118
These studies that include the formation of eutectic mixtures with therapeutic
agents demonstrated an improvement of the characteristics of the therapeutic agent.
These promising results lead to investigation and development of studies of solubility with therapeutic eutectic mixtures and using the eutectic mixtures as a vehicle to
solubilize poorly soluble drugs, to improve their solubility, as we can observe in
Fig. 3.5.
Shen and coworkers have studied the intestinal absorption of daidzein in the
presence of a eutectic mixture of borneol:menthol and with a microemulsion to
improve the bioavailability of daidzein. The results indicate that the eutectic mixture increased the solubility of daidzein, increasing the membrane fluidity and permeability through the intestinal mucosa. The use of daidzein borneol:menthol
microemulsion with a surfactant to improve the intestinal absorption could result in
a synergistic effect between the eutectic mixture and microemulsion with surfactant
(Shen et al. 2011).
Morrison et al. tested potential solubilization of drugs such as benzoic acid, griseofulvin, danazol, itraconazole, and AMG517 in NADES. In this study, was measured the solubility with pure NADES and mixtures of NADES and water in
different proportions, the results showed an increase of 5- to 22,000-fold in the solubility of the drugs comparing with water. In addition, NADES could represent a
promising vehicle for oral drug delivery, since their components are, in general,
pharmaceutically tolerable (Morrison et al. (2009); Vanda et al. 2018); Álvarez and
Zhang 2019).
0
50
100
150
200
250
300
Ib
u p r o f e n
M e n t h o l: Ib
u
( 3 : 1 )
B e n z o ic
A c id
M e n t h o l: B A
( 3 : 1 )
P h e n y la c e t ic
A c id
M e n t h o l: P A
( 2 : 1 )
C h o li n e C lo
r id
e : P A
(1
: 1 )
A c e t y l s a li c y li c A c id
C h o li n e C lo
r id
e : A A
( 1 : 1 )
M e n t h o l: A A
( 1 : 1 )
E t h a m
b u t o l
C it r ic
A c id
: E t h a m
b u t o l: H 2 O
( 2 : 1 : 1 0 )
L - A r g in
in
e
C it r ic
A c id
: L - A r g in
in
e : H 2 O
( 1 : 1 : 7 )
C it r ic
A c id
: L - A r g in
in
e : H 2 O
( 2 : 1 : 9 )
Solubility (mg/mL)
Solubility Enhancement
12,8x
2,08x
1,22x
1,37x
1,54x
2,59x
27,5x
1,07x
1,09x
Fig. 3.5 Representative results presented in the literature with enhancement of solubility of APIs
when present in the eutectic mixture as part of therapeutic deep eutectic systems (THEDES)
(Aroso et al. (2016); Duarte et al. (2017); Aroso et al. (2015); Barros et al. (2017); Santos
et al. 2019)
F. Santos and A. R. C. Duarte
These studies that include the formation of eutectic mixtures with therapeutic
agents demonstrated an improvement of the characteristics of the therapeutic agent.
These promising results lead to investigation and development of studies of solubility with therapeutic eutectic mixtures and using the eutectic mixtures as a vehicle to
solubilize poorly soluble drugs, to improve their solubility, as we can observe in
Fig. 3.5.
Shen and coworkers have studied the intestinal absorption of daidzein in the
presence of a eutectic mixture of borneol:menthol and with a microemulsion to
improve the bioavailability of daidzein. The results indicate that the eutectic mixture increased the solubility of daidzein, increasing the membrane fluidity and permeability through the intestinal mucosa. The use of daidzein borneol:menthol
microemulsion with a surfactant to improve the intestinal absorption could result in
a synergistic effect between the eutectic mixture and microemulsion with surfactant
(Shen et al. 2011).
Morrison et al. tested potential solubilization of drugs such as benzoic acid, griseofulvin, danazol, itraconazole, and AMG517 in NADES. In this study, was measured the solubility with pure NADES and mixtures of NADES and water in
different proportions, the results showed an increase of 5- to 22,000-fold in the solubility of the drugs comparing with water. In addition, NADES could represent a
promising vehicle for oral drug delivery, since their components are, in general,
pharmaceutically tolerable (Morrison et al. (2009); Vanda et al. 2018); Álvarez and
Zhang 2019).
0
50
100
150
200
250
300
Ib
u p r o f e n
M e n t h o l: Ib
u
( 3 : 1 )
B e n z o ic
A c id
M e n t h o l: B A
( 3 : 1 )
P h e n y la c e t ic
A c id
M e n t h o l: P A
( 2 : 1 )
C h o li n e C lo
r id
e : P A
(1
: 1 )
A c e t y l s a li c y li c A c id
C h o li n e C lo
r id
e : A A
( 1 : 1 )
M e n t h o l: A A
( 1 : 1 )
E t h a m
b u t o l
C it r ic
A c id
: E t h a m
b u t o l: H 2 O
( 2 : 1 : 1 0 )
L - A r g in
in
e
C it r ic
A c id
: L - A r g in
in
e : H 2 O
( 1 : 1 : 7 )
C it r ic
A c id
: L - A r g in
in
e : H 2 O
( 2 : 1 : 9 )
Solubility (mg/mL)
Solubility Enhancement
12,8x
2,08x
1,22x
1,37x
1,54x
2,59x
27,5x
1,07x
1,09x
Fig. 3.5 Representative results presented in the literature with enhancement of solubility of APIs
when present in the eutectic mixture as part of therapeutic deep eutectic systems (THEDES)
(Aroso et al. (2016); Duarte et al. (2017); Aroso et al. (2015); Barros et al. (2017); Santos
et al. 2019)
F. Santos and A. R. C. Duarte