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R. Cheng et al. / Polymer 68 (2015) 246e252
Table 1
Parameters for preparing hydrogels.
Hydrogels
NAA (mmol)
C18 (mmol)
BIS (mmol)
K2S2O8 (mmol)
NAA/C18/BIS (in mmol)
HG-0a
HG-1
HG-2
HG-3
4
4
4
4
0.6
0.2
0.4
0.6
0
0.04
0.04
0.04
0.04
10/1.5/0
10/0.5/0.5
10/1/0.5
0.2
0.2
0.2
10/1.5/0.5
a
No hydrogel was formed.
each sample and the average swelling ratio was accordingly
obtained.
[31,32]. The release tests were repeated for three times to obtain
average values.
2.6. pH responsivity of hydrogels
3. Results and discussion
The swelling behaviors of the hydrogels at different pH were
studied as follows. A piece of a dry hydrogel was immersed in
deionized water with pH 12 for 2 h. The weight of the swollen
hydrogel was recorded and the sample was immersed in deionized
water with pH 7 for another 2 h. The weight of the swollen hydrogel
was recorded again. Then, the sample was immersed alternately in
deionized water with pH 2 and pH 12 and weighed. In this process,
the pH of the solution was adjusted with NaOH and HCl aqueous
solutions. The measurement was repeated for 3 times for each
sample and the average value was accordingly obtained.
3.1. Preparation of the hydrogels
The synthesis of chiral, pH-responsive hydrogels with adjustable
cross-linking density was the primary purpose in the present study,
and it was also expected that the prepared hydrogels could show
enantio-differentiating release capability for chiral drugs. The ma-
jor preparation procedure is illustratively shown in Scheme 1. The
hydrogel networks were formed by free radical copolymerization of
hydrophilic monomer NAA and hydrophobic monomer C18 emul-
sified by SDS, by using K2S2O8 as initiator and BIS as chemical cross-
linking agent. In our earlier study, we noticed that the swelling ratio
of the hydrogels constructed by PNAA and hydroxypropyl-®-
2.7. Enantio-differentiating release of proline
cyclodextrin (HP-b-CD) was too large, which led to fragile hydrogels
after swelling [25]. In the hydrogels prepared in the present study,
the hydrophobic regions formed by C18 provided physical cross-
linking effects, and correspondingly led to the decreased swelling
ratio of the hydrogel. PNAA chains provided chirality and pH-
Referring to our early studies [28,29], enantio-differentiating
release of proline in deionized water was conducted in two
different modes: simultaneous release and separate release. In the
first mode, a certain amount of racemic proline enantiomers was
added in the polymerization system before adding initiator to
prepare the hydrogel containing racemic proline enantiomers. The
thus-obtained hydrogel was immersed in water (20 ml) and the
optical rotation of the outer solution was measured by a polarim-
eter. The concentration of the outer solution at different intervals
was determined based on optical rotations. The difference between
proline enantiomers released out of hydrogel was determined by
calculating the ratio of the weight of the difference released to the
weight of the enantiomers initially added. In the second one,
responsivity, since NAA derived from
chloride.
L-alanine and acryloyl
The strategy illustrated in Scheme 1 proved to be highly effec-
tive, providing hydrogels simultaneously showing pH re-
sponsibility and optical activity. The hydrogels also demonstrated
the expected enantio-differentiating release ability. All these in-
vestigations will be stated below.
Four hydrogels were designed mainly by changing the amount
of the hydrophobic monomer C18, by which to adjust the physical
crosslink regions in the obtained hydrogels. Table 1 shows the
specific formulae for preparing the hydrogels. Among the four
samples, HG-0 was prepared in the absence of BIS, and only formed
a sticky liquid rather than bulk hydrogel. It demonstrates that
physical crosslinking itself was too weak to provide hydrogels.
Namely, chemical cross-linking is still required to form hydrogels.
HG-1, HG-2 and HG-3 all formed hydrogels in quantitative due to a
reasonable combination of physical crosslinking regions derived
from C18 and chemical crosslinking formed by BIS.
release of L- or
only difference is that L- or
enantiomers was added in the reaction system to obtain the
hydrogel containing -proline or -proline. All the release tests
D-proline was performed in the same way, and the
D-proline instead of racemic proline
L
D
were repeated for three times, and the corresponding average value
was determined.
2.8. Enantio-differentiating release of racemic ibuprofen
The FT-IR spectrum of HG-1 is taken as the representative and
illustrated in Fig. 1. The spectra of NAA and C18 are also presented
for a clear comparison. Compared to the spectra of the two control
samples, the characteristic bands of C18 at 2934, 2885 cmꢁ1 (CeH),
1731 cmꢁ1 (eC]O) and the characteristic bands of NAA at 1652,
1559 (amide, eC(O)Ne) and 1731 cmꢁ1 (acid, eC]O) can be found
clearly in the spectrum of HG-1, demonstrating the successful for-
mation of the hydrogel. In addition, the peak around
1600 cmꢁ1 (C]C in both NAA and C18) vanished in HG-1, indicating
that no monomer remained in the hydrogel.
Ibuprofen (IBU), as a drug model, was also chosen to investigate
enantio-differentiating release of the chiral hydrogels in phosphate
buffered saline (PBS, pH ¼ 7.4). The PBS solution was prepared by
mixing 250 ml of 0.1 M KH2PO4 and 195.5 ml of 0.1 M NaOH
aqueous solutions. The hydrogel with racemic IBU was prepared by
adding 0.05 g racemic IBU dissolved in NaOH aqueous solution into
the polymerization system. The enantio-differentiating release of
racemic IBU in PBS was measured by polarimeter, and the total
release amount of racemic IBU was determined using UVevis
spectroscopy. UVevis spectra were measured as follows [30].
Firstly, UVevis absorption of the IBU solution in PBS (0.01/20 g/ml)
was measured as the reference. The IBU-loaded hydrogel (0.7066 g)
was placed in 20 ml PBS, and the UVevis absorption of the outer
solution was measured at 1 h interval from 1 h to 8 h. Herein, the
3.2. Swelling ratios of hydrogels
The swelling behavior of hydrogels is closely correlated with
their cross-linking density. Fig. 2 shows the swelling ratios of the
three hydrogels (HG-1, HG-2, and HG-3) as a function of swelling
UVevis absorption at
l
¼ 265 nm (the maximum absorption of
ibuprofen) was adopted to calculate the released IBU amount