ARTICLE pubs.acs.org/Langmuir
Flurbiprofen Encapsulation Using Pluronic Triblock Copolymers Shirin Alexander,*,† Terence Cosgrove,*,† Stuart W. Prescott,† and Thomas C. Castle‡ † ‡
School of Chemistry, University of Bristol, Bristol BS8 1TS, United Kingdom Revolymer Ltd., Dock Road, Mostyn, Flintshire CH8 9HE, U.K. ABSTRACT: Pulsed-field gradient stimulated-echo nuclear magnetic resonance (NMR) and surface tension measurements have been used to study the effect of drug addition on the micellization behavior of pluronic triblock copolymers (P103, P123, and L43). The addition of 0.6 wt % flurbiprofen to Pluronic P123 and P103 solutions reduced their cmc and promoted micellization. Also, a substantial increase in the hydrodynamic radius of Pluronic P103 from 5 to 10 nm was observed, along with an increased fraction of polymer micellized, demonstrating that the polymers solubilize this nonsteroidal anti-inflammatory drug.
1. INTRODUCTION The low solubility of highly hydrophobic drugs for oral dosage forms has been challenging, and different strategies have been applied in order to increase the adsorption and bioavailability of these drugs.1,2 Among those, water-soluble amphiphilic copolymers have been widely used to encapsulate and increase the aqueous solubility of poorly water-soluble drugs. Here, we demonstrate that amphiphilic triblock copolymers are able to solubilize a sparingly water-soluble drug, and by investigating the degree of encapsulation, we can estimate the maximum drug loading that is possible. Pluronic triblock copolymers, in particular, appear to have substantial potential as vehicles for controlled drug release and, above all, for the encapsulation of hydrophobic drugs. Pluronics are nonionic triblock copolymers with a central block of poly(propylene oxide) (PPO) and end blocks of poly(ethylene oxide) (PEO): [PEO-PPO-PEO]. Studies have shown that the micellization of pluronic polymers is highly temperature- and concentration-dependent.3,4 At low temperature and low polymer concentration, no micelle formation has been observed because of the solubility of both blocks in water, and the pluronics are present as unimers. However, with increasing temperature and polymer concentration, micelles are created5 because of the increasing hydrophobicity of the PPO blocks.68 The hydrophobic core of PPO then is able to accommodate and subsequently transport the hydrophobic drug molecules within the body, stabilized by the hydrophilic blocks of PEO.912 In this context, it is important to understand the behavior of the pluronic micelles in the presence of hydrophobic drugs. The effects of hydrophobic drug addition (such as ibuprofen and sodium naproxen) on pluronic copolymer solutions have been studied widely.9,13,14 It has been found that the addition of drugs to aqueous solutions of pluronic copolymers can influence properties such as the critical micelle concentration and temperature (cmc and cmt), the aggregation number, and the structure of the micelles. r 2011 American Chemical Society
Figure 1. Structure of flurbiprofen.
Table 1. Composition of Pluronics Used P123
P103
L43
ethylene oxide unitsa propylene oxide unitsa
40 70
34 60
13 22
Mn/kg mol1
b
6.3
5.5
2.0
Mw/kg mol1
7.1
5.6
2.1
polydispersity indexb
1.13
1.02
1.05
b
a
Values supplied by BASF.21 b Determined using MALDI-TOF MS.
In this study, we have investigated the micellar properties of pluronics upon encapsulation of flurbiprofen and drug release in vitro. Flurbiprofen is an effective nonsteroidal anti-inflammatory drug (NSAID) and analgesic agent of the phenylalkanoic acid series (ibuprofen, naproxen, and ketoprofen), which are used to treat pain, tenderness, swelling, and stiffness caused by osteoarthritis and rheumatoid arthritis. Studies have shown that flurbiprofen is superior to other drugs in terms of formal symptomatic side effects (pain, Received: March 25, 2011 Revised: May 18, 2011 Published: June 09, 2011 8054
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Table 2. cmc and cac Values, the Surface Excess, and the Surface Area of the Three Block Copolymers with and without Drug in WaterEthanol Solutions (90:10) copolymer
T (°C)
P103
25
P103 and drug P123
25 25
P123 and drug
25
cmc (wt %)
cac (wt %)
cac/cmc
0.16 ( 0.01 0.044 ( 0.012
cramping, and swelling) as well as having a high efficacy/tolerance ratio. (The recommended dosage for postoperative pain is 50100 mg and for arthritis it is 100200 mg, which is half of the required dosage for ibuprofen.)15,16 Flurbiprofen (Figure 1) will not dissolve readily in water or in gastric or intestinal fluids, and when taken in solid form, the adsorption may be incomplete and the bioavailability is low. However, it can be easily solubilized in the presence of pluronic micelles and hence can be transferred into the body. When there is a change in concentration or pH and the drug becomes more soluble, the micelles break down and the drug is released for absorption into the bloodstream. This article describes diffusion measurements that have been carried out using the pulsed-field gradient stimulated-echo nuclear magnetic resonance (PFGSE-NMR) technique for Pluronics P103, P123, and L43. Although the chosen pluronics each have 30% PEO in their structures as shown in Table 1, the effect of the addition of flurbiprofen on the cmc of the three different pluronics differs. In particular, it was found that the micellization of L43 was not observed at 298 K but micelles were present at 310 K. The comparison of the three pluronics presented here is constrained by this, with the studies of P103 and P123 being carried at out 298 K and L43 being studied at 310 K. A combination of surface tension, PFGSE-NMR, and ultravioletvisible spectroscopy data was used to describe these systems. The PFGSE-NMR technique is well established,17 and several research groups have investigated the micellization and selfdiffusion behavior of polymeric surfactants using it.1820 This method is particularly valuable when multicomponent systems (such as polymeric surfactants and drugs) are investigated because the components with very different sizes have different transitional diffusion coefficients. PFGSE-NMR is able to provide information on the dynamics of the components in the solution and their size, shape, and how they are distributed between the solution and the aggregates.
2. MATERIALS AND METHODS All compounds were used as received. Pluronics P103, P123, and L43 were provided by BASF. Flurbiprofen was supplied by Sigma-Aldrich. D2O (99.94 atom % D) and d6-ethanol (99 atom % D) were purchased from Goss Scientific Instruments Ltd. 2.1. Sample Preparation. The pluronic and the solvent (10% d6ethanol in D2O) were weighed into a vial and placed on a roller mixer for 2 h. The drug was then added to the solutions, and samples were sonicated for 2 h to ensure the merging of the drug into the micelles. They were left on a roller mixer for 24 h to reach equilibrium, before measurements. The drug was not soluble in water but after addition to pluronic solutions that were well above the critical micelle concentration, clear solubility was observed. Ethanol/water mixtures were used throughout this study because they were found to give the most reliable diffusion data. 2.2. PFGSE-NMR Spectroscopy. Pulsed-field gradient stimulatedecho (PFGSE-NMR) measurements were carried out at 298 K on a Bruker DSX-300 MHz spectrometer with a Diff 30 field gradient probe using a
A (Å2/molecule)
3.53 107
470
3.22 107
515
0.27
0.029 ( 0.003 0.007 ( 0.001
Γ (mol m2)
0.24
5 mm 1H/2H coil insert. The gradient pulse duration (δ) was set to 1 to 2 ms, and the magnetic field gradient (G) was increased from 0.05 to 10 T m1. The diffusion time (Δ) was set to 150 ms. Calibration of the instrument was carried out using a water/methanol reference sample. The stimulated-echo signals were Fourier transformed, and the resulting spectra (signal area as a function of gradient strength) were used to calculate the diffusion coefficients (D/m2 s1) for each chemically distinct species. The attenuation of the echo signal intensity follows eq 1 0 !1 δ AðGÞ g 2 2 2 A ¼ exp@γN G δg D Δ ð1Þ Að0Þ 3 where A(0) is the initial peak area, A is the peak area for each gradient step, and γN is the gyromagnetic ratio of the nuclei, which is 2.675 108 rad T1 s1 for a proton. ln(A(G)) versus [(GδγN)2(Δ δ/3)] can be plotted to give a straight line with a gradient of D. If the plot shows two distinct slopes, then the data is analyzed with two different diffusion coefficients. The hydrodynamic radii (Rh) can then be obtained from the StokesEinstein equation (eq 2), assuming that the aggregates are spherical and noninteracting. Rh ¼
kB T 6πηD
ð2Þ
where kB is the Boltzmann constant, T is the absolute temperature, and η is the viscosity of the solvent mixture. 2.3. Surface Tension. The surface tensions of the three pluronic solutions (10 wt %) in 10% ethanol and 90% H2O, with a drug concentration of 0.6 wt %, were determined using a model K100 tensiometer from the Kr€uss Surface Science Centre at Bristol University using the Wilhelmy plate method. All of the samples were filtered through a 0.45 μm Millipore filter to remove any impurities before the measurements. The measurements were carried out at 298 K for P123P103 and at 310 K for L43.
3. RESULTS AND DISCUSSION 3.1. Surface Tension Measurements and the Effect of Drug Addition on the cmcs. The cmc determination using the surface
tension method relies on the observation that increasing the polymeric surfactant concentration leads to a decrease in surface tension. Accordingly, at the cmc there should be a break point at which the surface tension does not decrease further on increasing the concentration but remains constant because of the formation of micelles. For polymers without any drugs, the Gibbs adsorption isotherm (eq 3) was used to calculate the surface excess concentration (Γ/ mol m2) and the surface area per molecule (A/Å2) (eq 4). 1 dγ Γ¼ ð3Þ RT d ln C A¼ 8055
1 ΓNΑ
ð4Þ
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Table 3. Aggregation Data Determined Using PFGSE-NMR and Surface Tension for 5 wt % Solutions of Pluronics in 10% d6-Ethanol/90% D2O % micellized
Rh of unimers
Rh of micelles
temperature
(fM) ( 1.1
(4% (Å)
(4% (Å)
(K)
P123
73 /99.7
b
22.4
87.5
298
P103
70a/98.4b
13.7
68.6
298
pluronic
L43 a
Figure 2. Plot of the surface tension of P123 in water/ethanol with and without flurbiprofen as a function of concentration at 25 °C. Values are averages over 10 measurements (1 SD.
where γ is the surface tension, C is the polymer concentration, and NA is Avogadro’s number. Values are summarized in Table 2. They show that the surface area that a block copolymer occupies increases by increasing the size of the middle block. The cac/cmc ratio (cac: critical aggregation concentration) can indicate the strength of the interaction between the micelles and the drug.22,23 The smaller the cac/cmc ratio, the stronger the polymer drug interaction. The cac values depend on the amount of drug present in the system; the higher the percentage of the drug present, the lower the cac. For systems with more than two components, the Gibbs adsorption isotherm cannot be used to separate the contributions of the components at the interface. In the presence of 0.6 wt % drug, the L43 solution was cloudy, indicating that not all of the drug molecules were solubilized, and this could be due to the low loading capacity of the small L43 micelles as drug carriers. The drug molecules precipitated as the concentration of the copolymers decreased. It may be concluded that L43 is not a suitable drug carrier, and this is due to the fact that the core size and aggregation number of the pluronic micelles are critical to the amount of drug that can be solubilized. A similar conclusion was derived by Sek et al. and Kabanov. They compared the solubility of a hydrophobic component in five different pluronics. The results showed that those with smaller PPO cores, smaller aggregation numbers, and a higher hydrophilic lipophilic balance, HLB, (e.g., L43) hinder the solubilization of hydrophobic substances.2426 Figure 2 shows the surface tension data of P123 with and without drug in water/ethanol at 25 °C plotted with respect to the copolymer bulk concentration. This copolymer decreases the surface tension of water/ethanol (50.2 mN m1) by about 13.4 mN m1 at the lowest concentration (0.0001 wt %). The cmc obtained by this method in pure water (0.0076 wt/v %) is between values previously published in the literature (0.03 and 0.004 wt %).27,28 This experiment was repeated three times to examine the reproducibility; each time the solution was filtered through a Millipore filter. Similar results were obtained in all three cases. In previous diffusion measurements, it was discovered that P123 contained some larger particles at concentrations around the cmc, which could be due to impurities and/or
a
11.1
310
PFGSE-NMR. b Surface tension.
the presence of diblock copolymers. Both of these could reduce the cmc value if they were surface-active. It is believed that the presence of impurities could affect the behavior of the micellization dynamics and broaden the cmc.29,30 For the pluronic/drug mixtures, the situation becomes more complex and a different type of surface tension behavior is observed (Figure 2). The surface tension for a pluronic/drug mixture was measured as a function of the pluronic concentration at 0.6 wt % drug concentration. Although the surface tension behavior of polymer/drug mixtures has not been reported in the literature, similar behavior has been observed for polymer/ surfactant complexes.3133 There are three distinct parts in the surface tension graphs of the mixture that are labeled ac. (a) Below the cac: Drug molecules are more hydrophobic than pluronics and therefore are either adsorbed at the liquidair surface on their own and/or form complexes with pluronic unimers at the surface. This lowers the surface tension (below that of the polymer alone) until it reaches the break point at the critical aggregation concentration (cac). (b) Above the cac: The cac represents the onset of drug absorption into the surfactant micelles. When micelles are formed, drug molecules become solubilized in the micelles. The increase in surface tension is caused by desorbing some of the drug molecules and/or polymer/ drug complexes from the surface into the solution. (c) Above the cuc: Complete uptake concentration (cuc) is the concentration at which nearly all of the drug molecules are taken up by the micelles. In section 3.2, we will show that almost all of the drug is located inside of the micelles; therefore, the plateau observed in the graph is purely due to the concentration of free surfactant at the interface remaining constant. However, the concentration of the free surfactant in the presence of drug is lower than that of the free surfactant without drug because the drug molecules increase the driving force for micellization. This is the reason for obtaining the slightly higher surface tension values in this region. 3.2. PFGSE-NMR Investigation of Pluronic P103 and Various Drug Concentrations. Pluronics P103, P123, and L43 were studied using PFGSE-NMR in 10% d6-ethanol/90%D2O. All of the triblock copolymers (except L43) were found to diffuse at two different rates in solution, with the faster rate corresponding to diffusion of the unimer and the slower rate corresponding to that of the micelle, indicating that the polymer is in slow exchange on the NMR timescale. The ratio of the two intensities gives the fraction of polymer micellized as shown in Table 3. The pluronics with larger hydrophobic (PPO) blocks formed micelles at lower concentrations (cmc) and displayed the greater 8056
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Table 4. Diffusion Coefficients of Flurbiprofen in D2O/ d6-Ethanol, Alone and in Micelles of 5 wt/v % Pluronic P103, and Diffusion Coefficient of the Polymer in the Micellesa
sample
drug/1010
polymer in
m2 s1
micelles/1010
((4%)
m2 s1 ((4%)
drug alone (0.5 wt %)
4.35
0.25% drug in micelle
0.213
0.167
0.50% drug in micelle 0.75% drug in micelle
0.185 0.110
0.147 0.097
The solution of flurbiprofen alone in D2O/d6-ethanol was adjusted to pH ∼12 to ensure complete solubility. The data was taken from the attenuation of the flurbiprofen aromatic group at δ ≈ 7.5 ppm. a
Figure 3. NMR attenuation plots for 5 wt/v % P103 solutions on addition of flurbiprofen in D2O/d6-ethanol (90:10). All data is taken from the PEO CH2 group peak at δ ≈ 3.6 ppm.
degree of micellization, as expected. However, the fraction of micellization (fM) determined by PFGSE-NMR is lower than that obtained using surface tension data, which is given by fM = (Ctot cmc)/Ctot. One possibility is that the system is in the “intermediate exchange” regime when considering the exchange of pluronic between the micellar and unimer phases on the NMR timescale; in contrast to the “fast” and “slow” exchange regimes, the interpretation of the data becomes less straightforward. If there were a fast exchange between the unimers and micelles during the diffusion time (Δ), then a single diffusion coefficient would be observed and it would be a population average of the coefficients for unimeric and micellar diffusion. If there were no or slow exchange of molecules between the two states, then two distinct diffusion coefficients with their relative intensities to micelles and unimers would be obtained. However, if the lifetime of the states comes close to the diffusion time, then two populations (unimeric and micellar chains) become less distinguishable in their diffusion coefficients;34 hence, the NMR experiment may underestimate the micellar population compared to the value obtained by surface tension. For Pluronic L43 at 310 K in this solvent mixture, no micellization was observed, and this is due to the ethanol that is a good solvent for both PPO and PEO. The addition of ethanol, therefore, increases the cmt and cmc and decreases the degree of micellization.35 This is true for all of the pluronics studied here, however, because the micellization of L43 is already very temperature- and concentration-sensitive and the presence of cosolvent has a more significant effect on the micellization behavior of L43 compared to that of P123 and P103. For L43 in pure water at 310 K, the fraction of polymer in micelles is 35% with an aggregation number of ∼8 and a core size of around 17 Å. As flurbiprofen is added to the solutions of P103 at different concentrations, a decrease in the NMR attenuation occurs, which means that the components move at slower rates, as seen in Figure 3. The fitted diffusion coefficients reveal that this is due to the growth of the micelles resulting from interactions with the drug molecules (Tables 4 and 5). As can be seen in Figure 3, Pluronic P103 in the presence of 0.75% drug has a much slower diffusion rate than that of the other
two concentrations. The diffusion data revealed two separate micellar diffusion rates, the slower of which diffused at around 3.7 1012 m2 s1 with an Rh of ∼410 Å with a proton fraction of about 50%. These larger aggregates suggest the onset of attractive interaction between the micelles or phase separation in the system that could be due to the loading capacity of P103 at 5 wt % being exceeded. The presence of separate diffusion coefficients for micelles, unimers, and large aggregates in the solution indicates the slow exchange of the polymer among all three states on the NMR timescale. The attenuation of the flurbiprofen intensities was fitted to a single diffusion coefficient (Figure 4), meaning that the flurbiprofen is either all solubilized or is in fast exchange between the aqueous solution and the micelle. The higher the concentration of drug, the lower the diffusion coefficient obtained from each drug signal. The fraction of flurbiprofen that is in the core of the micelle, ϕM, can be calculated using eq 5 Dflur ¼ ϕM Dmic þ ð1 ϕM ÞDfree
ð5Þ
where Dflur is the dynamically averaged diffusion coefficient of the flurbiprofen, Dmic is the diffusion coefficient of the micelle obtained from the polymer (peak) that is in slow exchange, and Dfree is the diffusion coefficient of free flurbiprofen in solution, taken as 4.35 1010 m2 s1 obtained independently from a dilute solution. These values are shown in Table 4. The diffusion coefficient observed for the drug is the weighted average of the diffusion coefficient of the drug in the aqueous solution and in the micelles; although the concentration of free drug is very small, the large difference in diffusion coefficients between free drug and drug in the micelles results in a change in the measured diffusion coefficient. Were a size of the polymer drug conjugate to be estimated from this diffusion coefficient using eq 2, the apparent size of the aggregate would be underestimated and would be smaller than the size of the micelle estimated from the diffusion coefficient of the polymer. The data in Table 5 illustrate that as the percentage of drug increases, the percentage of pluronic micellized, the aggregation number (N), and the hydrodynamic size of the micelles increase. Note that virtually all of the added flurbiprofen is solubilized in micelles. Estimates of the aggregation number were calculated using the volume of the micelles and the unimers.36 It should be noted that the figures for the aggregation number are higher than those obtained by SANS,9 and this is due to the fact that the Rh used to calculate the aggregating number does not exclude solvent in the 8057
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Table 5. Aggregation Data Determined Using PFGSE-NMR for 5 wt/v % Solutions of Pluronic P103 and P123 in D2O/d6-Ethanol with the Addition of Flurbiprofen at 298 K % flurbiprofen in micelle
% pluronic micellized
Rh of micelle /Å ((4%)
P103
P123
P103
P103
70
73
68
88
125
60
0.25
98.9
97.1
73
75
82
103
150
122
0.50 0.75
99.1 99.7
98.8 99.9
76 77
79 83
91 140
112 129
197 710
251 1000
flurbiprofen wt/v % 0.00
P123
Figure 4. NMR attenuation plots for various drug concentrations in P103 micelles in D2O/d6-ethanol (90:10). The data was taken from the attenuation of the flurbiprofen aromatic group at δ ≈ 7.5 ppm.
micelles and therefore overestimates the number of monomers in the micelles.37 3.3. Pluronic P123 and Flurbiprofen Interactions. The interaction between the drug and Pluronic P123 was also examined, and three different drug concentrations were used (0.25, 0.5, and 0.75 wt/v %). Figure 5 compares the hydrodynamic radius of the P103 and P123 micelles in the presence of various drug concentrations. Similar behavior was observed: as the drug concentration increased, the size of the micelles increased. As described above (Figure 3), larger aggregates are observed at drug concentrations above the loading capacity of the pluronics; however, the fraction of the larger aggregates at 0.75% drug for P123 micelles was 10% in comparison to 50% for P103. This indicates a higher maximum loading capacity for P123 compared to that for P103 and that larger pluronics are able to accommodate and transfer more drugs within their hydrophophic cores than are smaller ones. The percentage of flurbiprofen in the core of P123 micelles was calculated using eq 3 and is also summarized in Table 5. The aggregation number and the percentage of the drug in the micelles increase as the drug concentration increases. 3.4. Effect of Polymer Concentration on Drug Encapsulation. The efficiency of both drug encapsulation and release would be expected to be a function of the polymer concentration;13,38 the concentration of polymer at which all of the drug molecules are solubilized within the micelle is particularly relevant. Three different concentrations of Pluronic P103 were chosen with a fixed drug concentration (0.5 wt/v %). Three concentrations were chosen so
aggregation number (N) ((12%)
P123
P103
P123
Figure 5. Comparison of the hydrodynamic radius of the P103-drug complexes with P123 micelles at various drug concentrations in D2O/ d6-ethanol (90:10). Values were calculated using diffusion coefficients and are (4%.
Table 6. Aggregation Data Determined Using PFGSE-NMR for Different Concentrations of Pluronic P103 in D2O/d6Ethanol with the Addition of 0.5 wt % Flurbiprofen at 298 K P103%
diffusion coefficient of
% flurbiprofen
wt/v %
drug/1010 m2 s1 ((4%)
in micelle
0.0 0.06
4.3 2.4
53.2
1.0
0.51
90.2
5.0
0.19
99.1
that one is below, one is slightly above, and one is well above the cmc determined in section 3.1. The dispersion of drug and P103 (0.06 and 1 wt/v %) was not clear, and traces of undissolved drug molecules were observed. However, the solution of 5% P103 and drug was clear, and no solid was seen in the sample, indicating complete solubilization of the drug within the micelle (Table 6). The data shows that the fraction of the drug in the micelles increases as the Pluronic P103 concentration increases. This suggests that its release from pluronic micelles could be triggered by a change in the physiological concentration. On the basis of the similar behavior of P103 and P123 in their aggregation with flurbiprofen, it is anticipated that the interaction with P123 would produce similar results to those shown here. The diffusion coefficients of flurbiprofen in the solutions containing 0.5% drug and various Pluronic P103 concentrations were 8058
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drug release from pluronic micelles in vitro using SANS and PFGSE-NMR.
’ AUTHOR INFORMATION Corresponding Author
*E-mail:
[email protected].
’ ACKNOWLEDGMENT We thank Rob Dyer from Kr€uss Surface Science Centre for his assistance with the K100 surface tensiometer, Dr. Youssef Espidel for his support using PFGSE-NMR, and also the EPSRC and Revolymer Ltd. for funding this project. ’ REFERENCES Figure 6. Attenuation plots for fixed drug concentrations in various P103 concentrations. The data was taken from the attenuation of the flurbiprofen aromatic group at δ ≈ 7.5 ppm.
calculated using eq 1 and are shown in Table 6. The diffusion coefficients of drug decreased on increasing the polymer concentration in the solution. The same behavior was observed by Sang13 and Pai-Chie,38 who found a decrease in the diffusion coefficients for ketoprofen and lidocaine with pluronics. Hyung39 also observed that the diffusion coefficients of flurbiprofen decreased as the polymer concentration increased. Figure 6 illustrates a decrease in the effective diffusion coefficient of the drug in the presence of P103. This means that as the P103 concentration increases less drug would be released into the bulk and a larger amount of drug is able to dissolve and be accommodated within the micelle cores.
4. CONCLUSIONS The surface tension measurements showed that the aggregation behavior of Pluronics P123, P103, and L43 is sensitive to the presence of the hydrophobic drug because of the formation of drug/micelle and drug/unimer complexes. Also, it can be concluded that L43 is unlikely to be a suitable drug carrier because of its small micellar size and the very high sensitivity of the aggregation to temperature. The diffusion of Pluronic P103 dispersions, with and without flurbiprofen, was studied using PFGSE-NMR. The data showed that P103 alone in D2O/d6-ethanol had a hydrodynamic radius of ∼6 nm. For samples containing flurbiprofen, the percentage of drug interacting with the polymer micelles increased with the drug concentration and the hydrodynamic radius of the pluronic increased to ∼15 nm with the highest drug content. The flurbiprofen attenuation signals in all cases could be fitted to a single diffusion coefficient, indicating that flurbiprofen is in fast exchange between the aqueous solution and the micelle or is fully solubilized. The effect of varying the P103 concentration with a fixed drug concentration was also examined. Flurbiprofen solubility showed a strong dependence on micelle concentration, with a substantial portion, up to 99%, of flurbiprofen solubilized with increased P103 concentration. The interaction between the drug and Pluronic P123 was examined, and the result showed that larger pluronics are more appropriate as drug carriers because of the sizes of their cores. In a forthcoming paper, we are going to discuss the effect of pH on
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dx.doi.org/10.1021/la201124c |Langmuir 2011, 27, 8054–8060
