SI- Table 1. Selected physicochemical properties of p-type pharmaceutical chemicals
used in this study*
p-type chemical Structure
Hazardous
Molecular
Water
waste
weight
solubility
162.26
Completely
pKa
logKow
8.5
1.2
number
Nicotine
P075
miscible
Epinephrine
P042
183.2
0.01g/100mL 8.28
2.59
at 18C
Physostigmine
P204
275.34
1.33 g/100mL 6.12
at 20C
* D.V. Sweet, 1997, Registry of Toxic Effects of Chemical Substances (RTECS) - Comprehensive Guide
to Their RTECS. U.S. Department of Health and Human Services, National Institute of Occupational
Safety and Health, Cincinnati, Ohio 45226.
1.6
SI Computer Simulations
Combinatorial Screening of Polymer precursors for preparation of p-type
chemicals imprinted polymer
To understand nature of interactions between p-type chemicals and the polymer
adsorbents, Dell ™ Precision T7500 Workstation was used to run the software
Gaussian 4.21 (Gaussian, Inc. Willingford CT, USA). The steps followed for
prediction of binding nature in pre-polymer complex:
i.
2-D chemical structures of the functional monomer (itaconic acid), templates
(nicotine, epinephrine and physostigmine) and cross-linking monomers
(EGDMA) were prepared, then using molecular builder option 2 D structures
were converted to 3-D structures.
ii.
The geometric optimization was carried out on the semi-empirical (SE)
quantum mechanical approach (PM3 method) to obtain optimized energy
structures with aid of Polak – Ribiere algorithm until the root mean square
gradient was 0.01; which is the acceptable in molecules optimization.
iii.
The binding energy of monomer-template complexes were computed on
Haltree-Fock (HF) method with 6-31G basis set in a virtually created 18.6Ǻ
solvent (water) box. The minimum binding energies between the optimized
conformations of 1: 1 ratio of template–monomer complexes was computed.
The interaction energy between a pair of molecules in the solvent box was
calculated according to following equation:
E = E (T-F-X complex) –
E(T)(F)(X)
SI-2
where E, binding energy and E interaction energy are in kcal/mol; T,
template (p-type chemical); F, functional monomer (itaconic acid) and X,
cross linking monomer (EGDMA)
iv.
This step was further extended to determine template accommodation
potential of the functional monomer using confirmation optimization the most
stable template–monomer complexes based on interaction energy scores.
For preparation of the imprinted polymer an appropriate functional monomer is very
importance to have high affinity for the template. The functional monomer suitable to
template p-type chemicals; where nicotine was selected as the model molecule and
then the virtual library of functional monomers by computing the interaction energies
nicotine and functional monomers. The software Gaussian 4.21 ver. was used in PM-3
semi-empirical mode, and the computed energies are given in Table SI.1.
Table SI-1: Interaction energies for functional monomer and nicotine
Functional Monomers
Interaction Energy
(E) kcal/mol
1-vinylimidazole
-0.026
2-vinylpyridine
-0.016
4-ethylstyrene
-0.036
4-vinylpyridine
-0.017
acrylamide
-0.075
acrylamido-2-methyl-1-propane- sulphonic acid
0.046
acrylic acid
-0.088
acrylonitrile
0.103
SI-3
Itaconicacid
-0.512
Methacrylamide
0.082
Methacrylic acid
-0.099
Methyl Methacrylic acid
-0.033
N-(2-aminethyl)-methacrylamide
-0.084
p-vinylbenzoic acid
0.014
Styrene
-0.072
trans-3-(3-pyridyl)-acrylic acid
0.041
Trifluoro methacrylic acid
0.266
Urocanic ethyl ester
0.133
Interaction energy is the measure of monomer-template stability. The monomer with
high interaction energy tends to have stable pre-polymer complex of nicotine and
functional monomer. Such complexes result in covalent imprinted polymers and from
these polymers removal of template after rebinding will be difficult
[43]
. Monomers
with lower interaction energies were preferred for creation of non-covalent imprint
polymers. These non-covalent imprinted polymers have reasonable binding capacity
and excellent molecular recognition properties. Nuclear magnetic resonance (NMR)
studies on nicotine in literature have indicated that nicotine is capable of interacting
with MAA
[1]
. Based on computer simulations carried out in this study, two
monomers namely itaconic acid (IA) and methacrylic acid (MAA), were chosen based
on interaction energies for preparation of nicotine MIPs. From the computationally
derived best functional monomers, a suitable cross-linker was selected following
similar procedure discussed above. Interaction energies between template-monomer
SI-4
complex and cross-linker given in the results indicated that EGDMA and TRIM could
form less interaction with itaconic acid and MAA (Fig.SI.1).
Table SI-2: Interaction energies for cross-linkers
Interaction
Energy
Template /Monomer
Cross-linker
(E)
kcal/mol
Ethylene glycol dimethacrylate (EGDMA)
-0.937
Pentaerythritol tetraacrylate (PETEA)
-0.668
Pentaerythritol triacrylate (PETRA)
-0.805
Trimethylpropane trimethacrylate (TRIM)
-0.914
Ethylene glycol dimethacrylate (EGDMA)
-0.176
Pentaerythritol tetraacrylate
-0.005
Pentaerythritol triacrylate (PETRA)
-0.019
Trimethylpropane trimethacrylate (TRIM)
-0.381
Nicotine/ Itaconic acid
Nicotine/Methacrylic acid
SI-5
a)
b)
Fig.SI.1. HyperChem simulated interactions between nicotine and (a) itaconic
acid and (b) methacrylic acid
Thus EGDMA was selected as best cross-linker for nicotine-itaconic acid MIP while
TRIM for nicotine-methacrylic acid MIP. In general, cross-linking monomer
calculations are 5 times more than functional monomer and hence cross-linking
monomer shows dominant role in forming 3D architecture of the binding site in
imprinted polymers. Here the interaction between cross-linker and functional
monomer-template is very crucial to decide binding site properties such as covalent or
non-covalent type imprints and the blend of cross-linker also provides physical
strength and feudality to the polymer architecture.
In non-covalent imprinting process, the formation of template-monomer complex is
very important for the MIP to have better capacity and selectivity. The formation of
Nic-IA and Nic-MAA complexes is the key step in preparation of MIP selective for
nicotine. Solvent that interacts strongly with nicotine leads to weaker Nic-IA or NicMAA complexes formation. The interaction energies (ΔE) of nicotine in different
solvent were calculated to characterize the strength of their respective interaction with
the solvent. The solvent of strong affinity to the template molecule have potential to
hinder the formation of hydrogen bond network between the template and the
monomer [133]. Nicotine interaction with monomers was optimized in various solvents
and interaction energies were computed. Similarly computations were carried out on
SI-6
itaconic acid as well as methacrylic acid which were used as monomers. Table SI-3
represents the interaction energies of nicotine, itaconic acid and methacrylic acid
studied with various solvents in virtual solvent environment of Hyperchem8.0
software.
Table SI-3: Computational selection of solvent for nicotine imprinting
Interaction energies ΔE (Kcal/mol)
Solvents
Dielectric Polarity
constant Index
Nicotine
Itaconic
acid
5.8
1221366.65
-2558281.96 -2552099.28
Dichloromethane 8.9
3.1
-642229.52
-1607760.84 -1609089.61
Chloroform
4.8
4.1
6955.787
6873.171
6125.551
Toluene
2.38
2.4
52399.45
32798.023
41205.288
Acetonitrile
37.5
Methacrylic
acid
Based on the interaction energy criteria two of the solvents were selected for the
preparation of nicotine MIPs. The amount of solvent used for synthesis also affects
the imprinting process. Low volume of solvent used causes the polymer to precipitate
early and would not form good MIP. A high volume of solvent would dilute the
solution and cause defects in the imprinting site. The optimized volume of solvent
used was 5ml. It has already been studied that MIP resulted from synthesis with a
volume of solvent below 5ml, the adsorption capacity of polymers decreases with
decrease in volume of solvent and at high volume above 5ml the adsorption capacity
decreases with increase in volume of solvent.
SI-7
Fig. SI.2: Initiation of polymerization
The termination of polymerization may take place by combination, disproportionation
and chain transfer. Nitrogen purging is very important for chain termination to occur
since the presence of oxygen can initiate another chain somewhere else along the
length of the polymer[3]. Nicotine forms hydrogen bonds with carboxyl groups in
methacrylic acid and Itaconic acid. The interaction takes place between basic
pyrrolidine-N and pyridine-N of nicotine and carboxyl groups in the monomers.
[4]
,
this is represented in the Fig SI-3. These interactions between nicotine and IA and
MAA simulated in Gaussian 4.21 ver. were depicted in Fig SI-4. Along with nicotine
MIPs, non-imprinted polymers (NIPs) were prepared to compare polymer capacity
and selectivity. The nicotine MIPs formed were colored with yellow while the nonimprinted polymers were colorless.
SI-8
Fig.SI.3: Schematic representation of nicotine imprinting using methacrylic acid
as functional monomer
1
2
Fig.SI.4: Schematic representation of the molecular imprinting of nicotine
showing binding cavity dimensions and functional groups orientation
SI-9