Materials Chemistry and Physics 132 (2012) 409–415
Contents lists available at SciVerse ScienceDirect
Materials Chemistry and Physics
journal homepage: www.elsevier.com/locate/matchemphys
Polymer nanocomposites for improved drug delivery efficiency
Vallerie H. DeLeon a , Thanh D. Nguyen a , Mangesh Nar b , Nandika A. D’Souza b,∗ , Teresa D. Golden a,∗
a
b
Department of Chemistry, University of North Texas, 1155 Union Circle #305070, Denton, TX 76203, USA
Departments of Mechanical and Energy Engineering/Materials Science and Engineering, University of North Texas, 1155 Union Circle #305310, Denton, TX 76205, USA
a r t i c l e
i n f o
Article history:
Received 12 July 2011
Received in revised form
10 November 2011
Accepted 20 November 2011
Keywords:
Biomaterials
Composite materials
Mechanical properties
Powder diffraction
a b s t r a c t
The drug release rate was studied for an anti-inflammatory drug, ibuprofen, in a modified carrier polymer
matrix. Nanohybrids were synthesized of layered double hydroxide functionalized with ibuprofen. The
ibuprofen was tethered with the layered double hydroxide and blended into the polymer, Poly l lactic
acid (PLLA). Effective weight percentages of 3 and 5% of the nanohybrids were used in the polymer producing nanocomposite films. Corresponding films of 1.2 and 2 wt.% of pure ibuprofen were used in the
polymer. The cumulative drug release rate of the nanocomposite films increased from ∼10% to 60%. The
mechanism for release changed from diffusion control (stage 1) to a mix diffusion/ion-exchange control
(stage 2) for the nanocomposite films. There was an improvement of elastic modulus for the nanocomposite films. These results indicated that nanocomposite films showed a significant improvement over
the non-nanocomposite films.
© 2011 Elsevier B.V. All rights reserved.
1. Introduction
Inflammation following the introduction of medical implants
continues to be a significant problem. Following cardiovascular
surgery such as angioplasty, stent insertion or bypass grafting,
30–50% of surgeries show a 50% or more return to the presurgery state [1]. Drug delivery systems based on polymers have
increasingly been used in biological systems [2]. The use of polymers in drug release films is important due to the ability to
optimize mechanical properties, permeability, and water vapor
transmission [3]. These biodegradable polymers are valuable for
drug control release [4] and as drug vehicles to target specific
tissues or cells in such applications as anti-cancer [5,6], microbial [7], and pain management [8]. Drug release films are also
applicable for treatments which incorporate sutures, stents, tissue
engineering and rapidly dissolving films [3,9]. A large part of the
success of the drug delivery system is attributed to the efficiency
of drug release and sustained long term release has been shown
to improve therapeutic effectiveness [10,11]. Polymers that have
been used in drug delivery vehicles include polyvinyl alcohol [12],
polylactic–polyglycolic acid [13], poly (ethylene oxide) and polycaprolactone [14]. The cumulative drug release reported for these
polymers range from 80% within an hour, to 50% in 36–48 h, and
37% in 24 h [12,13,15].
The robustness of the biodegradable polymers films has been
a concern when trying to increase sustained release times [16].
∗ Corresponding authors. Tel.: +1 940 565 2888; fax: +1 940 565 4318.
E-mail addresses: ndsouza@unt.edu (N.A. D’Souza), tgolden@unt.edu
(T.D. Golden).
0254-0584/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.matchemphys.2011.11.046
Nanoplates mixed in the polymer medium, such as clays and
layered double hydroxides (LDHs), improve mechanical performance by enhancing interfacial area through the dispersion of
the nanoplates in the medium. These nanoplates can either be
cation exchanging or anion exchanging. Layered double hydroxides are valuable pharmaceutical additives that are used as
antacids and anti-peptic reagents [17]. Other additives can form
an LDH hybrid that can efficiently enter cells in time and dosedependent manners. Choy et al. have synthesized various LDH
drug related hybrids. In one study, using a LDH-DNA hybrid
(c-myc antisense oligonucleotide), there was an increased efficacy of 65% on cancer cell growth inhibition compared to the
non-hybrid [18].
LDHs have a stacked layered structure with a general formula
[MII 1−x MIII x (OH)2x ]x+ (An− )x/n ·mH2 O, where MII represents a divalent metal, MIII represents a trivalent metal, and An− represents
an interlayer anion. The individual layers have a brucite-like structure, in which a fraction of the divalent metal is replaced with a
trivalent metal. The replacement gives the layers a positive charge,
and anions are intercalated between these layers to maintain the
electroneutrality [6,7,19,20]. This ability to intercalate anions is
the route to incorporate a range of pharmaceuticals within the
LDHs, further their stacked structure offers environmental protection to the intercalated drug. Controlled and sustained release of the
drug from LDH particles is dependent upon several factors such as
rigidity of the layers, particle size and diffusion path length. The
release of non-steroidal anti-inflammatory drugs (NSAIDs) such
as ibuprofen has been an area of increased interest. The use of
layer double hydroxides intercalated with anti-inflammatory drugs
has been reported by Ambrogi et al. [21,22]. They reported 100%
release over 100 min from a 50% (w w−1 ) ibuprofen intercalated
410
V.H. DeLeon et al. / Materials Chemistry and Physics 132 (2012) 409–415
LDH, which showed improved controlled release compared to
immediate release in commercial ibuprofen tablets.
The dual functionality of decreased cell proliferation and
enhanced mechanical properties by LDH intercalated with nonsteroidal anti-inflammatory drugs such as ibuprofen, make it an
excellent candidate for polymer nanocomposites [23–26]. The
objective of this paper is to compare the efficacy of nanocomposite versus non-nanocomposite polymers as drug release films.
Incorporation of the NSAID into the LDH is first confirmed using
FTIR and XRD. The cumulative drug release and kinetics of the
release of the two architectures are compared. The relative effects
on mechanical robustness are determined for the nanocomposite
and non-nanocomposite films.
2. Experimental
2.1. Chemicals
Poly l-lactic acid (PLLA) was supplied by NatureWorks LLC (MN,
USA) and dried in an oven for 48 h at 35 ◦ C. Dichloromethane
(>99.8% purity, EMD), sodium hydroxide (50% NaOH solution,
Sigma–Aldrich), aluminum nitrate nonahydrate (Al(NO3 )3 ·9H2 O,
Alfa Aesar), zinc nitrate hexahydrate (Zn(NO3 )2 ·6H2 O, Alfa Aesar),
and sodium salt of ibuprofen (isobutyl phenyl propionic acid,
Sigma) were used as received for the synthesis of the nanocomposites.
2.2. Preparation of nanocomposites
To prepare 2 g of 2:1 ratio Zn–Al LDH nitrate, 0.083 M
Al(NO3 )3 ·9H2 O and 0.250 M Zn(NO3 )2 ·6H2 O were dissolved
in 130 ml of deionized water (Millipore MilliQ Academic,
18.2 M cm−1 ) heated to 60 ◦ C. The solution was neutralized with
NaOH to precipitate 2:1 Zn–Al LDH nitrate. The precipitate was then
aged in the mother liquid for 24 h at a temperature between 90 and
100 ◦ C under a nitrogen gas blanket, after which it was allowed to
cool then centrifuged to separate the precipitate. It was washed
two more times with deionized water to remove any remaining
ions from the mother liquid. The crystalline white solid obtained
was LDH NO3 (Zn–Al LDH nitrate).
To intercalate the ibuprofen into the LDH NO3 , a 2:1molar ratio
of the sodium salt of ibuprofen to the LDH NO3 was added in 50 ml
of deionized water. The mixture was stirred under a nitrogen gas
blanket for 1 h before the precipitate was separated and washed
twice with deionized water by centrifugation. This slight excess,
in the place of 1:1, was used to facilitate the anion exchange. The
crystalline white solid obtained was dried in a vacuum oven at 40 ◦ C
and designated as LDH Ibu (Zn–Al LDH Ibuprofen). For every gram
of LDH Ibu, 0.409 g corresponded to Ibuprofen.
The nanocomposites were then prepared by the solution casting route. Initially, the LDH Ibu powder was dispersed in 75 ml of
dichloromethane and stirred for 10 min. Then 3.0 g of PLLA was
added and the mixture was heated at 40 ◦ C with vigorous stirring for
4 h. The resulting dispersion was allowed to age for 24 h. Nanocomposite films were prepared by spin casting and the samples were
dried under vacuum at 35 ◦ C for 2 days to remove any residual
solvent. The LDH Ibu amounts in the polymer corresponded to
effective weight percentages of 3 and 5% nanocomposites, which
are referred to as 3LDH Ibu and 5LDH Ibu, respectively. Polymers
with weight percentages of 1.2 and 2% pure ibuprofen correspond
to the percent of ibuprofen in each nanocomposite respectively (no
LDH) and were used as standards, and are referred to as 1.2Ibu and
2Ibu, respectively or PLLA Ibu as a whole.
2.3. Characterization
FTIR measurements were performed using a Nicolet Nexus 6700
FT-IR spectrometer (Nicolet, USA) having a resolution of 4 cm−1 and
a scan range of 4000–400 cm−1 . A total of 64 scans per sample were
performed.
XRD measurement was conducted on the LDH NO3 , PLLA Ibu
and LDH Ibu samples. For all samples, diffractograms were obtained
with a Rigaku model D/Max–Ultima III X-ray diffractometer (44 mA
and 40 kV). Each sample was scanned from 2◦ to 70◦ (2), with a
step size of 0.05◦ and a dwell time of 1.34 s, using Cu K␣ radiation
( = 1.5405 Å).
Dynamic mechanical analysis (DMA) was done on parent PLLA,
PLLA Ibu, and LDH Ibu samples for their viscoelastic properties with
a dynamic mechanical analyser RSA III (TA Instruments, New Castle,
DE). The tests were carried out in tensile mode. The sample dimensions were 25 mm × 5 mm with mean thickness of 0.15 ± 0.001 mm.
The samples were scanned from −50 to 100 ◦ C at heating rate
of 3 ◦ C min−1 , a frequency of 1 Hz with strain amplitude of 0.25%
(strain was determined from separate strain amplitude sweep at
1 Hz for establishment of linear viscoelastic region). All measurements were done in triplicate.
2.4. Drug release studies
High performance liquid chromatography (HPLC) was used to
study the drug release profiles. The films were soaked in phosphatebuffered solution (PBS) at pH 7.4 and incubated at 37 ◦ C for 10
days to simulate internal conditions and body fluids. Aliquots of
the medium were collected for HPLC analysis on a Thermo SpectraSystem LC. The HPLC conditions were as follows: reverse phase
column, Thermo C18 (150 × 4.6 mm); mobile phase, 60:40 acetonitrile (with 0.1% trifluoracetic acid) in water (pH of 2.55); flow rate of
1.5 ml min−1 ; 20-␮l injection; UV/vis detection at 220 nm. Ibuprofen (Ibu) eluted with these HPLC conditions at a retention time of
3.9 min. The peak areas were used to calculate the concentrations
of ibuprofen released from the films. All samples were measured
in triplicate for statistical analysis. The percent cumulative drug
release was reported.
3. Results
3.1. Ibuprofen incorporation into LDH and polymer
FTIR was used to confirm the nitrate anions exchange with
ibuprofen anions. Fig. 1 shows the FTIR spectra of pure ibuprofen
(Ibu) (A), the LDH NO3 (B), and the LDH Ibu (C). The spectrum of the
pure Ibu (A) shows alkyl stretching peaks around 3000–2800 cm−1 ,
carbonyl stretch at 1703 cm−1 , and the asymmetric and symmetric
RCOO− stretches at 1550 and 1400 cm−1 [21,27]. For the LDH NO3
(B), the peaks around 3380, 1384 cm−1 , and 426 cm−1 in the spectrum indicate the presence of the nitrate interlayer anion and also
confirm the Zn–Al LDH structure, as do the other broad peaks below
1000 cm−1 . The loss of the characteristic nitrate peak (1384 cm−1 )
and the presence of the ibuprofen anion peaks for the LDH Ibu
(C) confirm the replacement of nitrate by the Ibu into the LDH
interlayer. The C–H stretching vibrations at 2962 cm−1 , show the
presence of the methyl group of the ibuprofen, and the absorption
band at 1550 cm−1 corresponds to C C stretch. These results confirm the intercalation of the ibuprofen into the Zn–Al LDH layers
[28,29].
X-ray diffraction was used as well to analyze the anion exchange
of nitrate with ibuprofen. Fig. 2 shows the LDH NO3 and LDH Ibu
diffraction patterns. The as-prepared LDH nitrate has 0 0 1 reflections from (0 0 3) to (0 0 1 5), indicating the crystallinity of the
V.H. DeLeon et al. / Materials Chemistry and Physics 132 (2012) 409–415
411
20000
760
624
1399
1463
(0015)
(0012)
(009)
(009)
(006)
(006)
10000
5000
1514
2962
3435
Intensity (cps)
426
1384
1550
(003)
(003)
587
751
1293
B
C
LDH Ibu
15000
1400
1476
1367
1058
1703
3086
2962
2867
3360
1550
LDH NO 3
3380
Absorbance
A
0
10
20
30
40
Two Theta (degrees)
4000
3500
3000
2500
2000
1500
1000
500
Wavenumber (cm -1 )
Fig. 1. FTIR spectra of (A) sodium salt of ibuprofen, (B) LDH NO3 , (C) LDH Ibu.
material. A d-spacing of 8.9 Å was calculated from the 0 0 1 reflections, this corresponds to a gallery height of 4.1 Å for the nitrate
with a brucite layer of 4.8 Å. When the nitrate anion is replaced
with ibuprofen, the basal spacing expands to 24.7 Å, as calculated
from the 0 0 3 reflection at 2 3.56◦ . This d-spacing increase from
8.9 Å to 24.7 Å confirms the intercalation of ibuprofen between the
layers. An approximate arrangement of ibuprofen between the layers is shown in Fig. 3 showing that the ibuprofen can exist in a
tilted double-layer arrangement within the gallery. The size of the
ibuprofen molecule is ∼11 Å, and the XRD d-spacing increase fits
well with an interpenetrating double-layer arrangement model of
the molecules in the gallery space [30]. Other researchers have
shown with molecular dynamic (MD) simulations similar orientation and geometry in Mg–Al and other LDHs [23,31,32]. They
also found a bilayer arrangement of the ibuprofen within the
Fig. 2. XRD patterns of LDH NO3 and LDH Ibu.
Table 1
Metal and elemental analysis for LDH Ibu in wt.%.
LDH Ibu (experimental)
LDH Ibu (theoretical)
% error
Zn
Al
C
H
N
25.9
26.8
3.3
5.4
5.56
2.9
29.6
31.1
4.8
5.48
5.43
0.9
0.06
0
interlamellar space of the LDH where the ibuprofen anions are tilted
so that the carboxylic groups come closer to the hydroxyl groups
on the brucite sheet.
In addition, metal and elemental analyses for the LDH
Ibu after intercalation is shown in Table 1. When compared to the theoretical percentages derived from the formula
Zn2 Al(OH)6 (C13 H17 O2 )·2H2 O, these amounts suggest a nearly complete exchange of the nitrate for ibuprofen. The negligibly small
amount of nitrogen (0.06%) and the similarity between the
Fig. 3. Representation of intercalation of ibuprofen into the LDH layers. Zn (red), Al (yellow), hydroxide (blue), and Ibu molecule is represented in the center. (For interpretation
of the references to color in this figure legend, the reader is referred to the web version of the article.)
412
V.H. DeLeon et al. / Materials Chemistry and Physics 132 (2012) 409–415
0.4
Intensity (cps)
A
9
PLLA
1.2 Ibu
3 LDH
4.50x10
PLLA
1.2 Ibu
3 LDH
0.3
9
3.00x10
E'
Tan (delta)
2Ibu
0.2
9
1.50x10
0.1
1.2Ibu
0.00
A
0
10
20
30
20
40
60
0.0
100
80
o
Temperature ( C)
40
Two Theta (degrees)
9
6.0x10
PLLA
2 Ibu
5 LDH
B
P
0.3
9
4.0x10
0.2
I
I
E'
P
P
5LDH Ibu
9
2.0x10
Tan(delta)
Intensity (cps)
(003)
PLLA
2 Ibu
5 LDH
0.1
0.0
I
B
3LDH Ibu
0
20
30
Two Theta (degrees)
Fig. 4. (A) XRD patterns of 1.2 and 2 wt.% ibuprofen loaded into the polymer with
no LDH and (B) XRD patterns of 3 and 5 LDH Ibu nanocomposites (P – polymer PLLA,
I – ibuprofen).
theoretical and observed percentages show successful exchange
and intercalation.
XRD measurements of the PLLA with ibuprofen only are shown
in Fig. 4A. The XRD pattern shows a broad amorphous peak
superimposed by two crystalline peaks at 16.73 and 19.1 ◦ 2theta
corresponding to the polymer in the 1.2Ibu and 2Ibu films. Ibuprofen alone has been mixed into other biodegradable, biocompatible
polymers and copolymers (ex. PEG, PLA, PCL, PLGA) with a range of
30–60% drug release [33–35]. Drug burst release is a major problem
with ibuprofen-loaded polymers, however, nanopolymeric loaded
ibuprofen decreases drug burst release [33–35]. For our nanocomposites, XRD measurements were also conducted on the LDH Ibu
nanocomposites in order to study the dispersion of the LDH Ibu
in the PLLA matrix. When 3 and 5% of the LDH Ibu was dispersed
in the PLLA matrix, there was a slight additional gallery spacing
increase for the 5LDH Ibu, resulting in a shift to lower 2 of the
(0 0 3) reflection peak and increased d-spacing as shown in Fig. 4B
and Table 2.
Table 2
XRD parameters measured from the (0 0 3) reflection peak of LDH nitrate, LDH Ibu
and 5LDH Ibu.
Sample
2 (◦ )
d (Å)
FWHM
LDH nitrate
LDH Ibu
5LDH Ibu
9.88
3.56
3.32
8.39
24.76
26.59
0.28
0.69
0.62
40
60
80
0.0
100
o
Temperature ( C)
40
Fig. 5. (A) Storage modulus E (open markers) and loss factor tan ı (solid markers)
curves of the PLLA, 1.2Ibu and 3LDH Ibu and (B) storage modulus E (open markers)
and loss factor tan ı (solid markers) curves of the PLLA, 2Ibu and 5LDH Ibu.
3.2. Dynamic mechanical analysis (DMA)
Fig. 5 shows the relaxation spectrum in terms of storage modulus (E ) and the loss tangent (tan ı) versus temperature at the
frequency of 1 Hz for the virgin PLLA, the non-nano and nanocomposite films. E represents the stiffness of a viscoelastic material and
is proportional to the energy stored during a loading cycle. On the
80
% Cumulative Drug Release
10
20
70
60
50
1.2Ibu
2Ibu
3LDH Ibu
5LDH Ibu
40
30
20
10
0
0
10
20
30
40
50
Time(Hours)
Fig. 6. Drug release profiles of 1.2Ibu, 2Ibu, 3LDH Ibu, and 5LDH Ibu films.
V.H. DeLeon et al. / Materials Chemistry and Physics 132 (2012) 409–415
413
Table 3
Thermal properties of the cooling and second heating of PLLA, 1.2Ibu, 2Ibu, 3LDH Ibu and 5LDH Ibu from DSC results and Tg from DMA.
Sample
Tg DMA
(◦ C)
Tg DSC
(◦ C)
Cp (J g−1 ◦ C)
Tcc (◦ C)
Hcc (J g−1 )
Tm (◦ C)
PLLA
3LDH Ibu
5LDH Ibu
1.2Ibu
2Ibu
32
45
45
60
60
54.3
43.9
40.1
52.0
48.8
0.674
0.397
0.386
0.465
0.481
125.7
99.1
94.0
97.4
91.1
−37.3
−33.8
−30.0
−38.9
−40.1
–
152.0
145.3
151.2
144.9
other hand, tan ı is defined as the ratio of loss modulus E to storage modulus (E /E ). It is a measure of the energy lost, expressed
in terms of recoverable energy, and represents mechanical damping or internal friction in a viscoelastic system. Fig. 5 shows the
results of the E -temperature of the samples. The glassy modulus
of the films containing ibuprofen are higher than the unmodified
PLLA film. E increases even more with the addition of the LDH, the
nanocomposite films have a higher modulus than the PLLA and nonnano films. PLLA has a glassy modulus at −40 ◦ C of 2.63 GPa while
the 3LDH Ibu and 5LDH Ibu have values of 3.97 and 4.52 GPa, respectively. This indicates a 50–70% increase in modulus. Table 3 shows
the DSC results for the various samples. The glass transition of the
non-nano and nanocomposite films are higher than that of PLLA
as extracted from the temperatures corresponding to the peak tan
delta (Fig. 5). There is no effect of concentration on the glass transition temperature. Ibuprofen appears to retard the chain mobility
of the PLLA but when the ibuprofen is tethered from the nanoclay,
the combination is less effective in decreasing the glass transition
of the PLLA. Crystallinity of the non-nano and nanocomposite films
are higher than that of PLLA.
Tmc (◦ C)
Hmc
(J g−1 )
39.5
54.0
51.2
47.7
53.1
29.3
41.2
39.9
35.3
39.3
–
96.7
98.1
98.7
95.5
–
−10.1
−11.2
−2.7
−4.7
(1) The parabolic diffusion model describes the diffusioncontrolled release of a drug from the medium and is generally
expressed as:
1 − Mt /Mo
t
= kd t −0.5 + a
(2) The modified Freundlich model explains experimental data
on ion exchange and diffusion-controlled processes and is
expressed as:
Mo − Mt
= km t b
Mo
(3) The Elovich model describes the adsorption of surrounding
anions on clays (such as phosphates in solution and the release
of Ibu) and for release is written as:
7.3
1.2Ibu
2Ibu
3LDH Ibu
5LDH Ibu
7.2
pH
The control release of the Ibu from the nanocomposite was also
studied with HPLC (Fig. 6). Standard solutions of PBS were used to
create a calibration curve of peak area versus concentration. Then
the measured concentrations of ibuprofen released from the films
were used to find the percent cumulative drug release over time.
This technique measures the amount of drug being released from
a film and the curves obtained can be used to study how the drug
interacts with the film and medium.
The amount of LDH Ibu loaded into PLLA corresponds to the
effective weight percentages of 3 and 5% LDH Ibu, which are
referred to as 3LDH Ibu and 5LDH Ibu, respectively. As a comparison and to test the performance of the LDH, comparative
amounts of pure ibuprofen only were loaded into PLLA with
weight percentages of 1.2 and 2% ibuprofen, which are referred
to as 1.2Ibu and 2Ibu, respectively. The ibuprofen drug release
profiles are shown in Fig. 6. For the nanocomposites, the drug
release followed a conventional two-stage elution profile, with
a quick release (the first 15 h) followed by a slower release (up
to 50 h). The non-nano films only showed some dissolution of
the ibuprofen from the polymer film at very short times (<5 h)
and then a flat profile. This dissolution of the ibuprofen at very
short times for the polymer film was probably due to release of
the drug absorbed on the surface. The percent cumulative drug
release increase with the amount of ibuprofen in the nanocomposites: 5LDH Ibu > 3LDH Ibu. Thus, LDH works synergistically to
strengthen PLLA while facilitating drug release. A slow, more controlled release is obtained by incorporating the ceramic component,
LDH, into the polymer allowing a mixture of diffusion and ionexchange.
The films were soaked in phosphate-buffered solution (PBS)
at pH 7.4 and incubated at 37 ◦ C for 10 days to simulate internal conditions and body fluids. The pH of the solutions was
c (%)
taken before aliquots of the medium were injected into the HPLC
at pre-determined time intervals and plotted in Fig. 7. For the
nanocomposite films, the pH of the solutions matches the twostage elution profile of the cumulative drug release profile, where
the pH increases within the first 10 h then drops (indicating a quick
release of Ibu into solution), and then slowly decreases over a longer
period of time (indicates the slower release after 15 h) and finally
reaches an equilibrium pH. However, for the PLLA Ibu (without
LDH), the initial pH drops due to residual Ibu associated with the
surface of the film and shows no sign of continued release (indicating dissolution of the Ibu from the polymer surface as indicated in
Fig. 6).
First order, parabolic diffusion, modified Freundlich, and Elovich
kinetic models were utilized to study the release kinetics of the
ibuprofen release from the nanocomposites [36,37].
3.3. Drug release studies
164.2
161.0
156.4
161.0
156.9
Hm
(J g−1 )
7.1
7.0
6.9
0
30
60
90
120
150
Time (Hours)
Fig. 7. pH trends for 1.2Ibu, 2Ibu, 3LDH Ibu, and 5LDH Ibu films soaked in PBS
medium over 144 h.
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V.H. DeLeon et al. / Materials Chemistry and Physics 132 (2012) 409–415
B
0.00
-0.15
log(1-(M t /M 0 ))
0.8
(1-(M t /Mo ))/t
A
1.2Ibu
2Ibu
3LDH Ibu
5LDH Ibu
1.0
0.6
0.4
0.2
-0.30
1.2Ibu
2Ibu
3LDH Ibu
5LDH Ibu
-0.45
0.0
-0.60
0.2
0.4
0.6
0.8
1.0
0.0
0.4
0.8
1.2
1.6
log(t)
-0.5
t
C
1.0
1-(Mt /M o )
0.8
0.6
1.2Ibu
2Ibu
3LDH Ibu
5LDH Ibu
0.4
0.2
0
1
2
3
4
ln(t)
Fig. 8. Parabolic diffusion model (A), modified Freundlich model (B), and Elovich model (C) for 1.2Ibu, 2Ibu, 3LDH Ibu, and 5LDH Ibu films.
1−
M t
Mo
= ke ln(t) + b
In the above equations, Mo is the initial concentration of Ibu in
the film, Mt is the concentration at some time (t), k is the corresponding release rate constant, and a and b are some constants not
clearly resolved [37,38].
The different dissolution-diffusion kinetic models were applied
and the corresponding linear correlation coefficients (R2 ) and
release rate constants (k) are reported in Table 4. The first order
is not observed here due to poor linear correlation and complexity
of the system. Because the drug release profiles show a two-stage
release for each model, the samples were split into stage I (<12 h),
stage II (>12 h), and total overall release.
Parabolic diffusion (Fig. 8A), a diffusion-controlled release
model, overall best describes the non-nano samples with release of
the ibuprofen from the surface of the polymer film. It also describes
the first stage of the two-stage drug elution profile for the nanocomposite films. Stage I of the parabolic diffusion model showed similar
values for R2 and k trends for all samples with the slope increasing with higher percentages of ibuprofen and 0.97–0.98 linear
correlation. In stage II the non-nano has steeper slopes than the
nanocomposites and overall the non-nano has greater k constants
and better linear correlation values compared to the nanocomposites.
Modified Freundlich (Fig. 8B) and Elovich (Fig. 8C) models
account for both diffusion and ion-exchange controlled release and
best describes the overall drug release from the nanocomposite
films with R2 of 0.91–0.95. However, the Elovich model fits the
total release best (R2 = 0.94–0.95) because it accounts for release
over an exponential time (t). These models fit poorly for the nonnano films and stage I of the nanocomposites with R2 values
between 0.80 and 0.88, indicating that stage I is diffusion controlled. The non-nano films have zero valued slopes and negligible
R2 since there is no release mechanism after the initial dissolution of the Ibu from the surface. The PLLA alone does not release
the ibuprofen very well, so the addition of the LDH is important.
Nanocomposite films have good linear correlation in stage II with
R2 = 0.95–0.99, confirming that ion-exchange dictates the release
mechanism in stage II for these nanocomposite films. The LDH layers protect the ibuprofen allowing a slow, more controlled release
obtained by incorporating the ibuprofen into the ceramic component, LDH, rather than directly into the polymer. Ibuprofen is
protected by the LDH layers which allows water and counter ions
inside the matrix giving a mixture of diffusion and ion-exchange
mechanism.
Relating this data to the nanocomposites, there can be heterogeneous diffusion from the flat surface via ion exchange as well
as short diffusion paths within the LDH [39]. The data suggest the
release of ibuprofen is a mixture of diffusion and ion-exchange,
with the initial fast rate of release due to the diffusion of the
absorbed drug from the surfaces of the LDH into the solution and
the longer release due to ion-exchange of the ibuprofen. This indicates that both cumulative drug release and kinetics are improved
by extending the release time period using these nanocomposite
films.
−0.1969
1.0345
0.94
−0.1424
0.8314
0.95
Ibuprofen was successfully intercalated into inorganicbiodegradable polymer composites of LDH and PLLA. Cumulative
drug release was significantly improved from the nanocomposite
architecture. Drug release studies showed a two-stage mechanism
for release of the ibuprofen from the nanocomposite films, but
a single staged release from the non-nano. The LDH works synergistically to strengthen PLLA while facilitating drug release. At
shorter times periods (<5 h), the drug is released by diffusion, while
ion-exchange predominates at longer time periods. Ibuprofen can
intercalate into LDH by an ion-exchange mechanism, maximizing
therapeutic activity while minimizing toxic side effects.
Acknowledgment
The authors acknowledge support for aspects of this work by
the National Science Foundation (Grant CHE-0840518).
−0.0150
0.9774
0.62
−0.14685
0.9948
0.87
−0.1331
0.9013
0.97
References
Note. I, stage I (hours 0–12 h); II, stage II (after 12 h); T, total release.
0
0.9355
–
−0.0273
0.9929
0.88
−0.0206
0.9929
0.71
0
0.9321
–
−0.0327
1.0085
0.85
Elovich
ke
b
R2
415
4. Conclusions
−0.1623
1.0119
0.95
−0.1725
1.0080
0.85
−0.3442
0.91
−0.3996
0.98
0
–
Modified Freundlich
−0.0339
km
R2
0.85
−0.0214
0.71
−0.0283
0.88
0
–
−0.0157
0.62
−0.1901
0.83
−0.2909
0.99
−0.2523
0.93
−0.2338
0.80
1.1067
−0.2722
0.92
0.2048
−0.0245
0.94
1.3040
−0.4009
0.97
0.2395
−0.0273
0.96
1.2960
−0.3933
0.97
1.1387
−0.2526
0.93
0.3668
−0.0342
0.98
1.3250
−0.3744
0.97
1.1889
−0.2266
0.97
0.5402
−0.0625
0.86
II
1.1042
−0.2663
0.92
II
I
Parabolic diffusion
1.2931
kd
a
−0.2941
R2
0.98
3LDH Ibu
T
II
2Ibu
I
I
T
1.2Ibu
Table 4
Variables and correlation values from dissolution equations for samples 1.2Ibu, 2Ibu, 3LDH Ibu and 5LDH Ibu.
I
II
T
5LDH Ibu
T
V.H. DeLeon et al. / Materials Chemistry and Physics 132 (2012) 409–415
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