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The rise of deep eutectics from nature to cosmetics

Article · February 2016

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 Mickaël Laguerre, Alexis Lavaud – Naturex, France SUSTAINABILITY

The rise of deep eutectics

from nature to cosmetics
Deep eutectic solvents probably evolved a b
very early in the history of living organisms Mp Mp Mp Mp
and may reflect a fundamental component
of the chemistry of life. Scientists are now Mp (A)

rediscovering all kinds of molecule Mp (B)

combinations engineered by nature into Mp (A)
DTf
these unique mixtures. Harnessing these Mp (B)
DTf
bio-inspired solvents for eco-extraction
Ep Ep
purposes is one of the most exciting ways
to recover phytoactive molecules using the
same strategy adopted by plants for their
survival. 100% (A) 50% Ec 100% (B) 100% (A) 50% Ec 100% (B)

The depletion of fossil resources, Mole fraction Mole fraction

combined with changes in the regulatory,
environmental and toxicological frameworks
for solvents, puts heavy selective pressure
on the development of alternatives to
petro-based organic solvents. Finding
sustainable and eco-friendly extraction
technologies capable of producing extracts
with novel phytochemical profiles and
enhanced efficacy has become increasingly
important.
Andrew Abbott’s discovery
of a new type of solvents
During the past decade, a new generation
of bio-inspired multi-molecular solvents has
emerged with a great potential for many
industrial applications, especially for the
cosmetics sector. In 2003, Andrew Abbott
and his collaborators from the University
of Leicester1 first coined them as deep
eutectic solvents from the Greek term
‘eutektos’ meaning ‘easily melted’.
Figure 1: Schematic representation of the difference between ‘eutectic solvents’ a) and ‘deep
eutectic solvents’ b) on a two-component phase diagram. [Mp: Melting point; Tf: magnitude of
the depression of the melting point; Ep: eutectic point; Ec: eutectic composition].
The solvents can be defined as a formation of a eutectic between two
combination of compounds endowed components, they differ, however, from
with a melting point, or a glass transition most eutectic mixtures, in their very large
temperature, much lower than those decrease in melting point (DTf), which can
of their individual components taken be as high as 100-200˚C2 (Fig. 1).
separately. In other words, these solvents Therefore, Abbott et al. added the term
refer to liquids close to the eutectic ‘deep’ to the already known concept of
composition of the mixture (the so-called eutectic solvents to highlight this difference
eutectic point) that is the molar ratio of and to give rise to the so-called ‘deep
the components which gives the lowest eutectic solvents’ or ‘DES’.
melting point (Fig. 1). Among many of their idiosyncrasies is
Put simply, one can imagine solid the fact that they do not exhibit vapour
powders, or compounds with a melting pressure, meaning that they do not
point at room temperature, which, when evaporate at room temperature.
mixed in the right proportions, produce a Furthermore, their unusual physical
liquid solvent through the formation of a chemical properties make them particularly
eutectic mixture (eutectigenesis). If deep effective in solubilising compounds that
eutectic solvents result from the standard are usually poorly soluble in water or lipid

Ordered system: solid (crystalline phase) Disordered system: liquid

A A A B B B B A B A
A A B B
A A A B B B B B
Eutectigenesis
A A + B B Cavity
A A A B B B B
A A B B A B
A A A B B B
A A B B B B A

Figure 2: A simplified view of the eutectigenesis phenomenon at the supramolecular level.

February 2016 P E R S O N A L C A R E 45
 SUSTAINABILITY

phases. These revolutionary solvents are Anti-wrinkle*

Radiance & whitening*
not only easy to produce and handle, but Anti-wrinkle* Regenerating*
Firming*
they are also unreactive to air and moisture Photo-ageing*
Photoprotection*
Regenerating*
which are key prerequisites for their use as Antioxidant Aftersun
extraction and/or formulation fluids for the Hair shine Antioxidant
Hair repair Hair shine
cosmetics sector. Hair repair
Mechanistically speaking, combinations
Radiance & whitening*
are formed between DES components, Energising Calming*
rearranging the molecular lattice by Antioxidant Antioxidant*
Anti-ageing Regenerating
increasing the void volume.3 DES behave Hair shine Hair shine
like a sliding puzzle: molecules can only Hair repair Hair repair

move if there is space (void) next to them

that is big enough for the molecule in Antioxidant*
Radiance & whitening*
question. For example the packing of Antioxidant
Calming
molecules in a solid A is too compact to Dermo-purifying
Dermo-purifying
Photoprotection
allow for movement, meaning that the Hair shine
Hair shine
Hair repair
void between molecules is very low (Fig. 2). Hair repair

This packing can be weakened by

introducing new molecules – for instance B
– that will associate with A, thus disrupting
the crystalline structures to generate a less
ordered system. By doing so, cavities are
created in the vicinity of both molecules,
allowing them to move. Introducing more
void into the system, makes molecules
more diffusible – hence the mixture
becomes liquid.
The recipe to prepare DES is relatively
easy: mix an asymmetric quaternary
ammonium (a powder) with a hydrogen-
bond donor (powder or viscous liquid) in
various molar ratios (1:1, 1:2, 1:3), apply
moderate heat, then select the mixture
that stays stable, clear and limpid at room
temperature. Not all combinations form a
melt, much less a stable one. Making DES
is both an art and a science and knowing
the theoretical background of eutectics –
hole theory for instance – makes it possible
to prepare less viscous and more stable
mixtures, all the while fine-tuning their
Figure 3: The first series of the Eutectys collection (*in vitro proven benefits).
sugars, amino acids, quaternary led to the epiphany – was the realisation
ammoniums, polyols, and certain organic that drought tolerance in plants is often
acids. With the exception of sugars, which accompanied with the accumulation of
may serve as cell energy providers, the sugars, amino-acids, quaternary
other compounds are present in such large ammonium and organic acids, all perfect
amounts that it does not make sense to candidates for constituting eutectics.
consider them as mere intermediates in They soon realised that under extreme
metabolic pathways. These compounds environmental conditions such as drought,
must serve an ignored but crucial basic salt stress, and high or low temperatures,
function in living organisms. living cells may survive by forming deep
Robert Verpoorte and his collaborators eutectic liquids in which the membranes,
from the Universities of Leiden and Delf enzymes and metabolites remain stable,
started considering the problem from a and wherein, the last molecules of water
new perspective. The first hint came from are strongly retained, and freezing is
the experimental observation that these prohibited by the very low melting point
primary metabolites were able to form deep of the eutectic mixture.5
eutectic mixtures. The second hint – which To understand such a breakthrough
a 4.0
3.8
3.6 Phelonic acids concentration: +18%
3.4
3.2
3.0
Response units (x102)

solvation properties. Accordingly, a lot of 2.8

2.6
hydrogen-bond donors available in nature 2.4
2.2
have been tested to date, such as amides, 2.0
1.8
amines, acids, alcohols, and so on.4 1.6
1.4
The wide range of available natural 1.2
1.0
hydrogen-bond donors, along with the 0.8
0.6
multiple methods for combining them 0.4
0.2
with quaternary ammoniums, means 0
–0.2
that this novel class of liquids is almost –0.4

infinitely tunable: myriad DES can be 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

created, thus opening an avenue for their Acquisition time (mn)

use in industry.
b 80

Do plant cells contain liquids n

Protective gain (%)

Dexamethasone 10 mM
n
60 ***
other than water and lipids? Horsetail GlyH2O 0.01%
n Horsetail GlyH2O 0.1%
n
The story about deep eutectic solvents 40
x5
Horsetail EutectysTM BLA 0.01%
took an unexpected turn when suspicions ** n Horsetail EutectysTM BLA 0.1%
began to grow that nature had been using 20

them long before the advent of green **p<0.01, ***p<0.001

chemistry. Considering the data which has
been collected in the last decades using
metabolomics, it is indeed worth asking
why a few very simple compounds are
always present in considerable amounts in
all plant cells.5 Such molecules include
0
TNFa inhibition
Figure 4: Horsetail Eutectys: a) augmented phytoactive content [LC/UV chromatogram of
Horsetail Eutectys BLA (red) compared to a standard horsetail glycerine extract (blue) at 280 nm];
and b) enhanced biological property [Horsetail Eutectys BLA showed soothing properties at 0.1%
by inhibiting the release of TNF-a in HaCaT keratinocyte cells].

46 P E R S O N A L C A R E February 2016

hypothesis, we must recall that cells
have been hitherto considered to contain
two immiscible liquid phases: water and
lipid. And yet cells contain numerous
compounds of intermediate polarity in high
concentrations that neither dissolve in
lipids nor water. This raises the question of
how these compounds are biosynthesised,
stored and/or transported. While most
enzyme-mediated reactions in the cells
occur in water, scientists were puzzled: how
do these reactions function with substrates
and products that are poorly hydrosoluble?
Furthermore, the biosynthesis of water-
insoluble polymers such as cellulose,
amylose, and lignins probably requires a
stage in which the macromolecule is
dissolved to enable the further addition of
building blocks. The occurrence of DES
may explain the presence of compounds
like flavonoids, anthocyanins and polymers
at much higher levels in plants than can
be solubilised in water.
Logically, Verpoorte et al. added the
adjective ‘natural’ to the term already
proposed by Abbott et al. of ‘deep eutectic
solvents’ to give rise to the so-called
‘natural deep eutectic solvents’ or NaDES.
However, the name introduces some
artificial differences between NaDES
and DES. Indeed, though they were not
specifically labelled as NaDES, most of the
DES used before the introduction of the
concept by Verpoorte’s group were in fact
true NaDES, being formed from naturally
arising building blocks. Most of the DES
were NaDES, but were never labelled as
such.
Deep eutectic solvents:
a game-changer in
botanical extraction
Apart from implying a paradigmatic change
in ‘cellular green chemistry’, deep eutectic
solvents have an enormous potential for
a wide range of industrial applications.
Among different sectors, cosmetics is
probably the best suited for them, due to
the need for botanical actives and the
endless search for novelty. The biomimicry
approach is also particularly relevant to
the cosmetic market for another reason:
eutectic extracts are created through a
technology that plants naturally use to
solubilise essential molecules, as
phytochemicals are not always soluble in
lipid or water phases. Added to the fact
that there is a strong demand from
consumers and manufacturers for
biodegradable, nonvolatile, low-toxicity, and
100% natural solvents, NaDES can now be
imagined as a new natural alternative for
botanical extraction. Despite such great
potential, their implementation beyond the
laboratory scale has been quite limited.
However, this situation has recently
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SUSTAINABILITY
a 1.8
1.7
1.6
A higher content in phenolic acids
1.5
1.4
Response units (x102)
1.3
1.2
1.1
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
–0.1
6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
Acquisition time (mn)
b 40
***
Inhibition of melanin
30
synthesis (%)
n Rose of Jericho GlyH2O 0.1%
n Rose of Jericho EutectysTM BG 0.1%
20
10
***p<0.001
0
Melanin inhibition on NHEM-LP
Figure 5: Rose of Jericho Eutectys: a) augmented phytoactive content [LC/UV chromatogram of
Rose of Jericho Eutectys BG (red) compared to a standard Rose of Jericho glycerine extract
(blue) at 280 nm]; and b) enhanced biological property [Rose of Jericho Eutectys BG showed
whitening properties at 0.1% by inhibiting the synthesis of melanin in normal melanocytes from
human epidermis].
changed with the launch of the first-ever perspective, this collection exemplifies our
botanical extracts based on NaDES: way of thinking at Naturex: figuring out
the Eutectys collection. what customers want before they know
These eutectic extracts are obtained themselves. Henry Ford once said: “If I’d
using a patented extraction process6 called asked customers what they wanted, they
eutectigenesis-assisted extraction, which would have told me ‘a faster horse’!”
consists of extracting the active secondary To date, we are poised near a paradigm
metabolites of the plant through the shift in the production of cosmetic
formation of a eutectic between the plant’s ingredients, of which, Eutectys may
primary metabolites. Concerning the constitute the tipping point. PC
botanical origin, the Eutectys collection is
composed of six high-definition extracts References
including olive leaf, saffron flower, horsetail, 1 Abbott AP, Capper G, Davies DL, Rasheed RK,
rosemary, rose of Jericho, and sea fennel, Tambyrajah V. Novel solvent properties of choline
all well-known for their regenerating, chloride/urea mixtures. Chem Commun (Camb)
radiance and anti-ageing properties (Fig. 3). 2003; 7(1): 70-1.
Interestingly, these liquid extracts are 2 Abbott AP, Capper G, Gray S. Design of improved
endowed with augmented phytoactive deep eutectic solvents using hole theory.
profiles and improved in vitro efficacy Chemphyschem 2006; 7 (4): 803-6.
compared to standard glycerin extracts 3 Abbott AP, Boothby D, Capper G, Davies DL,
(Figs. 4 and 5). With regard to the freedom Rasheed RK. Deep eutectic solvents formed
to operate, it is worth mentioning that between choline chloride and carboxylic acids:
our NaDES, along with the corresponding versatile alternatives to ionic liquids. J Am Chem
extracts, and their use in cosmetic Soc 2004; 126 (29): 9142-7.
formulation, are all covered by our own 4 Smith EL, Abbott AP, Ryder KS. Deep eutectic
patent application and also by a group of solvents (DESs) and their applications. Chem Rev
patents (granted) whose exclusive license 2014; 114 (21): 11060-82.
has recently been obtained by Naturex 5 Choi YH, van Spronsen J, Dai Y et al. Are natural
from Scionix Ltd. deep eutectic solvents the missing link in
understanding cellular metabolism and
Conclusion physiology? Plant Physiol 2011; 156 (4):
Finally, by creating these six Eutectys, we 1701-5.
have paved the way to the development of 6 Lavaud A, Laguerre M, Birtic S et al. Solvant
a new generation of botanical liquid eutectique d’extraction, procédé d’extraction par
extracts that anticipates the demand of the eutectigénèse utilisant ledit solvant, et extrait
cosmetics market. From a general issu dudit procédé d’extraction, 2015.
February 2016 P E R S O N A L C A R E 47