By complexing with hydrophobic compounds, cyclodextrins afford increased solubility and thermodynamic stability to hardly soluble compounds, thereby underlining their invaluable applications in pharmaceutical and other industries. However, common cyclodextrins such as β-cyclodextrin, suffer from limited solubility in water, which often leads to precipitation and formation of unfavorable aggregates, driving the search for better solvents. Here, we study the solvation of cyclodextrin in deep eutectic solvents (DESs), environmentally friendly media that possess unique properties. We focus on reline, the DES formed from choline chloride and urea, and resolve the mechanism through which its constituents elevate β-cyclodextrin solubility in hydrated solutions compared to pure water or dry reline. Combining experiments and simulations, we determine that the remarkable solubilization of β-cyclodextrin in hydrated reline is mostly due to the inclusion of urea inside β-cyclodextrin’s cavity and at its exterior surfaces. The role of choline chloride in further increasing solvation is twofold. First, it increases urea’s solubility beyond the saturation limit in water, ultimately leading to much higher β-cyclodextrin solubility in hydrated reline in comparison to aqueous urea solutions. Second, choline chloride increases urea’s accumulation in β-cyclodextrin’s vicinity. Specifically, we find that the accumulation of urea becomes stronger at high reline concentrations, as the solution transitions from reline-in-water to water-in-reline, where water alone cannot be regarded as the solvent. Simulations further suggest that in dry DES, the mechanism of β-cyclodextrin solvation changes so that reline acts as a quasi-single component solvent that lacks preference for the accumulation of urea or choline chloride around β-cyclodextrin.

1.
Y.
Liu
,
Y.
Chen
,
X.
Gao
,
J.
Fu
, and
L.
Hu
,
Crit. Rev. Food Sci. Nutr.
1
(
2020
).
2.
G.
Astray
,
C.
Gonzalez-Barreiro
,
J. C.
Mejuto
,
R.
Rial-Otero
, and
J.
Simal-Gándara
,
Food Hydrocolloids
23
,
1631
(
2009
).
3.
H.
Arima
,
K.
Motoyama
, and
T.
Higashi
,
Chem. Pharm. Bull.
65
,
341
(
2017
).
4.
Q.-D.
Hu
,
G.-P.
Tang
, and
P. K.
Chu
,
Acc. Chem. Res.
47
,
2017
(
2014
).
5.
P.
Jansook
,
N.
Ogawa
, and
T.
Loftsson
,
Int. J. Pharm.
535
,
272
(
2018
).
6.
P.
Saokham
,
C.
Muankaew
,
P.
Jansook
, and
T.
Loftsson
,
Molecules
23
,
1161
(
2018
).
7.
C.
Lipinski
,
Am. Pharm. Rev.
5
,
82
(
2002
).
8.
K. T.
Savjani
,
A. K.
Gajjar
, and
J. K.
Savjani
,
Int. Scholarly Res. Not.
2012
,
195727
.
9.
C.
Müller
,
Chem. Biodiversity
6
,
2071
(
2009
).
10.
P.
Legrand
,
E. A.
Romero
,
B. E.
Cohen
, and
J.
Bolard
,
Antimicrob. Agents Chemother.
36
,
2518
(
1992
).
11.
S. C.
Owen
,
A. K.
Doak
,
P.
Wassam
,
M. S.
Shoichet
, and
B. K.
Shoichet
,
ACS Chem. Biol.
7
,
1429
(
2012
).
12.
S. L.
McGovern
,
B. T.
Helfand
,
B.
Feng
, and
B. K.
Shoichet
,
J. Med. Chem.
46
,
4265
(
2003
).
13.
T.
Lipiäinen
,
M.
Peltoniemi
,
S.
Sarkhel
,
T.
Yrjönen
,
H.
Vuorela
,
A.
Urtti
, and
A.
Juppo
,
J. Pharm. Sci.
104
,
307
(
2015
).
14.
C.
Schönbeck
,
T. L.
Madsen
,
G. H.
Peters
,
R.
Holm
, and
T.
Loftsson
,
Int. J. Pharm.
531
,
504
(
2017
).
15.
S.
Saha
,
A.
Roy
,
K.
Roy
, and
M. N.
Roy
,
Sci. Rep.
6
,
35764
(
2016
).
16.
N.
Mennini
,
M.
Bragagni
,
F.
Maestrelli
, and
P.
Mura
,
J. Pharm. Biomed. Anal.
89
,
142
(
2014
).
17.
T.
Loftsson
and
M. E.
Brewster
,
J. Pharm. Sci.
101
,
3019
(
2012
).
18.
A. W.
Coleman
,
I.
Nicolis
,
N.
Keller
, and
J. P.
Dalbiez
,
J. Inclusion Phenom. Mol. Recognit. Chem.
13
,
139
(
1992
).
19.
A. K.
Chatjigakis
,
C.
Donzé
,
A. W.
Coleman
, and
P.
Cardot
,
Anal. Chem.
64
,
1632
(
1992
).
20.
D.
Harries
,
D. C.
Rau
, and
V. A.
Parsegian
,
J. Am. Chem. Soc.
127
,
2184
(
2005
).
21.
M.
Tanaka
,
T.
Miki
, and
T.
Shono
,
J. Chromatogr. A
330
,
253
(
1985
).
22.
T.
Cserháti
,
J.
Bojarski
,
É.
Fenyvesi
, and
J.
Szejtli
,
J. Chromatogr. A
351
,
356
(
1986
).
23.
V.
Zia
,
R. A.
Rajewski
, and
V. J.
Stella
,
Pharm. Res.
17
,
936
(
2000
).
24.
C.
Zou
,
L.
Li
,
D.
Miki
,
D.
Li
,
Q.
Tang
,
L.
Xiao
,
S.
Rajput
,
P.
Deng
,
L.
Peng
,
W.
Jia
,
R.
Huang
,
M.
Zhang
,
Y.
Sun
,
J.
Hu
,
X.
Fu
,
P. S.
Schnable
,
Y.
Chang
,
F.
Li
,
H.
Zhang
,
B.
Feng
,
X.
Zhu
,
R.
Liu
,
J. C.
Schnable
,
J.-K.
Zhu
, and
H.
Zhang
,
Nat. Commun.
10
,
436
(
2019
).
25.
L.
Zhang
,
J.
Zhou
, and
L.
Zhang
,
Carbohydr. Polym.
94
,
386
(
2013
).
26.
D. Y.
Pharr
,
Z. S.
Fu
,
T. K.
Smith
, and
W. L.
Hinze
,
Anal. Chem.
61
,
275
(
1989
).
27.
J. A.
McCune
,
S.
Kunz
,
M.
Olesińska
, and
O. A.
Scherman
,
Chemistry
23
,
8601
(
2017
).
28.
A. P.
Abbott
,
G.
Capper
,
D. L.
Davies
,
R. K.
Rasheed
, and
V.
Tambyrajah
,
Chem. Commun.
2003
,
70
.
29.
A.
Triolo
,
F.
Lo Celso
, and
O.
Russina
,
J. Phys. Chem. B
124
,
2652
(
2020
).
30.
L.
Sapir
,
C. B.
Stanley
, and
D.
Harries
,
J. Phys. Chem. A
120
,
3253
(
2016
).
31.
E. L.
Smith
,
A. P.
Abbott
, and
K. S.
Ryder
,
Chem. Rev.
114
,
11060
(
2014
).
32.
Y.
Dai
,
J.
van Spronsen
,
G.-J.
Witkamp
,
R.
Verpoorte
, and
Y. H.
Choi
,
Anal. Chim. Acta
766
,
61
(
2013
).
33.
A.
Paiva
,
R.
Craveiro
,
I.
Aroso
,
M.
Martins
,
R. L.
Reis
, and
A. R. C.
Duarte
,
ACS Sustainable Chem. Eng.
2
,
1063
(
2014
).
34.
M.
Gilmore
,
M.
Swadzba-Kwasny
, and
J. D.
Holbrey
,
J. Chem. Eng. Data
64
,
5248
(
2019
).
35.
T.
Moufawad
,
L.
Moura
,
M.
Ferreira
,
H.
Bricout
,
S.
Tilloy
,
E.
Monflier
,
M.
Costa Gomes
,
D.
Landy
, and
S.
Fourmentin
,
ACS Sustainable Chem. Eng.
7
,
6345
(
2019
).
36.
A.
Cantelli
,
P.
Franchi
,
E.
Mezzina
, and
M.
Lucarini
,
ChemPhysChem
22
,
517
(
2021
).
37.
M. E.
Di Pietro
,
M.
Ferro
, and
A.
Mele
,
J. Mol. Liq.
311
,
113279
(
2020
).
38.
T.
El Achkar
,
T.
Moufawad
,
S.
Ruellan
,
D.
Landy
,
H.
Greige-Gerges
, and
S.
Fourmentin
,
Chem. Commun.
56
,
3385
(
2020
).
39.
A.
Yadav
and
S.
Pandey
,
J. Chem. Eng. Data
59
,
2221
(
2014
).
40.
X.
Meng
,
K.
Ballerat-Busserolles
,
P.
Husson
, and
J.-M.
Andanson
,
New J. Chem.
40
,
4492
(
2016
).
41.
L.
Sapir
and
D.
Harries
,
J. Chem. Theory Comput.
16
,
3335
(
2020
).
42.
D.
Shah
and
F. S.
Mjalli
,
Phys. Chem. Chem. Phys.
16
,
23900
(
2014
).
43.
O. S.
Hammond
,
D. T.
Bowron
, and
K. J.
Edler
,
Angew. Chem., Int. Ed.
56
,
9782
(
2017
).
44.
E.
Posada
,
N.
López-Salas
,
R. J. J.
Riobóo
,
M. L.
Ferrer
,
M. C.
Gutiérrez
, and
F.
Del Monte
,
Phys. Chem. Chem. Phys.
19
,
17103
(
2017
).
45.
P.
Kumari
,
Shobhna
,
S.
Kaur
, and
H. K.
Kashyap
,
ACS Omega
3
,
15246
(
2018
).
46.
Q.
Gao
,
Y.
Zhu
,
X.
Ji
,
W.
Zhu
,
L.
Lu
, and
X.
Lu
,
Fluid Phase Equilib.
470
,
134
(
2018
).
47.
M.
Kuddushi
,
G. S.
Nangala
,
S.
Rajput
,
S. P.
Ijardar
, and
N. I.
Malek
,
J. Mol. Liq.
278
,
607
(
2019
).
48.
G. C.
Dugoni
,
M. E.
Di Pietro
,
M.
Ferro
,
F.
Castiglione
,
S.
Ruellan
,
T.
Moufawad
,
L.
Moura
,
M. F.
Costa Gomes
,
S.
Fourmentin
, and
A.
Mele
,
ACS Sustainable Chem. Eng.
7
,
7277
(
2019
).
49.
P. J.
Smith
,
C. B.
Arroyo
,
F.
Lopez Hernandez
, and
J. C.
Goeltz
,
J. Phys. Chem. B
123
,
5302
(
2019
).
50.
A.
Triolo
,
F.
Lo Celso
,
M.
Brehm
,
V.
Di Lisio
, and
O.
Russina
,
J. Mol. Liq.
331
,
115750
(
2021
).
51.
E. O.
Fetisov
,
D. B.
Harwood
,
I.-F. W.
Kuo
,
S. E. E.
Warrag
,
M. C.
Kroon
,
C. J.
Peters
, and
J. I.
Siepmann
,
J. Phys. Chem. B
122
,
1245
(
2018
).
52.
J.
Wyman
,
Adv. Protein Chem.
19
,
223
(
1964
).
53.
H. W.
Horn
,
W. C.
Swope
,
J. W.
Pitera
,
J. D.
Madura
,
T. J.
Dick
,
G. L.
Hura
, and
T.
Head-Gordon
,
J. Chem. Phys.
120
,
9665
(
2004
).
54.
L.
Tavagnacco
,
U.
Schnupf
,
P. E.
Mason
,
M.-L.
Saboungi
,
A.
Cesàro
, and
J. W.
Brady
,
J. Phys. Chem. B
115
,
10957
(
2011
).
55.
R. B.
Best
,
X.
Zhu
,
J.
Shim
,
P. E. M.
Lopes
,
J.
Mittal
,
M.
Feig
, and
A. D.
MacKerell
,
J. Chem. Theory Comput.
8
,
3257
(
2012
).
56.
O.
Guvench
,
S. S.
Mallajosyula
,
E. P.
Raman
,
E.
Hatcher
,
K.
Vanommeslaeghe
,
T. J.
Foster
,
F. W.
Jamison
, and
A. D.
MacKerell
,
J. Chem. Theory Comput.
7
,
3162
(
2011
).
57.
W. K.
Lay
,
M. S.
Miller
, and
A. H.
Elcock
,
J. Chem. Theory Comput.
13
,
1874
(
2017
).
58.
S.
Weerasinghe
and
P. E.
Smith
,
J. Phys. Chem. B
107
,
3891
(
2003
).
59.
B.
Hess
,
H.
Bekker
,
H. J. C.
Berendsen
, and
J. G. E. M.
Fraaije
,
J. Comput. Chem.
18
,
1463
(
1997
).
60.
S.
Nosé
,
J. Chem. Phys.
81
,
511
(
1984
).
61.
M.
Parrinello
and
A.
Rahman
,
Phys. Rev. Lett.
45
,
1196
(
1980
).
62.
U.
Essmann
,
L.
Perera
,
M. L.
Berkowitz
,
T.
Darden
,
H.
Lee
, and
L. G.
Pedersen
,
J. Chem. Phys.
103
,
8577
(
1995
).
63.
B.
Hess
,
C.
Kutzner
,
D.
Van Der Spoel
, and
E.
Lindahl
,
J. Chem. Theory Comput.
4
,
435
(
2008
).
64.
B.
Lovrinčević
,
A.
Bella
,
I.
Le Tenoux-Rachidi
,
M.
Požar
,
F.
Sokolić
, and
A.
Perera
,
J. Mol. Liq.
293
,
111447
(
2019
).
65.
M.
Brehm
and
B.
Kirchner
,
J. Chem. Inf. Model.
51
,
2007
(
2011
).
66.
E. F.
Pettersen
,
T. D.
Goddard
,
C. C.
Huang
,
G. S.
Couch
,
D. M.
Greenblatt
,
E. C.
Meng
, and
T. E.
Ferrin
,
J. Comput. Chem.
25
,
1605
(
2004
).
67.
A. R.
Sá Couto
,
A.
Ryzhakov
, and
T.
Loftsson
,
J. Drug Delivery Sci. Technol.
48
,
209
(
2018
).
68.
I.
Shumilin
,
C.
Allolio
, and
D.
Harries
,
J. Am. Chem. Soc.
141
,
18056
(
2019
).
69.
I.
Shumilin
,
B.
Bogoslavsky
, and
D.
Harries
,
Colloids Surf., A
599
,
124889
(
2020
).
70.
S.
Shimizu
and
D. J.
Smith
,
J. Chem. Phys.
121
,
1148
(
2004
).
71.
S. N.
Timasheff
,
Advances in Protein Chemistry
(
Academic Press
,
1998
).
72.
V. A.
Parsegian
,
Int. Rev. Cytol.
215
,
1
(
2002
).
73.
D.
Harries
and
J.
Rösgen
, in
Methods Cell Biology
, 1st ed., edited by
J. J.
Correria
and
H. W.
Detrich
(
Elsevier
,
London
,
2008
), pp.
679
735
.
74.
R.
Stokes
,
Aust. J. Chem.
20
,
2087
(
1967
).
75.
J. B.
Macaskill
,
M. S.
Mohan
, and
R. G.
Bates
,
Anal. Chem.
49
,
209
(
1977
).
76.
E. S.
Courtenay
,
M. W.
Capp
,
C. F.
Anderson
, and
M. T.
Record
,
Biochemistry
39
,
4455
(
2000
).
77.
G.
Castellan
,
Physical Chemistry
, 3rd ed. (
Addison-Wesley Publishing
,
1983
).
78.
R. A.
Robinson
and
R. H.
Stokes
,
Electrolyte Solutions
(
Courier Corporation
,
2002
).
79.
M. T.
Record
and
C. F.
Anderson
,
Biophys. J.
68
,
786
(
1995
).
80.
J. G.
Kirkwood
and
F. P.
Buff
,
J. Chem. Phys.
19
,
774
(
1951
).
81.
I. L.
Shulgin
and
E.
Ruckenstein
,
J. Chem. Phys.
123
,
054909
(
2005
).
82.
T.
Kobayashi
,
J. E. S. J.
Reid
,
S.
Shimizu
,
M.
Fyta
, and
J.
Smiatek
,
Phys. Chem. Chem. Phys.
19
,
18924
(
2017
).
83.
S.
Weerasinghe
and
P. E.
Smith
,
J. Chem. Phys.
119
,
11342
(
2003
).
84.
M.
Fyta
and
R. R.
Netz
,
J. Chem. Phys.
136
,
124103
(
2012
).
85.
G. I.
Olgenblum
,
L.
Sapir
, and
D.
Harries
,
J. Chem. Theory Comput.
16
,
1249
(
2020
).
86.
L.
Sapir
and
D.
Harries
,
J. Chem. Theory Comput.
13
,
2851
(
2017
).
87.
F.
Biedermann
,
W. M.
Nau
, and
H.-J.
Schneider
,
Angew. Chem., Int. Ed.
53
,
11158
(
2014
).

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