sánchez-Camargo et al. [3]
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308 explored pressurized technologies using bio-based solvents. Figure 4 shows the three-

309 dimensional Hansen solubility sphere for the solvents predicted by the theoretical

310 assessment of HSP for this study. The graph shows the polar parameter (P-axis), the

311 hydrogen bonding parameter (H-axis) and the dispersion parameter (D-axis) for solvent
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312 selection. Blue dots inside the sphere show the solvents that dissolve the fucoxanthin

313 (dichloromethane, d-limonene, ethyl acetate, ethyl lactate, and acetone) while the red cubes

314 show the solvents that do not dissolve easily the fucoxanthin (n-hexane, ethanol, methanol,

315 and water). Among them, ethyl acetate (RED=0.243), d-limonene (RED=0.998), ethyl

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316 lactate (RED=0.998), and ethanol (RED=2.303), were the selected bio-solvents and their

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317 behavior was experimentally evaluated. Using static PLE extraction, d-limonene at 40°C

318 was the most selective solvent (according to the lowest Ra value), but the recovery of

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319 fucoxanthin was approximately half of the amount present in the biomass. The other three

320 solvents tested showed good recoveries of fucoxanthin, but were less selective, following

321
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the decreasing order: ethyl acetate > ethyl lactate > ethanol [3]. Another interesting work is
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322 the HSP estimation of malvidin-3,5-diglucoside from grape pomace employing water and

323 ethanol as solvents. The spherical radius was lower for ethanol (7.74 MPa1/2) than for water
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324 (9.73 MPa1/2). For ethanol, the optimal temperature conditions ranged between 298.2 and
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325 348.2 K with a maximum extraction predicted to occur near room temperature; for water,
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326 the optimized temperature conditions occured at higher temperatures (373.2 to 473.2 K)

327 with a minimum RED (0.98) ocurring at 423.2 K. However, at that high temperatures, the
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328 possibility of thermal degradation of the compound increased. For that reason, and as

329 predicted by HSP, ethanol would be a preferred solvent for extraction of malvidin-3,5-
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330 diglucoside [20].

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331 On the other hand, the application of new technologies, such as UAE and MAE compared

332 to traditional Soxhlet and maceration methods was studied for lipids extraction from

333 Tunisian date palm seeds. The calculated HSP values demostrated for all methods that

334 MeTHF can be employed as an alternative solvent to n-hexane for the extraction of
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335 triacylglycerides and fatty acids [81]. An interesting stategy for solvent selection for

336 extraction of α-mangostin from Garcinia mangostana L. was developed by

337 Bundeesomchok et al. [87] and is presented in Figure 4. As can be seen, a diagram of the

338 experimental design shows the evaluation of some altenative green solvents compared to

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339 dichloromethane using the computational software and experimental extractions (solid-

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340 liquid extraction). The computational predictive methods were performed by HSP and

341 COSMO-RS approach. After extraction, some steps involved as filtration, evaporation of

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342 the solvent and quantification of extraction yield and α-mangostin contents were carried

343 out in order to confirme the prediction. In this particular application, HSP method described

344
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dichloromethane as a good solvent for α-mangostin extraction, that was not in agreement
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345 with the experimental data obtained. A possible explanation can be found on the limitations
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346 observed in HSP simulation of non-standard solvents with large molecules or complex

347 multicomponent systems [87]. On the other hand, the experimental study confirmed that the
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348 COSMO-RS model was more accurate for selecting alternative solvents, concluding that
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349 dimethylcarbonate (DMC), 2-MeTHF and ethyl acetate were the promising green solvents

350 for the extraction of α-mangostin [87]. Regarding the limitations in the Hansen theory for
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351 the extraction of bioactive compounds from complex matrices, differences between

352 experimental and theoretical approaches can be explained by: 1) The presence of other
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353 compounds in the natural matrix that could interfere by enhancing or reducing the

354 extraction efficiency in relation to the predictions, and 2) HSP are based on thermodynamic

355 data and, therefore, kinetics phenomena, which are highly influenced by temperature, are

356 not taken into account. HSP approach shows many possibilities of alternative solvents, but

357 in some cases (e.g. d-limonene), they are unlikely to be used at the industrial level, due to
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358 their physicochemical characteristics, so a carefully selection must be done. This is the case

359 of the extraction of artemisinin (an antimalarial compound) from Artemisia annua L.

360 studied by Laboukhi-Khorsi et al. [88]. The theoretical screening using the Hansen

361 solubility parameters in practice (HSPiP) approach showed 26 solvents candidates to

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362 substitute n-hexane. According to the low RED values, dichloromethane (0.183), ethyl

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363 acetate (0.224), butylamine (0.267), isopropyl acetate (0.345), isopropanol (0.736) and

364 DMSO (0.900) were acceptable to provide good solubility for artemisinin. Laboukhi-

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365 Khorsi et al. argued the selection of the solvent by the physico-chemical properties of each

366 solvent: a) Dichloromethane was not selected by its very low boiling point and because it is

367
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recently suspected of causing cancer; b) acetate solvents are capable to solubilize many
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368 different families of compounds so lacking of selectivity, which requires additional

369 purification steps for recovery of analyte; c) butylamine was not picked since it possesses
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370 an unpleasant odor and low vapor pressure; d) DMSO presented the higher solubility for
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371 artemisinin (103.7 mg mL-1) but high energy is necessary for its recovery by distillation;
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372 and finally e) Isopropyl alcohol (IPA) was selected, because it is a food grade solvent with

373 very low global warming potential score and it has a low boiling point facilitating its
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374 recovery. Employing IPA as extraction solvent, the artemisinin extraction yield was 65% in

375 a single batch sequence [88].

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376
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377 5.1. Advances in tools for the “greenness” assessment for extraction processes.

378 The “greenness” assessment for extraction processes has attracted a great deal of interest

379 among chemists and researchers. Recently, a new interesting tool called Green Analytical

380 Procedure Index (GAPI) has been proposed to evaluate the green character of an entire
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381 analytical/extraction methodology, from sample collection to final determination [90].

382 Improving the idea of the National Environmental Methods Index (NEMI), Plotka-Wasylka

383 (2018) built a pictogram (with five pentagrams, see Figure 6) that can be used to evaluate

384 and quantify from green through yellow to red depicting low, medium to high

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385 environmental impact, respectively. It involves each step of an analytical/extraction

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386 methodology. Sample collection and preparation, reagents and solvents used, type of

387 method, and instrumentation are included in GAPI strategy. For further details, readers can

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388 refer to the remarkable Płotka–Wasylka’s review [90]. As discussed before, the use of HSP

389 or COSMO-RS method can help to improve the green character of processes, because they

390
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reduce the wasting of resources and time for the solvent extraction selection. To the best of
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391 our knowledge, there is no research works about the greenness assessing of extraction

392 processes employing HSP approach. However, some categories measured by GAPI such as
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393 solvents/reagents used (7), amount of solvents (9), health hazard (10), safety hazard (11),
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394 energy (12) could be improved for inclusion of HSP approach as selecting tool of bio-based
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395 solvent for green extraction methods.

396
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397 6. CONCLUDING REMARKS

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398 In the last few years, the application of Hansen solubility parameters to evaluate the
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399 solubility of different analytes from natural sources has considerably increased. This

400 approach has some important advantages in terms of simplicity and rational use of time and

401 resources. Lately, the employment of bio-solvents is preferred as alternative to replace

402 petroleum-based solvents; the possibility of its use has been also approached by using HSP,

403 with a high degree of success. Other methods to assess the theoretical solubility such
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404 COSMO-RS can be superior to HSP whenever accurate solubility calculations on pure

405 molecules are required. Nevertheless, both, HSP and COSMO-RS require of further

406 experimentation in order to validate the predicted solubility, although most cases good

407 match between predicted and experimental solubility has been reported. It is important to

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408 highlight that Hansen dataset of approx. 1000 values is public, thus, its use can be further

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409 implemented in research and control laboratories. As future recommendations, new data

410 and computational improvements are expected to be included in HSPiP in order to widen

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411 the range of applicability of the approach; this includes more data on ILs and NADEs and

412 the possibility of including formulae that facilitates the prediction of HSP of solvents under

413
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sub- and supercritical conditions. Although the possibility of estimating HSP of different
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414 NADES obtained from basic NADES components is a reality; more information is needed

415 in order to evaluate the correctness of the prediction. Nevertheless, this possibility is not
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416 presently available for ILs since no complete information on solubility of ILs can be
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417 obtained that could lead to the inclusion of such data in HSPiP. Moreover, new tools such
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418 as GAPI could generate a synergistic effect with the HSP approach, in order to improve the

419 “greenness” character of the processes.

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420

421 7. ACKNOWLEDGEMENTS
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422 A.P.S-C. thanks to the Administrative Department of Science, Technology and Innovation
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423 COLCIENCIAS (Colombia) for her postdoctoral fellowship (784-2017). M.B.

424 acknowledge MINECO for the “Juan de La Cierva-Formación” postdoctoral grant FJCI-

425 2016-30902. The authors want to thank Project AGL2017-89417-R (MINECO, Spain) for

426 the financial support.

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427

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658 [74] F. Chemat, M.A. Vian, G. Cravotto, Green extraction of natural products: Concept

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659 and principles, Int. J. Mol. Sci. (2012). doi:10.3390/ijms13078615.

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660 [75] M.M. Cascant, C. Breil, S. Garrigues, M. de la Guardia, A.S. Fabiano-Tixier, F.

661 Chemat, A green analytical chemistry approach for lipid extraction: computation

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662 methods in the selection of green solvents as alternative to hexane, Anal. Bioanal.
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663 Chem. 409 (2017) 3527–3539. doi:10.1007/s00216-017-0323-9.

664 [76] Y. Agata, H. Yamamoto, Determination of Hansen solubility parameters of ionic

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665 liquids using double-sphere type of Hansen solubility sphere method, Chem. Phys.

666 513 (2018) 165–173. doi:10.1016/j.chemphys.2018.04.021.

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667 [77] D.F. Tirado, M.J. Tenorio, A. Cabañas, L. Calvo, Prediction of the best cosolvents to

668 solubilise fatty acids in supercritical CO2 using the Hansen solubility theory, Chem.
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669 Eng. Sci. 190 (2018) 14–20. doi:10.1016/j.ces.2018.06.017.

670 [78] E. Yara-Varón, A.S. Fabiano-Tixier, M. Balcells, R. Canela-Garayoa, A. Bily, F.

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671 Chemat, Is it possible to substitute hexane with green solvents for extraction of
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672 carotenoids? A theoretical versus experimental solubility study, RSC Adv. 6 (2016)

673 27750–27759. doi:10.1039/C6RA03016E.

674 [79] A.P. Sánchez-Camargo, L. Montero, A. Cifuentes, M. Herrero, E. Ibáñez,

675 Application of Hansen solubility approach for the subcritical and supercritical

676 selective extraction of phlorotannins from Cystoseira abies-marina, RSC Adv. 6

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677 (2016) 94884–94895. doi:10.1039/C6RA16862K.

678 [80] I. Pagano, A. del P. Sánchez-Camargo, J.A. Mendiola, L. Campone, A. Cifuentes, L.

679 Rastrelli, E. Ibañez, Selective extraction of high-value phenolic compounds from

680 distillation wastewater of basil ( Ocimum basilicum L.) by pressurized liquid

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681 extraction, Electrophoresis. 39 (2018) 1884–1891. doi:10.1002/elps.201700442.

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682 [81] S. Ben-Youssef, J. Fakhfakh, C. Breil, M. Abert-Vian, F. Chemat, N. Allouche,

683 Green extraction procedures of lipids from Tunisian date palm seeds, Ind. Crops

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684 Prod. 108 (2017) 520–525. doi:10.1016/j.indcrop.2017.07.010.

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685 [82] E. Angles, P. Jaouen, J. Pruvost, L. Marchal, Wet lipid extraction from the microalga
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686 Nannochloropsis sp.: Disruption, physiological effects and solvent screening, Algal

687 Res. 21 (2017) 27–34. doi:10.1016/j.algal.2016.11.005.

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688 [83] M. Co, P. Koskela, P. Eklund-Åkergren, K. Srinivas, J.W. King, P.J.R. Sjöberg, C.

689 Turner, Pressurized liquid extraction of betulin and antioxidants from birch bark,
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690 Green Chem. 11 (2009) 668. doi:10.1039/b819965e.

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691 [84] A. Filly, A.-S. Fabiano-Tixier, Y. Lemasson, C. Roy, X. Fernandez, F. Chemat,

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692 Extraction of aroma compounds in blackcurrant buds by alternative solvents:

693 Theoretical and experimental solubility study, Comptes Rendus Chim. 17 (2014)
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694 1268–1275. doi:10.1016/j.crci.2014.03.013.

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695 [85] Y. Li, A.S. Fabiano-Tixier, C. Ginies, F. Chemat, Direct green extraction of volatile

696 aroma compounds using vegetable oils as solvents: Theoretical and experimental

697 solubility study, LWT - Food Sci. Technol. 59 (2014) 724–731.

698 doi:10.1016/j.lwt.2014.05.064.

699 [86] S. Al-Hamimi, A. Abellan Mayoral, L.P. Cunico, C. Turner, Carbon Dioxide
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700 Expanded Ethanol Extraction: Solubility and Extraction Kinetics of α-Pinene and

701 cis-Verbenol, Anal. Chem. 88 (2016) 4336–4345.

702 doi:10.1021/acs.analchem.5b04534.

703 [87] K. Bundeesomchok, A. Filly, N. Rakotomanomana, P. Panichayupakaranant, F.

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704 Chemat, Extraction of α-mangostin from Garcinia mangostana L. using alternative

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705 solvents: Computational predictive and experimental studies, LWT - Food Sci.

706 Technol. 65 (2016) 297–303. doi:10.1016/j.lwt.2015.08.036.

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707 [88] S. Laboukhi-Khorsi, K. Daoud, S. Chemat, Efficient Solvent Selection Approach for

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708 High Solubility of Active Phytochemicals: Application for the Extraction of an
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709 Antimalarial Compound from Medicinal Plants, ACS Sustain. Chem. Eng. 5 (2017)

710 4332–4339. doi:10.1021/acssuschemeng.7b00384.

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711 [89] D. Ballesteros-Vivas, G. Alvarez-Rivera, A. Sánchez-Camargo, E. Ibáñez, F. Parada-

712 Alfonso, A. Cifuentes, A multi-analytical platform based on pressurized-liquid

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713 extraction, in vitro assays and liquid chromatography/gas chromatography coupled to

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714 q-TOF mass spectrometry for food by-products revalorization. Part 1: Withanolide-

715 rich extracts from goldenberry (Ph, J. Chromatogr. A. 1584 (2019) 155–164.
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716 doi:S0021967318314559.
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717 [90] J. Płotka-Wasylka, A new tool for the evaluation of the analytical procedure: Green
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718 Analytical Procedure Index, Talanta. 181 (2018) 204–209.

719 doi:10.1016/j.talanta.2018.01.013.

720

721

722
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723 FIGURES

724 Figure 1. Annual number of publications (review, book chapter and conference papers)

725 dealing with Hansen Solubility Parameters. Literature search was performed in Scopus, for

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726 the 1971-2018 period.

727 Figure 2. Steps involved in COSMO-RS calculations: a) molecule emerged; (b) σ-surface;

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728 (c) energies of local surface interactions between σ-profiles of triacylglyderides (TAG) and

solvents; (d) σ-potentials of TAG and solvents [78].

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729

730 Figure 3. Milestones of the study of alternative green solvents for the extraction of

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731 bioactives from natural sources using Hansen Solubility Parameters approach.
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732 Figure 4. Three-dimensional Hansen solubility parameter sphere for solvent selection to

733 extract fucoxanthin from of P. Tricornutum. Blue dots inside the sphere dissolve the
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734 fucoxanthin and ret squares outside do not dissolve it. 1. n-hexane (behind the sphere) 2.
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735 Dichloromethane; 3. d-limonene; 4. Ethyl acetate; 5. Ethyl lactate; 6. Ethanol, 7. Acetone,

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736 8.Methanol, 9. Water. Reprinted with permission from Sánchez-Camargo et al. [3]

737 Figure 5. Strategy for extraction of G. mangostana fruit peels. DMC, dimethylcarbonate.
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738 2-MeTHF, 2-methyltetrahydrofuran. HPLC, high performance liquid chromatography.

739 HSPs, Hansen solubility parameters. COSMO, conductor like screening model for realistic
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740 solvation. Reprinted with permission from Bundeesomchok et al.[87]

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741 Figure 6. Green Analytical Procedure Index pictogram. Numbers in the pictogram

742 correspond to: (1) collection, (2) preservation, (3) transport, (4) storage, (5) type of method

743 (direct or indirect), (6) scale of extraction, (7) solvent/reagents used, (8) additional

744 treatments, (9) reagents and solvent amounts, (10) health hazard, (11) safety hazard, (12)
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745 energy, (13) occupational hazard, (14) waste, (15) waste treatment. Additional mark: Circle

746 in the middle of GAPI, procedure for qualification and quantification. Reprinted with

747 permission from Płotka-Wasylka [90]

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748

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761
760
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749

Figure 1.
1972
1974
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1980
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1994
D 1996

YEAR
1998
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2008
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2010
2012
2014
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2016
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0

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20
40
60
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NUMBER OF PUBLICATIONS
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763

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765

766

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769 Figure 2.
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781
782 Figure 3.
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797 Figure 4.
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804

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806 Figure 5.

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824 Table 1. Advantages and limitations of alternative green solvents for the extraction of

825 bioactive compounds from natural sources. Based and adapted with permission from Jeevan

826 Kumar et.al. (2017), Vovers et al. (2017b) and Abbott (2017) [25,30,31]

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Solvent type Advantages Limitations
Bio-based solvents - Derived naturally - Consistent feedstock
- Bio-based feedstocks supply

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- Efficient, eco-friendly and cost - More research on
effective kinetic performance and
- Low toxicity, degradability and thermodynamic studies

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renewability is needed
- Changes in operation
conditions, recycling

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performance or waste
treatment needs to be
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studied for industrial
extraction processes
Supercritical CO2 - Lower extraction time due to the - High pressure
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fast mass transfer equipment and

- High selectivity due to flexibility operational costs
of changing pressure and
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temperature or adding co-

solvents
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- Non-toxic, non-flammable and

inert
- Recycling the CO2 avoids
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greenhouse effect

Ionic-Liquids - Less hazardous - High cost

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- Non-flammable and remains in - New processing

liquid state for a broad range of equipment
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temperatures - Production, degradation

- Possesses both ions and enable to and ecosystem studies
design a suitable solvent are needed to identify
- Enables single solvent the environmental
extraction, instead of biphasic impact of an IL to be
system considered as a green
alternative
DES - Fluid systems composed of two - Studies on scaling-up
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or more eutectic solvents are essential to explore

- Occurs naturally, safe and the possibility to use
inexpensive them at industrial scale.
- Highly preferred due to bio-
degradability, non-toxicity, low
cost synthesis, low volatility and

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wide polarity
NADES - Composed of primary - Viscosity
metabolites such as amino acids, - Take away natural

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organic acids, sugars and choline resources that could be
derivatives used for other purposes
- Safe, bio-degradable, and low

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cost for synthesis
827
828

829
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830 Table 2. Comparative properties of Ionic Liquids and Deep Eutectic Solvents including
831 NADES. Reprinted with permission from Liu et al. [54].
Ionic Liquids Deep Eutectic Solvents
Distinguished Characterizations
Constituent salt salt, sugar, organic acid, amino acid, etc.

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Composition single salt Mixture
Intermolecular force ionic bonding hydrogen bonding
Molecular force strong Weak

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Free energy content 1–5 kcal/mol
Intermolecular <1.2 Å 2–5 Å
distance

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Conductivity often moderate to poor
Vapor pressure low Low
Cytotoxicity positive for many hard to detect
Identical Characterizations
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Melting point below arbitrary temperature, e.g., 100 °C, and some are liquid at or
below room temperature
Viscosity positive linear correlation with temperature
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Solvating properties a range of polar and nonpolar compounds

Mobility depends on the size of mobile species and the availability of holes of
appropriate dimensions
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832 Table 3. Recent application of Hansen solubility parameters for green selective extraction of bioactive compounds from natural
833 sources between 2009 and 2019.

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Did the
experimental
Compound/ Extraction Solvent predicted by Solvent to be Optimal extraction data

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Year Source Reference
Fraction of interest process HSP replaced conditions corroborated
HSP solvent

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prediction?
383.2 K, 5 MPa, two 5
2009 Birch barks Betulin PLE Ethanol Water Yes [83]
min extraction cycles

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Flavonoids

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2009 Grape pomace (Malvidin-3,5- PLE Ethanol Water No specified Yes [20]
diglucoside)
S/L ratio: 1:4 g/mL,

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Blackcurrant buds Volatile aroma Methyl magnetic stirring, at
2014 SLE n-hexane Yes [84]
(Ribes nigrum L.) compounds (VACs1) tetrahydrofurane boiling point of the
solvent, 2 h

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S/L ratio 3.75:25 g/mL,
Sweet basil leaves
Volatile aroma magnetic stirring,

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2014 (Ocimum SLE Sunflower oil Dichloromethane Yes [85]
compounds (VACs2) controlled temperature,
basilicum)
45 h
CXLE: 313.2K, 9.3
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Boswellian sacra α-pinene CXLE, SFE, CXLE: (63:31 mol MPa, 0.31 molar
2016 Ethanol Yes [86]
tree resin Cis-verbenol SLE ethanol/mol CO2) fraction of CO2 in
ethanol.
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Essential oils Stirring: 4000 rpm

2016 Caraway seeds SLE D-limonene n-hexane Yes [69]
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(monoterpenes) Time: 1h

Cystoseira-abies Acetone:water 373.2 K, 10.3 MPa,

2016 Phlorotannins PLE Ethanol Partially [79]
marina (70:30 %v/v) 20 min
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α-carotene, β- S/L ratio: 30:125 g/mL,

CPME (Cyclopentyl
2016 Dried carrot carotene, lutein, SLE n-hexane Magnetic stirring, 328.2 Yes [78]
methyl ether)
lycopene K, 1 h in the dark

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S/L ratio: 2:20 g/mL,
Garcinia magnetic stirring, at
2016 α-mangostin SLE Ethyl acetate Dichloromethane No [87]
mangostana L. boiling point of the

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solvent, 1 h
S/L ratio: 1:6 g/mL,
Artemisia annua L. magnetic stirring, 313.2

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2017 Artemisinin SLE Isopropanol n-hexane Yes [88]
leaves K, three 6 h extraction
cycles.
- Soxhlet No significant

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- UAE 2-Methyl differences were
2017 Date palm seed Date palm seed oil n-hexane Yes [81]
- MAE tetrahydrofuran detected between

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- Maceration extraction processes
Stirring: 4000 rpm
2017 Dried carrots β-carotene SLE D-limonene n-hexane Yes [69]
Time: 1h

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Nannochloropsis Methyl-tert-butyl ether Chlorinated Vortex, 2500 rpm,
2017 Triacylglycerides SLE Yes [82]

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sp and CMPE solvents 293.2 K, 10 min.

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Phaeodactylum PLE, CXLL PLE: 313.2 K, 10.3
2017 Fucoxanthin D-limonene Acetone Yes [3]
tricornutum MPa, 20 min.
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2017 Rapeseed Rapeseed oil SLE D-limonene n-hexane 4000 rpm, 1h Yes [69]
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D-limonene Soxhlet extraction: S/L

2017 Salmon fish lipids TAGs Soxhlet n-hexane Partially [75]
p-cymene ratio: 1:12 g/mL; 8h.
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For RA: 323.2 K, 10.4

Distillation
Rosmarinic acid Ethanol- and MPa, water-ethanol
wastewater of
2018 (RA), PLE Ethyl lactate-water No specified mixture 25:75 (% v/v) Partially [80]
basil (Ocimum
Cafeic acid (CA) mixtures For CA: 323.2 K ,
basilicum L.)
10.4MPa, 100% wt.
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ethanol

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318.15 K, 20MPa,
2018 Dunaliella salina β-carotene SFE Ethanol as co-solvent Neat SC-CO2 [19]
5% w/w Yes
Oleic acid,
Fatty acids 318.2 K, 9.5 and 9.8

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2018 Linoleic acid, SFE Ethanol as co-solvent Neat SC-CO2 Partially [77]
standards MPa, 5% w/w.
Stearic acid
Withanolide E, 4-

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Goldenberry Ethanol-Ethyl acetate 398.2 K, 10.0 MPa,
2019 hydroxywithanolide PLE No specified Partially [89]
calyces mixtures 75% EtOH v/v
E.
834 1 VACs: (monoterpenes, oxygenated monoterpenes, sesquiterpenes, oxygenated sesquiterpenes); 2 VACs: (Linalool, eugenol, estragole, eucalyptol, trans-

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835 anethole, limonene); SFE: Supercritical fluid extraction; PLE: Pressurized Liquid Extraction; SC-CO2: Supercritical carbon dioxide; CXLE: CO2 expanded
836 ethanol extraction; CXLL: CO2 expanded d-limonene extraction; SLE: Solid-liquid extraction; S/L ratio: Solute to solvent ratio; UAE: Ultrasound assisted

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837 extarction, MAE: Microwave assisted extraction; TAGs: Triacylglycerides, Diacylglycerides, free fatty acids and ergosterol
838

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Highlights

• Hansen solubility parameters is used as solvent selection tool for green extraction

• In the last 10 years, there has been a notably increase on HSP research publications

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• Emerging extraction technologies have been employed Hansen approach with success

• Solubility of terpenes, phenolic compounds and fatty acids have been predicted by HSP

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• COSMO-RS is another powerful approach employed to understand solubility

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mechanism

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