16082
J. Phys. Chem. C 2010, 114, 16082–16086
Micellization of Poly(ethylene glycol)-block-Poly(caprolactone) in Compressible Near Critical Solvents Jade Green, Zachary Tyrrell, and Maciej Radosz* Soft Materials Laboratory, Department of Chemical and Petroleum Engineering, UniVersity of Wyoming, Laramie, Wyoming 82071-3295 ReceiVed: January 22, 2010; ReVised Manuscript ReceiVed: July 8, 2010
Micelles of hydrophilic-hydrophobic block copolymers, such as poly(ethylene glycol)-block-poly(caprolactone) (PEG-b-PCL), are useful for delivery of hydrophobic drugs. Such micelles can be formed by liquid solvent displacement or dialysis. A more recent approach is to use supercritical fluids as solvents, but the selection criteria for solvents are not well understood. The compressible solvents studied in this work can induce pressuretunable micellization of PEG-b-PCL. Their capacity and selectivity, and hence their ability to form micelles, depends on their density, polarity, and hydrogen bonding potential. By mixing two solvent components, such as dimethyl ether (good solvent) and trifluoromethane (selective antisolvent), one can control not only the micellization temperature and pressure, but also the bulk separation pressure (cloud pressure), crystallization temperature, and melting temperature. This can be utilized to develop efficient ways to prepare micellar precursors for drug-loaded nanoparticles. Introduction Amphiphilic block copolymers can self-assemble to form nanosized micelles in aqueous solutions, and have been used for the delivery of hydrophobic drugs.1-5 Typically, such micelles are prepared by dissolving the copolymer in an organic solvent such as acetone or THF. Next, water is added slowly to induce micellization. Finally, a separation method such as dialysis or freeze-drying is employed to recover the micelles.6-8 However, these methods are time-consuming, and can leave trace amounts of potentially toxic organic solvents. Alternatively, micelles can be prepared by using a supercritical fluid, which allows for complete solvent removal, since the solvent exists as a gas at ambient conditions. Also, supercritical fluids possess liquid-like density, high diffusivity, and low viscosity, which are potentially advantageous for micelle production. Furthermore, the solvent density, and hence its capacity, can be tuned by using pressure, temperature, or both.9 This allows more flexibility in polymer dissolution, micelle formation, and micelle precipitation. Winoto et al.10 demonstrated micelle formation for a model diblock system of polystyrene-block-polyisoprene in subcritical and supercritical propane. Tyrrell et al.11 characterized poly(ethylene glycol)-block-poly(caprolactone) (PEG-b-PCL) phase behavior in solutions with trifluoromethane and chlorodifluoromethane. They demonstrated that PEG(5K)-b-PCL(5K) can indeed form micelles in trifluoromethane, in the pressure range of 600-1200 bar, but not in chlorodifluoromethane. These findings provided a hint that solvent properties can influence the probability of micellization, but not enough to understand how specific solvent properties affect the micellization pressure and temperature for a given polymer-solvent pair, and specifically how to control the solvent capacity and selectivity. The objective of this work, therefore, is to investigate the solvent effect on the micellization pressure of PEG-b-PCL using four solvents that differ in critical properties, polarity, and * To whom correspondence should be addressed. E-mail: radosz@ uwyo.edu.
Figure 1. Structures of solvents and polymer.
hydrogen bonding potential. Hence, they differ in capacity and selectivity at a given pressure and temperature. A specific aim of this work is to understand how to control the temperaturepressure maps that show the onset of micellization and bulk phase separation, for the purpose of understanding how the size and shape of the micellar and other phase regions depend on solvent properties. In a separate project, we study the micelle and precipitated block copolymer morphology. Experimental Section Materials. The polymers, PEG (5K), PCL (5K), PCL (12.6K), PEG-PCL (5K-5K), and PEG-PCL (5K-11K), obtained from Polymer Source Inc., have polydispersity index (PDI) values of 1.08, 1.49, 1.43, 1.10, and 1.12, respectively. The approximate number averaged molecular weight is given in parentheses. The solvents trifluoromethane, dimethyl ether, tetrafluoroethane, and hexafluoroethane are obtained from Airgas (99.5% purity). The solvent structures and properties are shown in Figure 1 and Table 1, respectively. PEG-b-PCL structure is also shown in Figure 1 for reference.
10.1021/jp100646a 2010 American Chemical Society Published on Web 09/14/2010
Poly(ethylene glycol)-block-Poly(caprolactone)
J. Phys. Chem. C, Vol. 114, No. 39, 2010 16083
TABLE 1: Properties of Solvents
1,1,1,2-tetrafluoroethane trifluoromethane dimethyl ether hexafluoroethane
critical temp [°C]
critical pressure [bar]
dipole moment [D]
101.1 26.1 128.0 19.9
40.6 48.8 54.0 30.3
2.1 1.6 1.3 0.0
Cloud Point, Micellization, Crystallization, and Melting Experiments. The cloud pressure (CP) and micellization pressure (MP) experiments are carried out in a small variablevolume (∼1 cm3) cell, equipped with a borescope for visual observation of the phase transitions, with transmitted- and scattered-light intensity probes, and with a floating piston, so that the pressure can be changed without changing the mixture composition. The apparatus also has a data-acquisition system that allows for measurements at constant temperature and pressure and for increasing and decreasing pressure and temperature at constant rate. The CP is detected by a transmittedlight intensity (TLI) probe. The MP is detected by a scatteredlight intensity (SLI) probe. A more detailed description of this experimental approach is documented elsewhere.10,12,13 A known amount of copolymer is loaded into the cell and pressurized with a known amount of solvent, both obtained by weighing the cell. Next, the cell is brought to and maintained at a desired pressure and temperature to dissolve the copolymer completely. After the mixture is stirred in the one-phase region for 90 min to reach equilibrium, there are two choices: an isothermal experiment or an isobaric experiment. For the isothermal experiment, the pressure is lowered slowly until the solution becomes cloudy at the onset of phase separation indicated by decreasing TLI. In this study, a pressure rate as low as 15 bar/min is chosen to obtain a reproducible CP, to within (3 bar.10 The bulk phase boundary can also be approached from the two-phase side upon compression, which leads to an increase in TLI. Before taking a new data point, the solution is allowed to equilibrate in the one-phase region at a much higher pressure than the expected CP for 15 min. For all data points, the TLI results are stored and analyzed as a function of temperature, pressure, and time. Micelle formation is probed with high-pressure dynamic light scattering. The SLI and hydrodynamic radius increase sharply at the MP. In this work, we focus on the low concentration range. For these measurements, we couple the high-pressure cell with an Ar+-ion laser (National Laser, model 800BL) operating at a λ ) 488 nm wavelength with a Brookhaven BI-9000AT correlator, as described by Winoto et al.10 The coherence area is controlled by a pinhole placed before the detector. The laser and detector are linked to the high-pressure cell by optical fibers produced by Thorlabs. The high-pressure optical interface design is different from, but inspired by, the approach described by Koga et al.3 The scattered-light intensity is recorded and measured for isothermal measurements upon increasing or decreasing pressures at a rate of 30-60 bar/min. The isobaric experiments are to determine crystallization and melting temperatures. In these experiments, the pressure is held constant while the temperature is lowered slowly until the polymer starts to crystallize. Then the temperature is increased slowly until the polymer is fully melted. In this study, a temperature rate as low as 0.4 deg/min is used to achieve a reproducible crystallization and melting temperature. Before a new data point is taken, the solution is allowed to equilibrate at much higher temperature than the expected crystallization temperature for at least 15 min. This bulk phase separation is
Figure 2. Example TLI pressure diagram of poly(ethylene glycol)b-poly(ε-caprolactone) (Mw ) 5000-b-11000) in a supercritical mixture of 66% dimethyl ether and 33% trifluoromethane at 80 °C. The concentration of polymer in solution was ∼1 wt %.
Figure 3. Example SLI pressure diagram of poly(ethylene glycol)-bpoly(ε-caprolactone) (Mw ) 5000-b-11000) in supercritical dimethyl ether at 80 °C. The concentration of polymer in solution was ∼2 wt %.
probed using TLI. The TLI data are stored and analyzed as a function of temperature, pressure, and time. In this work, the crystallization temperature is taken to be the start of the TLI drop, and the melting temperature is taken as the end of the TLI increase. Results and Discussion Transmitted and Scattered Light Intensity Examples. A typical sample graph of TLI plotted against pressure is shown in Figure 2. In this work, the CP is determined to be the inflection point of the TLI curve, which corresponds to a peak in its first derivative. The onset and end of TLI change are measures of the polymer nonuniformity, but they are not crucial to this work. Figures 3 and 4 are examples of two typical SLI curves. Figure 3 illustrates an example with no micellization; the SLI increases sharply at the CP, but remains constant until then. In contrast, Figure 4 illustrates an example with micellization. Upon decreasing pressure, the SLI starts increasing at MP, and then increases sharply at CP. Cloud Pressure Can Characterize Solvent Capacity and Selectivity. For a given solvent, its capacity scales with its density and hence it increases with increasing pressure at the same temperature. For two solvents, therefore, a lower cloud pressure suggests a higher capacity, and vice versa. By the same token, for the same solvent, a large difference in cloud pressure for two different polymer solutes, for example two homopolymer
16084
J. Phys. Chem. C, Vol. 114, No. 39, 2010
Figure 4. Example SLI pressure diagram of poly(ethylene glycol)-bpoly(ε-caprolactone) (Mw ) 5000-b-11000) in a supercritical mixture of 66% dimethyl ether and 33% trifluoromethane at 80 °C. The concentration of polymer in solution was ∼1 wt %.
Figure 5. Example pressure temperature phase diagram of polystyreneb-polybutadiene (Mw ) 37000-b-13000) in propane. The concentration of polymer in solution was ∼0.5 wt %. Replotted on the basis of data taken from Winoto et al.14
solutes that will form two blocks in a diblock, suggests a high selectivity and hence a high probability of forming micelles. If the solvent is selective enough, it induces aggregation of the less-soluble blocks in the micelle core, while leaving the other block of the copolymer exposed to the solvent in the outer shell, or corona. The CP at a given temperature is the specific pressure at which the capacity of the solvent is just enough to allow complete dissolution of the polymer (D in Figure 5). Above the CP, the polymer is dissolved and, below the CP, the polymer forms a distinct separate phase and the solution becomes opaque, or “cloudy” (E in Figure 5). Similarly, for block-copolymers that have different block solubility, the MP at a given temperature is the specific pressure at which solvent selectivity forces the less-soluble block to aggregate as micelles (B in Figure 5). In the region below the MP but above the CP, a micellar solution exists as a result of nano-, rather than bulk, phase separation (C in Figure 5). At pressures above the MP, the solvent is no longer selective enough to induce aggregation, so micelles cease to exist (A in Figure 5). The region between the CP curve and the MP curve is the micellar region. High Solvent Capacity Leads to Low Cloud Pressure. Hexafluorethane has the lowest capacity for PEG-PCL: it does not dissolve this polymer at any pressure up to 1800 bar and temperature up to 180 °C. Of the solvents that can dissolve PEGPCL, trifluoromethane requires the highest pressures, up to around 1600 bar, as shown in Figure 6, and hence has the lowest
Green et al.
Figure 6. Pressure-temperature phase diagram of poly(ethylene glycol) (Mw ) 5000) and the corresponding poly(ε-caprolactone) block copolymer (Mw ) 5000-b-11000) in supercritical trifluoromethane. The concentration of polymer in solution was ∼1 wt %. Note: Micelles are present above the copolymer CP to over 1800 bar (the actual MP is beyond the pressure range).
Figure 7. Pressure-temperature phase diagram of poly(ethylene glycol) (Mw ) 5000), poly(ε-caprolactone) (Mw ) 12600), and the corresponding block copolymer (Mw ) 5000-b-11000) in supercritical dimethyl ether. The concentration of polymer in solution was ∼1 wt %. Note: Micelles were formed at a copolymer concentration of ∼2 wt % in a very small region at lower temperatures.
capacity for PEG-PCL. Even though its CP sharply decreases upon cooling, down to about 800 bar at ambient temperature, it is still much higher than that for PEG, which is also shown in Figure 6. The CP for PCL in this solvent is above 1800 bar, an experimental limit in this work. By contrast, dimethyl ether requires the lowest pressures, only around 100-200 bar, as shown in Figure 7, suggesting a high capacity for this copolymer. The CP’s for both corresponding homopolymers are also low and hence their capacities are high. Finally, the CP of tetrafluoroethane shown in Figure 8 falls between those for dimethyl ether and trifluoromethane, suggesting intermediate capacity. For the halogen-containing solvents, their capacity qualitatively scales with their polarity; it increases with increasing polarity. As shown in Table 1, tetrafluoroethane has the highest dipole moment due the orientation of highly electronegative fluorine atoms opposite from weakly electronegative hydrogen atoms. Trifluoromethane has an intermediate dipole moment, and intermediate capacity. Hexafluoroethane has a zero dipole moment, and turns out to be a nonsolvent for the homopolymers and the copolymer as well. Dimethyl ether has a relatively weak dipole moment but enough to exhibit high capacity for all three
Poly(ethylene glycol)-block-Poly(caprolactone)
Figure 8. Pressure-temperature phase diagram of poly(ethylene glycol) (Mw ) 5000), poly(ε-caprolactone) (Mw ) 5000), and the corresponding block copolymer (Mw ) 5000-b-5000) in supercritical tetrafluoroethane. The concentration of polymer in solution was ∼1 wt %.
polymers due to its relatively high densities at comparable temperatures and pressures, and due to its similar chemical structure. Solvent Selectivity Leads to Micelle Formation. Due to its capacity difference for the two homopolymers, PEG (CP ≈ 400 bar at 40 °C) and PCL (over 1800 bar), trifluoromethane should have a high selectivity for their corresponding blocks, which suggests a probability of micelle formation. Micelles are in fact confirmed with SLI in a large region extending above the polymer cloud pressure curve in Figure 6 (shown with squares) to over 1800 bar (the actual MP beyond the pressure range). This finding is consistent with the data for another PEG-b-PCL (5K-2.3K) reported by Tyrrell et al.11 By contrast, dimethyl ether exhibits similarly high capacities for both homopolymers. The difference in the cloud pressure between PEG and PCL is ∼100 bar over the entire temperature range investigated (Figure 7). One therefore expects low selectivity and hence low probability of micelle formation, as confirmed from SLI for a polymer concentration of 1 wt %. However, when the polymer concentration is increased to 2 wt %, micelle formation is detected in a very small region at lower temperatures. This concentration effect on micellization will be further discussed in the next section. For tetrafluoroethane, the difference between the cloud pressures for the respective homopolymers is enough (250-600 bar, as shown in Figure 8) to suggest selectivity for PEG over PCL, but micelles are not found. This is because, as illustrated in Figure 8, the CP of the copolymer lies above the CP of the PCL homopolymer, which prevents the PCL blocks from aggregating in micelle cores. The reason that the copolymer CP is higher than the PCL CP in this case can be explained by considering the molecular weight effect. For any polymer in a supercritical solvent, increasing molecular weight leads to an increase in its cloud pressure at a given temperature. The copolymer molecular weight in this case is much higher than that of the corresponding homopolymer molecular weights, which by itself shifts the CP up by about 150 bar, just enough to shift it beyond the CP observed for PCL alone. One way to explain the observed differences in solvent selectivity is on the basis of hydrogen bonding potential between the solvents and each block of the copolymer. Hydrogen bonding requires a specific orientation between an electronegative site with lone pairs of electrons on one molecule and, for example,
J. Phys. Chem. C, Vol. 114, No. 39, 2010 16085
Figure 9. Pressure-composition phase diagram of poly(ethylene glycol)-b-poly(ε-caprolactone) (Mw ) 5000-b-11000) in supercritical trifluoromethane/dimethyl ether mixtures. The concentration of polymer in solution was ∼1 wt %.
a hydrogen site polarized by a bond to an electronegative atom of a second molecule. In the case of the solvents and copolymer in this work, there is potential for hydrogen bonding between the hydrogen atoms of tetrafluoroethane and trifluoromethane and the many lone pairs of electrons on the oxygen atoms along the PEG chain. Dimethyl ether, while similar to PEG in chemical structure, is unlikely to form hydrogen bonds with PEG. As shown in Figure 1, PCL also has oxygen atoms with lone pairs of electrons, but they are spaced at a greater distance than the oxygen atoms of PEG. The reason that trifluoromethane is more selective than tetrafluoroethane is that its hydrogen bonding potential difference (PEG versus PCL) is higher than that for tetrafluoroethane. Mixed Solvents Allow for Adjustable Capacity/Selectivity. Dimethyl ether is found to have high capacity and but low selectivity. One way to increase its selectivity is to mix it with a more selective solvent (antisolvent), such as trifluoromethane. To explore this idea, one needs micelle-formation and cloudpressure data for a range of mixture ratios. Figure 9 shows the copolymer CP for PEG-b-PCL (5K-11K) in trifluoromethane + dimethyl ether as a function of percent of dimethyl ether in the solvent mixture at different temperatures. The solvent capacity is found to be directly proportional to dimethyl ether percent; the higher the dimethyl ether percent, the lower the CP, and hence the higher the capacity. This result suggests a convenient way to adjust the solvent capacity by changing the solvent composition. The crystallization and melting temperatures for PEG-b-PCL (5K-11K) in trifluoromethane + dimethyl ether mixtures are shown in Figures 10 and 11, respectively. It turns out that the crystallization and melting temperatures decrease with decreasing trifluoromethane concentration. At 1200 bar, for example, the crystallization temperature decreases from 30 °C in pure trifluoromethane to 10 °C in pure dimethyl ether. Therefore, the crystallization temperature can also be controlled by changing solvent composition. The micellar regions for PEG-b-PCL (5K-11K) in trifluoromethane + dimethyl ether mixtures are shown in Figure 12. As expected, the micellization pressure increases with increasing trifluoromethane concentration. More important, the size of the micellar region (measured as the pressure difference between MP and CP), which depends on the solvent selectivity, increases with increasing trifluoromethane concentration. All in all, these results suggest that not only the solvent capacity, but also its selectivity, the solid-liquid transitions,
16086
J. Phys. Chem. C, Vol. 114, No. 39, 2010
Figure 10. Pressure-temperature phase diagram depicting crystallization temperatures of poly(ethylene glycol)-b-poly(ε-caprolactone) (Mw ) 5000-b-11000) in supercritical trifluoromethane, dimethyl ether, and subsequent mixtures. The concentration of polymer in solution was ∼1 wt %.
Green et al.
Figure 12. Pressure-temperature phase diagram of poly(ethylene glycol)-b-poly(ε-caprolactone) (Mw ) 5000-b-11000) in supercritical trifluoromethane, dimethyl ether, and subsequent mixtures. Micellar regions are shown as shaded regions between the micellization point curve and the cloudpoint curve. Note: The upper limit of the shaded region for trifluoromethane depicts the upper limit of the equipment, not the micellization boundary. The concentration of copolymer in solution was ∼1 wt % for all but the pure dimethyl ether, which was ∼2 wt %.
temperature, and melting temperature. This can be utilized to develop efficient ways to prepare micellar precursors for drugloaded nanoparticles. Acknowledgment. The authors would like to acknowledge the National Science Foundation (Grant No. CBET 0726316) for supporting this work. References and Notes
Figure 11. Pressure-temperature phase diagram depicting melting temperatures of poly(ethylene glycol)-b-poly(ε-caprolactone) (Mw ) 5000-b-11000) in supercritical trifluoromethane, dimethyl ether, and subsequent mixtures. The concentration of polymer in solution was ∼1 wt %.
and the micellar region can be controlled continuously by changing the solvent composition. This provides a crucial variable for efficient ways to prepare micellar precursors for drug-loaded nanoparticles. Conclusion The compressible solvents studied in this work can induce pressure-tunable micellization of PEG-b-PCL. Their capacity and selectivity, and hence their ability to form micelles, depends on their density, polarity, and hydrogen bonding potential. By mixing two solvent components, such as dimethyl ether (good solvent) and trifluoromethane (selective antisolvent), one can control not only the micellization temperature and pressure, but also the bulk separation pressure (cloud pressure), crystallization
(1) Kabanov, A. V.; Alakhov, V. Y. Amphiphilic Block Copolymers: Self-Assembly and Applications; Elsevier: Amsterdam, The Netherlands, 1997. (2) Kataoka, K.; Kwon, G.; Yokoyama, M.; Okano, T.; Sakurai, Y. J. Controlled Release 1992, 24, 119. (3) Koga, T.; Zhou, S.; Chu, B.; Fulton, J. L.; Yang, S.; Ober, C. K.; Erman, B. ReV. Sci. Instrum. 2001, 72, 2679. (4) Kwon, G.; Naito, M.; Yokoyama, M.; Okano, T.; Sakurai, Y.; Kataoka, K. J. Controlled Release 1997, 48, 195. (5) La, S. B.; Okano, T.; Kataoka, K. J. Pharm. Sci. 1996, 85, 85. (6) Gaucher, G.; Dufresne, M.-H.; Sant, V.; Kang, N.; Maysinger, D.; Leroux, J.-C. J. Controlled Release 2005, 109, 169–188. (7) Gref, R.; Minamitake, Y.; Peracchia, M.; Trubetskoy, V.; Torchilin, V.; Langer, R. Science 1994, 263, 1600–1603. (8) Vangeyte, P.; Gautier, S.; Je´roˆme, R. Colloids Surf., A 2004, 242, 203–211. (9) Kendall, J. L.; Canelas, D. A.; Young, J. L.; DeSimone, J. M. Chem. ReV. 1999, 99, 543–563. (10) Winoto, W.; Adidharma, H.; Shen, Y.; Radosz, M. Macromolecules 2006, 39, 8140–8144. (11) Tyrrell, Z.; Winoto, W.; Shen, Y.; Radosz, M. Ind. Eng. Chem. Res. 2009, 48, 1928–1932. (12) Chan, A. K. C.; Russo, P.; Radosz, M. Fluid Phase Equilib. 2000, 173, 149. (13) Łuszczyk, M.; Radosz, M. J. Chem. Eng. Data 2003, 48, 226– 330. (14) Winoto, W.; Tan, S. P.; Shen, Y.; Radosz, M.; Hong, K.; Mays, J. W. Macromolecules 2009, 42 (18), 7155–7163.
JP100646A
