Microencapsulation of herbicide MCPA with native β-cyclodextrin and its methyl and hydroxypropyl derivatives: An experimental and theoretical investigation

Article abstract of DOI:10.1016/j.molstruc.2013.12.067

When a pesticide is released into the environment, most of it is lost before it reaches its target. An effective way to reduce environmental losses of pesticides is by using controlled release technology. Microencapsulation becomes a promising technique for the production of controlled release agricultural formulations. In this work, the microencapsulation of chlorophenoxy herbicide MCPA with native β-cyclodextrin and its methyl and hydroxypropyl derivatives was investigated. The phase solubility study showed that both native and β-CD derivatives increased the water solubility of the herbicide and inclusion complexes are formed in a stoichiometric ratio of 1:1. The stability constants describing the extent of formation of the complexes have been determined by phase solubility studies. ¹H NMR experiments were also accomplished for the prepared solid systems and the data gathered confirm the formation of the inclusion complexes. ¹H NMR data obtained for the MCPA/CDs complexes disclosed noticeable proton shift displacements for OCH₂ group and H6 aromatic proton of MCPA provided clear evidence of inclusion complexation process, suggesting that the phenyl moiety of the herbicide was included in the hydrophobic cavity of CDs. Free energy molecular mechanics calculations confirm all these findings. The gathered results can be regarded as an essential step to the development of controlled release agricultural formulations containing herbicide MCPA.

Full text of DOI:10.1016/j.molstruc.2013.12.067

Journal of Molecular Structure 1061 (2014) 76–81
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Microencapsulation of herbicide MCPA with native b-cyclodextrin
and its methyl and hydroxypropyl derivatives: An experimental
and theoretical investigation
b
c
b
a,b
Jorge Garrido a,b, , Fernando Cagide , Manuel Melle-Franco , Fernanda Borges , E. Manuela Garrido
⇑
a Departamento de Engenharia Química, Instituto Superior de Engenharia do Porto (ISEP), Instituto Politécnico do Porto, 4200-072 Porto, Portugal
b CIQ, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, 4169-007 Porto, Portugal
c CCTC, Departamento de Informática, Universidade do Minho, 4710-057 Braga, Portugal
h i g h l i g h t s
ꢀ
ꢀ
ꢀ
ꢀ
Microencapsulation of herbicide MCPA with different b-CDs has been investigated.
Formation of the inclusion complexes increased the water solubility of MCPA.
1H NMR data obtained provided clear evidence of inclusion complexation process.
Computer models were used to compare different b-CDs binding affinity for MCPA.
a r t i c l e i n f o
a b s t r a c t
Article history:
When a pesticide is released into the environment, most of it is lost before it reaches its target. An effec-
tive way to reduce environmental losses of pesticides is by using controlled release technology. Microen-
capsulation becomes a promising technique for the production of controlled release agricultural
formulations. In this work, the microencapsulation of chlorophenoxy herbicide MCPA with native
b-cyclodextrin and its methyl and hydroxypropyl derivatives was investigated. The phase solubility study
showed that both native and b-CD derivatives increased the water solubility of the herbicide and inclu-
sion complexes are formed in a stoichiometric ratio of 1:1. The stability constants describing the extent of
formation of the complexes have been determined by phase solubility studies. 1H NMR experiments were
also accomplished for the prepared solid systems and the data gathered confirm the formation of the
inclusion complexes. 1H NMR data obtained for the MCPA/CDs complexes disclosed noticeable proton
shift displacements for OCH2 group and H6 aromatic proton of MCPA provided clear evidence of inclusion
complexation process, suggesting that the phenyl moiety of the herbicide was included in the hydropho-
bic cavity of CDs. Free energy molecular mechanics calculations confirm all these findings.
The gathered results can be regarded as an essential step to the development of controlled release
agricultural formulations containing herbicide MCPA.
Received 20 September 2013
Received in revised form 18 December 2013
Accepted 19 December 2013
Available online 3 January 2014
Keywords:
Phenoxyacetic acid herbicides
MCPA
b-Cyclodextrin
Inclusion complex
Ó 2014 Elsevier B.V. All rights reserved.
1. Introduction
will have to increase by 60% from its 2005–2007 levels [1]. How-
ever, the intensification of production can be associated with sig-
The world’s population is set to grow considerably over the
coming years, albeit at a slower rate than in the past, and with con-
siderable differences across regions [1]. Over the next four decades,
the world’s population is forecast to increase by 2 billion people to
exceed 9 billion people by 2050. Recent FAO estimates indicate
that to meet the projected demand, global agricultural production
nificant negative environmental effects, including groundwater
pollution, soil erosion and a loss in biodiversity. Some 20–40% of
the world’s potential crop production is already lost annually be-
cause of the effects of weeds, pests and diseases [2]. The use of pes-
ticides has been one of the main tools to combat a variety of pests
that could destroy crops and to improve the quality of the food
produced. However, the adverse impacts of these compounds on
the environment and ecosystems cannot be ignored. In fact, pesti-
cides can have a significant negative environmental effect, by con-
taminating soil, surface and ground water, and contribute to a loss
⇑
Corresponding author at: Departamento de Engenharia Química, Instituto
Superior de Engenharia do Porto (ISEP), Instituto Politécnico do Porto, 4200-072
Porto, Portugal. Tel.: +351 228340500.
E-mail address: jjg@isep.ipp.pt (J. Garrido).
0022-2860/$ - see front matter Ó 2014 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molstruc.2013.12.067

J. Garrido et al. / Journal of Molecular Structure 1061 (2014) 76–81
77
in biodiversity. Therefore, the growing concern about environmen-
2.2. Phase solubility studies
tal protection, human health, and food safety has brought renewed
interest in pesticide use in agriculture.
Phase solubility studies were carried out according to the meth-
od described by Higuchi and Connors [16]. Excess amount of MCPA
(25 mg) was added to 7.5 mL of aqueous solutions containing
various concentrations of b-CD (0–9 mM) and (2-hydroxypropyl)-
b-cyclodextrin and methyl-b-cyclodextrin (0–35 mM). Then, the
suspensions were shaken on a rotary shaker at 25 2 °C for 4 days.
After equilibrium was reached, suspensions were centrifuged and
the supernatant was withdrawn and properly diluted. The concen-
tration of MCPA was determined by spectrophotometry (Shimadzu
UV–Vis Spectrophotometer, UV-1700 PharmaSpec, Japan) at
228 nm. The apparent stability constants Ks were calculated from
phase solubility diagrams with the assumption of 1:1 stoichiome-
try according to Eq. (1):
Controlled release formulations give a high promise for enhanc-
ing the efficacy of biological active agents in the agrochemical do-
main, since they can contribute to diminish the harmful effects of
pesticides and to reduce their environmental pollution [3–6]. Con-
trolled release pesticide formulations can maintain the concentra-
tion threshold of the active ingredient which controls the pest in
the soil or plant for longer by releasing it at an appropriate speed,
thereby reducing its level in the environment because lower
amounts or fewer applications are required in order to achieve
the pursued biological effect. Microencapsulation becomes one of
the most important industrial processes used for the production
of controlled release agricultural formulations [7–9]. The main
objective of encapsulation is to protect the core material from ad-
verse environmental conditions, such as undesirable effects of
light, moisture, and oxygen, thereby contributing to an increase
in the shelf life of the product, and promoting a controlled libera-
tion of the encapsulate [10].
Ks ¼ slope=S0ð1 ꢁ slopeÞ
ð1Þ
S0 is the solubility of MCPA in absence of CDs.
2.3. Preparation of the complexes
Cyclodextrins, CDs, are macrocyclic oligosugars most commonly
The preparation of MCPA/b-cyclodextrin (b-CD), (2-hydroxy-
propyl)-b-cyclodextrin (HP-b-CD) and methyl-b-cyclodextrin
(Me-b-CD) inclusion complexes has been performed by a co-evap-
oration procedure as described elsewhere [9]. Briefly, MCPA and
each of the CDs under study (equimolar ratio) were completely dis-
solved in a solution of ethanol and water (v/v = 1:20). The disper-
sion of MCPA in the aqueous CDs solutions was protected from
light and mechanically shaken at room temperature and 100 rpm
in an IKA KS 4000i incubator shaker (IKA, Germany) for 48 h to
achieve equilibrium of the complexation reaction. After evapora-
tion of the ethanol from the reaction mixture, the uncomplexed
MCPA was removed by filtration. The filtrate was evaporated under
reduced pressure in a Büchi Rotavapor (Büchi, Germany) to remove
the solvent and dried in vacuum to give the MCPA/b-CD, MCPA/HP-
b-CD and MCPA/Me-b-CD complexes.
composed of 6, 7, or 8 glucosidic units bearing the names
a-1, b-2
and -3 CD, respectively [11]. Among them, b-CD is receiving
c
increasing attention due its low cost and high capacity to interact
with a wide variety of molecules, including pesticides and drugs.
Chemically modified CD derivatives have been prepared with a
view to extend the physicochemical properties and inclusion
capacity of parent CDs. Cyclodextrins have been used for the
molecular encapsulation in a broad variety of applications, espe-
cially in pharmaceutical and environmental chemistry, because
these types of compounds are very convenient due to their great
variability of molecular shape and molecular properties. CDs, with
lipophilic inner cavities and hydrophilic outer surfaces, are capable
of interacting with a large variety of guest molecules to form
noncovalent inclusion complexes.
As a part of an extended project aimed to validate the applica-
tion of nanotechnology for chlorophenoxy herbicides management
an experimental and theoretical study of the inclusion effect of
native b-CD and its methyl and hydroxypropyl derivatives on the
properties of MCPA (4-chloro-2-methylphenoxyacetic acid) has
been performed. MCPA is in the top five of the most commonly
used pesticide active ingredients in the home and garden sector
in the US and herbicide active ingredients in the EU and still
remain one of the most often used herbicides for rice crops in
Portugal [12,13]. It has been described that the formation of an
inclusion complex between MCPA and CDs increased the aqueous
solubility of this herbicide [9,14,15]. In the present study the
influence of the pattern of substitution and reactivity of different
b-CD on the quality of the interactions and stability of MCPA inclu-
sion complexes is evaluated with the aim to contribute to the
future applications of CDs namely to improve commercial formula-
tion and for environmental protection.
2.4. Physicochemical characterisation of MCPA-CD complexes
2.4.1. UV–Vis spectroscopy
Spectrophotometric measurements were performed to quantify
MCPA in its free and CD-complexed form. Standard curves of MCPA
were prepared in deionised water.
Complete spectrophotometric scans between 190 and 300 nm
were performed to monitor any changes in the UV spectra of the
MCPA. The absorbance maxima of 228 nm, was used to quantify
MCPA concentration.
2.5. Nuclear magnetic resonance studies
1H NMR data were acquired at room temperature and recorded
on a Bruker Avance III operating at 400 MHz. Chemical shifts are
expressed in d (ppm) values relative to tetramethylsilane (TMS)
as internal reference. Chemical shifts changes (
according to the formula d = d(complex)–d(free)
Dd) were calculated
2. Materials and methods
D
.
All NMR experiments were carried out in deuterated water
(D2O), except for MCPA. Owing to MCPA extremely poor aqueous
solubility the spectra was acquired in deuterated methanol
(CD3OD). The proton chemical shifts of MCPA obtained in CD3OD
are quite similar to that found in literature using D2O as
solvent [17].
2.1. Chemicals
MCPA, b-cyclodextrin, (2-hydroxypropyl)-b-cyclodextrin (0.8
molar substitution) and methyl-b-cyclodextrin (1.6–2.0 mol CH3
per unit anhydroglucose) were purchased from Sigma–Aldrich
Química S.A. (Sintra, Portugal). Deuterated solvents and tetrameth-
ylsilane (TMS) were obtained from Merck (Lisbon, Portugal). All
other reagents and solvents were pro analysis grade and used
without additional purification. Deionised water (conductiv-
2.6. Computer modelling
Molecular mechanics simulations were performed in order to
model the effect of the pattern of substitution (functional groups)
ity < 0.1 l
S cmꢁ1) was used throughout all the experiments.

78
J. Garrido et al. / Journal of Molecular Structure 1061 (2014) 76–81
Table 1
in the molecular recognition between MCPA and the different CDs
under study. All calculations were done with the Tinker software
suite [18] with the Optimized Potentials for Liquid Simulations
(OPLS) [19] combined with the TIP3P model for explicit water
[20]. OPLS was chosen as it includes parameters specifically de-
rived for carbohydrates. Implicit solvent calculations were com-
puted with the Generalized Born model augmented with an
accessible Surface Area term (GBSA) [21,22].
Solubility of MCPA (S0), slope (
a), stability constant (Ks) and correlation coefficient
(R2) in the different cyclodextrins.
S0 SDa (ꢂ10-3 M)
a
SDa
Ks SDa (M-1
)
R2
b-CD
HP-b-CD
Me-b-CD
0.00272 5 ꢂ 10ꢁ5
0.00222 4 ꢂ 10ꢁ5
0.00232 2 ꢂ 10ꢁ5
0.30 0.05
0.45 0.03
0.45 0.01
162 12
0.998
0.999
0.998
334
9
398 13
a
Standard deviations were calculated on triplicate trials.
3. Results and discussion
from the straight-line portion of the phase solubility diagrams,
according to the equation previously presented (see experimental).
Stability constants calculated for b-CD, HP-b-CD and Me-b-CD
were 162 12, 334 9 and 398 13 M-1, respectively. As can be
seen, the stability constants calculated for HP-b-CD and Me-b-CD
systems are two fold greater than that obtained for the b-CD indi-
cating that these complexes are more stable. The higher associa-
tion constant values obtained using HP-b-CD and Me-b-CD were
expected considering that the polarity of the substituents of the
host could contribute to the complex formation. Thus less polar
groups like 2-hydroxypropyl or methyl can be more favourable
to the formation of the complex [24].
In aqueous solutions cyclodextrins are able to form inclusion
complexes with many drugs by taking up a drug molecule, or more
frequently some lipophilic moiety of the molecule, into the central
cavity. No covalent bonds are formed or broken during the com-
plex formation, and drug molecules in the complex are in rapid
equilibrium with free molecules in the solution [23].
The physicochemical properties of free drug molecules are dif-
ferent from those bound to the cyclodextrin molecules. Methodol-
ogies that can be used to observe these changes in additive
physicochemical properties may be utilised to determine the stoi-
chiometry of the complexes formed and the numerical values of
their stability constants [23]. These include changes, for instance,
in solubility, UV/Vis absorbance and nuclear magnetic resonance
(NMR) chemical shifts.
3.2. Nuclear Magnetic Resonance analysis (NMR)
Various known methods have been used for the formation of
the inclusion complexes. The selection of the method of prepara-
tion of the inclusion compounds and its effectiveness highly
depends on the nature of the drug and cyclodextrin [9]. The prep-
aration of MCPA/CDs solid systems was performed using the
co-evaporation method.
One-dimensional proton nuclear magnetic resonance spectros-
copy (1H NMR) analysis was employed to verify and characterize
the inclusion of the MCPA in the CDs under study. NMR is a pow-
3.1. Phase solubility studies
The formation of inclusion complexes MCPA/CDs was con-
firmed by UV–Vis spectrophotometry. The stoichiometric ratio
and stability constants were derived from the changes in the solu-
bility of MCPA in the presence of increasing amounts of b-CD, HP-
b-CD and Me-b-CD. The phase solubility plots obtained at 25 °C are
shown in Fig. 1. As can be seen, in all cases AL-type solubility dia-
grams were obtained as the MCPA solubility increased linearly
with the increment of b-CD, HP-b-CD and Me-b-CD concentration,
according to the classification established by Higuchi and Connors
[16]. The diagrams obtained indicate that the solubility of the
MCPA is significantly increased by the presence of the macrocycles.
Table 1 summarizes the MCPA solubility, slope, stability con-
stant and correlation coefficient of the phase solubility diagrams
for the different cyclodextrins under study. Since the slope of the
diagrams is less than 1, the complex stoichiometry was assumed
to be 1:1. The stability constants, Ks, were therefore calculated
erful and simple technique that can be used in the study of the
1
inclusion process of a guest in the hydrophobic cavity of CDs. H
NMR can provide unique structural information about the inclu-
sion of a guest into the cavity of the CDs and the stoichiometry
of the system. Through the proton chemical shift displacements di-
rectly involved in the encapsulation process important information
about the formation of the complexes can be attained [25].
Accordingly, 1H NMR data was acquired to confirm the
formation of the inclusion complexes of the herbicide MCPA with
different types of CDs. The spectra of MCPA, CDs (HP-b-CD and
Methyl-b-CD) and the inclusion complexes (MCPA/HP-b-CD and
MCPA/Methyl-b-CD) are shown in Figs. 2 and 3. The NMR data
related to the MCPA/b-CD complex has been reported in a previous
study [9]. The numbering of the hydrogen atoms faced inside and
outside of the CDs cavity has been ascribed in accordance with
the literature [26].
As the formation of host-guest inclusion complexes induces
variable levels of changes on the chemical shifts (d) of the hydro-
gens either of the ligand or the CD, the chemical displacement of
the proton signals of MPCA/CDs complexes with respect to the na-
tive samples per si (MCPA and the corresponding CDs) have been
determined. The chemical shift data (d) of MCPA and HP-b-CD
before and after the formation of inclusion complex are listed in
Table 2. The upfield shifted proton signals, with respect to the na-
tive compounds, are caused by anisotropic effects and indicate the
presence of host-guest interactions in the CD cavity.
18
16
14
12
10
8
6
4
2
0
0
5
10
15
20
25
30
35
From data analysis one can conclude MCPA protons undergo
upfield displacements in the presence of cyclodextrin, namely H6
and CH2 protons due probably to host-guest interactions. The
previous assumptions are also sustained by the noticeably dis-
placements observed for the H30, H50 and H60 protons of HP-b-CD
[CD] / mM
Fig. 1. Phase solubility diagram for MCPA and increasing concentrations of (d, –)
b-CD, HP-b-CD and Me-b-CD in water at 25 °C. Each point
represents the mean of three determinations.
(
,
)
(
,
)

J. Garrido et al. / Journal of Molecular Structure 1061 (2014) 76–81
79
OR
O
H
6'
H
OH
O
5'
O
2
1
4'
3
4
O
1'
H
RO
2'
H
OR
3'
6
Cl
H
O
5
7
R= H or
OH
Fig. 2. 1H NMR spectra of MCPA, HP-b-CD and MCPA/HP-b-CD inclusion complex.
cavity. This effect could be as well a consequence of the occurrence
of a strong interaction between the host (MCPA) and the guest (HP-
b-CD). In summary the data clearly indicate the insertion of the
aromatic part of MCPA into the CD cavity.
Similar results were obtained for the complex MPCA/Methyl-b-
cyclodextrin. Significant upfield chemical shift variations of proton
signals in the complex with respect to the native compounds have
been also detected (Table 3). Noticeable upfield shift displace-
ments were also observed for OCH2 group and the H6 aromatic
proton of MCPA.
understand the increased solubility/binding of MCPA with func-
tionalized b-CDs.
Two different methylated b-CDs with one and two methyl
groups per anhydroglucose unit have been studied; 7Me-b-CD
[28] and 14Me-b-CD (heptakis (2, 6-di-O-methyl)-b-cyclodextrin)
[29], respectively. In order to calculate the binding energies differ-
ences the free energy of solvation of seven different systems were
computed, namely: MCPA, b-CD, 7Me-b-CD, 14Me-b-CD, MCPA-b-
CD, MCPA-7Me-b-CD and MCPA-14Me-b-CD. Firstly systems were
solvated inside a cubic box of water with ꢃ4 nm side. Secondly, 7
nanoseconds of NPT molecular dynamics simulations were run
with 1 femtosecond time steps at room temperature. The final step
involved analyzing the energetics of snapshot conformations at 1
picosecond intervals with an implicit solvent model. MCPA-7Me-
b-CD and MCPA-14Me-b-CD complexes yielded a 1.8 kcal/mol in-
crease in binding energy with respect to MCPA-b-CD. Entropy
and zero point energy corrections were also calculated but yielded
quite similar values for b-CD and Me-b-CDs and will not be
discussed here. Similar energetics has been obtained in a previous
study of cholesterol complexed with 14Me-b-CD and HP-b-CD [30].
The lowest energy configurations for MCPA-b-CD and MCPA-
14Me-b-CD complexes are represented in Fig. 4. Interestingly, the
The stoichiometry of the complexes has been also determined by
1
comparing the H NMR integration data between the H6 proton in
MPCA and H10 proton of the corresponding CD. For the MPCA/HP-
b-CD and MPCA/Methyl-b-CD complexes a relationship of approxi-
mately 1:7 was obtained corresponding to a 1:1 stoichiometry.
3.3. Computer modelling
Computer models have been extensively used in order to under-
stand inclusion complexes of functionalized and pure b-CDs [27].
Thus, molecular mechanics simulations have been performed to

80
J. Garrido et al. / Journal of Molecular Structure 1061 (2014) 76–81
O
OR
H
OH
O
2
6'
H
1
3
4
O
5'
4'
O
1'
H
RO
6
2'
H
OR
3'
Cl
5
H
O
R= H or Me
7
Fig. 3. 1H NMR spectra of MCPA, methyl-b-CD and MCPA/methyl-b-CD inclusion complex.
Table 2
Table 3
1H NMR chemical shift (d) data of MCPA, HP-b-CD and MCPA/HP-b-CD complex.
1H–NMR chemical shift (d) data of MCPA, Methyl-b-CD and MCPA/Methyl-b-CD
complex.
H
MCPA
HP-b-CD
MCPA/HP-b-CD
Dd
Assignment
(CD3OD)
(D2O)
(D2O)
H
MCPA
Methyl-b-CD
MCPA/Methyl-b-CD
Dd
Assignment (CD3OD)
(D2O)
(D2O)
H3
H5
H6
7.129
7.087
6.761
4.666
–
–
–
–
7.084
7.032
6.648
4.524
2.210
5.064
4.893
3.836
3.693
3.693
3.595
3.438
0.980
ꢁ0.045
ꢁ0.055
ꢁ0.113
ꢁ0.142
ꢁ0.022
ꢁ0.109
ꢁ0.110
ꢁ0.103
ꢁ0.098
ꢁ0.098
ꢁ0.065
ꢁ0.096
0.094
H3
H5
H6
CH2
CH3
H1
H10
CH30
CH3
7.129
7.087
6.761
4.666
2.232
–
–
–
–
–
–
–
–
7.054
7.021
6.619
4.523
2.192
5.074
4.862
3.405
3.219
ꢁ0.075
ꢁ0.066
ꢁ0.142
ꢁ0.143
ꢁ0.040
ꢁ0.156
ꢁ0.151
ꢁ0.116
ꢁ0.131
CH2
CH3
H10
H10
H30
H60
H50
H20
H40
2.232
–
–
–
–
–
–
–
–
–
5.180
5.003
3.939
3.791
3.791
3.660
3.534
1.074
–
5.220
5.018
3.521
3.350
0
0
CH3
resulting complexes. This finding confirms the molecular origin
of the experimental observations.
orientation of MCPA differs: for MCPA-b-CD the carboxylic group
sticks out from the narrower side of b-CD (Fig. 4a) while for
MCPA-14Me-b-CD the carboxylic group points into the opposite
direction (Fig. 4b). Summing up, MCPA flips orientation when
bound to functionalized b-CDs increasing the stability of the
4. Conclusion
The native CDs can be chemically modified by hydroxyalkyla-
tion, alkylation or sulfoalkylation. The principal aim of such
modification is to increase the solubility and safety profile of the

J. Garrido et al. / Journal of Molecular Structure 1061 (2014) 76–81
81
Fig. 4. Molecular models of MCPA (sphere model) inside (a) b-CD and (b) 14Me-b-CD (stick model).
parent native cyclodextrins. In recent years, b-CD has gained
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The high aqueous solubility of modified cyclodextrins such as HP-
b-CD and Me-b-CD allows extension of the applications as the
method of preparation of the inclusion compounds is easier
compared to native b-CD.
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The inclusion complexation behaviour, characterization, and
binding ability of herbicide MCPA with b-CD, Me-b-CD and HP-b-
CD were investigated. The phase solubility study showed that in
all cases b-CDs increased the water solubility of the herbicide
and the inclusion complexes have been formed in a stoichiometric
ratio of 1:1. Stability constants were calculated from the phase sol-
ubility diagrams and indicated the following trend: Me-b-CD ꢄ HP-
b-CD > b-CD. NMR studies were also accomplished for the prepared
solid systems and the data gathered confirm the formation of the
MCPA/HP-b-CD and MCPA/Methyl-b-CD inclusion complexes. The
complex stoichiometric ratio of both systems was of 1:1. Computer
models on functionalized b-CDs showed also an increased binding
affinity for MCPA compared to pure b-CD accounting for these
experimental findings.
This inclusion complexation could be regarded as an important
step in the design of novel formulations of MCPA with enhanced
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Aknowledgments
Financial support from Fundacão para a Ciência e Tecnologia
FCT/MCTES project PTDC/AGRAAM/105044/2008, National Funds
PIDDAC also co-financed by the European Community Fund FEDER
through COMPETE – Programa Operacional Factores de Competiti-
vidade (POFC), is gratefully acknowledged. F. Cagide (SFRH/BPD/
74491/2010) thanks FCT grant. MMF acknowledges support by
the Portuguese ‘‘Fundação para a Ciência e a Tecnologia’’ through
the program Ciência 2008 and contract PEst-OE/EEI/UI0752/2011
and resources from the project SeARCH (Services and Advanced
Research Computing with HTC/HPC clusters) funded under con-
tract CONC-REEQ/443/2005. MMF wished to thank J.W. Ponder
for help with tinker and W.L. Jorgensen for providing us with
recent OPLS parameters.
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Appendix A. Supplementary material
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.molstruc.2013.
12.067. These data include MOL files and InChiKeys of the most
important compounds described in this article.