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Single-Solvent Preparation of Crew-Cut Aggregates of Various Morphologies from an Amphiphilic Diblock Copolymer Luc Desbaumes and Adi Eisenberg* Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec, Canada H3A 2K6 Received May 29, 1998. In Final Form: October 14, 1998 Crew-cut aggregates of different morphologies, prepared from polystyrene-b-poly(acrylic acid) (PS-bPAA) (with long PS blocks and short PAA blocks), were obtained through a single-solvent method. Low alkanols (i.e., methanol to n-butanol) were used as solvents. The hydrophobic block is solubilized at elevated temperatures, and on cooling, the decrease in temperature induces self-assembly. The short PAA block remains soluble throughout. Since the low alkanols have relatively low boiling points, confinement under pressure is required. However, it is the elevated temperature, rather than the pressure, which is responsible for the success of the method. Parameters such as the temperature, the copolymer concentration, and the nature of the solvent have a morphogenic effect, leading to the formation of aggregates with a range of morphologies.
Microphase separation is known to occur in the solid state for copolymers and polymer blends composed of incompatible blocks.1 Similarly, in solution, diblock copolymer amphiphiles can self-assemble in the presence of a selective solvent for one of the blocks to form aggregates or micelles.2 These micelles are referred to as regular or reverse when obtained in polar or apolar solvents, respectively. A distinction can also be made between star and crew-cut micelles.3 The corona of a crew-cut aggregate is short compared to the diameter of the core, while the reverse is true for star micelles. Star micelles have been studied extensively, and their formation by direct dissolution in water is frequently possible. For example, aggregates of polystyrene-b-poly(ethylene oxide) (PS-bPEO)4 as well as polystyrene-b-poly(sodium acrylate) (PSb-PANa)5 diblock copolymers with long PEO or PANa blocks compared to the PS blocks have been prepared this way. Crew-cut aggregates can be obtained from a range of polymers,6 including asymmetric polystyrene-b-poly(acrylic acid) diblock copolymers7 (PS-b-PAA) consisting of a short PAA block and a long PS block. Stable aggregates of a range of morphologies are obtained under various conditions.8-11 The method of preparation consists of the dissolution of the copolymer in a good solvent for both (1) Molau, G. E. Colloidal and Morphological Behavior of Block and Graft Copolymers; Plenum Press: New York, 1971. Estes, G. M.; Cooper, S. L. Multiphase Polymers. Adv. Chem. Ser. 1976, 176, 181-293. Folkes, M. J. Processing, Structure and Properties of Block Copolymers; Elsevier Applied Science Publishers Ltd.: London, 1985. Bates, F. S.; Fredrickson, G. H. Annu. Rev. Phys. Chem. 1990, 41, 525. (2) Price, C. In Developments in block copolymers: Goodman, I., Ed.; Applied Science Publishers: London, 1982; Vol. 1, pp 39-80. Selb, J.; Gallot, Y. In Developments in block copolymers; Goodman, I., Ed.; Elsevier Applied Science: London, 1985; Vol. 2, pp 27-96. Tuzar, Z.; Kratachvol P. Adv. Colloid Interface Sci. 1976, 6, 201. (3) Halperin, A.; Tirell, M.; Lodge, T. P. Adv. Polym. Sci. 1992, 100, 31. (4) Wilhelm, M.; Zhao, C.-L.; Wang, Y.; Xu, R.; Winnik, M. A.; Mura, J.-L.; Riess, G.; Croucher, M. D. Macromolecules 1991, 24, 1033. (5) Astafieva, I.; Zhong, X. F.; Eisenberg, A. Macromolecules 1993, 26, 7339. (6) Gao, Z.; Varshney, S. K.; Wong, S.; Eisenberg, A. Macromolecules 1994, 27, 7923. Honda, C.; Sakaki, K.; Nose, T. Polymer 1994, 35, 5309. (7) Zhang, L.; Shen, H.; Eisenberg, A. Macromolecules 1997, 30, 1001. (8) Zhang, L.; Eisenberg, A. J. Am. Chem. Soc. 1996, 118, 3168. (9) Zhang, L.; Yu, K.; Eisenberg, A. Science 1996, 272, 1777. Zhang, L.; Eisenberg, A. Macromolecules 1996, 29, 8805.
blocks (e.g., THF, DMF, and dioxane) followed by the addition of a solvent selectively bad for one of the blocks (e.g., water for polystyrene). The hydrophobic polystyrene blocks then assemble to form the core of the aggregates. Dialysis against water is needed in the last step of the preparation to remove the organic solvent from the core. The conditions leading to the formation of crew-cut aggregates of a range of different morphologies have been explored.8-16 Three contributions to the free energy are involved: the stretching of the PS block, the repulsive interactions of the corona chains, and the core-corona interface energy.15 The morphologies can be controlled by a broad range of parameters such as the water content,15 the composition of the copolymer,8,10,12,14,15 the addition of ions,9,13,15 the copolymer concentration,15 the nature of the solvent,13,15 and the homopolymer content.8,15 Possible pharmaceutical applications16 and environmental preoccupations make it desirable to avoid the toxic organic solvents (i.e., DMF, THF, and dioxane) which are currently used in the preparation of crew-cut aggregates. Direct dissolution in water is possible for star micelles since the hydrophilic block is relatively long while the hydrophobic block is short. Preparation of crew-cut aggregates through a similar method would require a marginal solvent for the long core-forming block, which would, however, also keep the hydrophilic corona-forming block in solution after micellization. To date, crew-cut aggregates have not been obtained in a single hydrophilic (10) Yu, K.; Zhang, L.; Eisenberg, A. Langmuir 1996, 12, 5980. (11) Zhang, L.; Eisenberg, A. Science 1995, 268, 1728. (12) Shen, H.; Zhang, L.; Eisenberg, A. J. Phys. Chem. B 1997, 101, 4697. (13) Yu, Y.; Eisenberg, A. J. Am. Chem. Soc. 1997, 119, 8383. (14) Yu, K.; Eisenberg, A. Macromolecules 1996, 29, 6359. (15) Zhang, L.; Eisenberg, A. Formation of Crew-Cut Aggregates of Various Morphologies from Amphiphilic Block Copolymers in Solution Polym. Adv. Technol. 1998, submitted for publication. (16) Mu¨ller, R. H. Colloidal Carriers for Controlled Drug Delivery and Targeting; CRC Press: Boca Raton, FL, 1991. Kabanov, A. V.; Alakhov, V. Y. Micelles of Amphiphilic Block Copolymers as Vehicles for Drug Delivery. In Amphiphilic Block Copolymers: Self-Assembly and Applications; Alexandrinis, P., Lindman, B., Eds.; Elsevier: Amsterdam, The Netherlands, in press. Kwon, G.; Naito, M.; Yokoyama, M.; Okano, T.; Sakurai, Y.; Kataoka, K. J. Controlled Release 1997, 48, 195.
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Single-Solvent Preparation of Crew-Cut Aggregates
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solvent because the length of the hydrophobic core block makes them insoluble. The purpose of this paper is to describe the preparation of crew-cut aggregates through a single-solvent method. The approach involves the use of elevated temperatures to solubilize the polymer and then to form the aggregates on cooling. Evidently, the use of high temperatures frequently requires the use of elevated pressures. Very little work has been done in the area of block copolymer micelles at high temperatures or elevated pressures. Ylitalo and Frank17 published a study of the copolymer PS-b-PEP at high temperature in n-heptane. Their work was motivated by the applications of micelles under conditions involving high temperatures and elevated pressures (e.g., as lubricants). They found a pressure dependence of both the critical micellization temperature (cmt) and the critical micellization concentration (cmc). The cmt decreases as a function of pressure, typically ∼15 °C for 60 atm at low pressures; the effect levels off at high pressures. Consequently, the cmc increases with pressure at all temperatures, again to level off at high pressures. They used a simple thermodynamic model, involving a positive volume change upon micellization when pressure is applied, to predict the formation of micelles and to characterize the decrease in the cmt. The first solvent we tried was water. It proved unsatisfactory, even at temperatures of 200 °C (and elevated pressures). However, we wanted to stay at temperatures below 200 °C, to avoid polymer decomposition. Therefore, low alkanols were tried (specifically methanol, ethanol, 2-propanol, and n-butanol). Among these, ethanol is most attractive as it is toxicologically relatively harmless and also environmentally acceptable. The boiling points of these alcohols18 (64.7, 78.4, 82.5, and 117.5 °C, respectively) are low, and raising the temperature to the range of 110200 °C requires the use of elevated pressures. Methanol (Fisher Scientific), ethanol (Commercial Alcohols Inc.), 2-propanol (BDH), and n-butanol (Calendon) were used as received. The copolymer used, PS386-b-PAA79, a diblock copolymer with 386 PS units and 79 PAA units, was synthesized by sequential anionic polymerization. Both the copolymer and the alcohol were placed in a vial in the pressure vessel. Some solvent was added to the bottom of the vessel surrounding the vial, in order both to obtain good heat transfer and to provide a solvent reservoir so that condensation did not remove significant amounts of solvent from the vials during cooling. The system was then heated to the desired temperature and maintained for 4-8 h. Next, the system was cooled, and the reactor was opened when the internal and external pressures had equalized (at a temperature below 40 °C). The solution could then be either dialyzed or flooded with water to obtain samples for transmission electronic microscopy (TEM). A description of the preparation of the grids can be found elsewhere.8 Finally, TEM was carried out on a Philips EM410 microscope operating at an acceleration voltage of 80 kV in order to characterize the morphologies. We now report the effects of some relevant parameters (i.e., the nature of the solvent, the temperature, and the concentration) on the formation of crew-cut aggregates by the single-solvent method. An example of the influence of the nature of the solvent is illustrated in Figure 1. Under similar conditions (same temperature, concentration, and
time), tubules were obtained in methanol (Figure 1A), vesicles in ethanol (Figure 1B), interconnected vesicles in propanol (Figure 1C), and solid spheres in butanol (Figure 1D). Because of the time needed to heat and cool (∼1 and 3 h, respectively), aggregates with the predominant morphologies shown here are often seen in the presence of those of other morphologies. This is especially the case for all bilayer morphologies for which vesicles are seen along with tubules and occasionally sheets. For example, small vesicles are seen together with tubules with a very small inner diameter in methanol. In ethanol, however, mainly vesicles (larger than those in methanol) appear on the grid and tubules are seldom seen. In propanol, isolated vesicles and tubules can be found along with interconnected vesicles, which is probably a trapped intermediate morphology between vesicles and tubules. This is supported by the fact that in methanol and ethanol vesicles are sometimes seen attached to the ends of the tubules. We also believe that all the minority morphologies (representing less than 10% of the aggregates) are on their way to the predominant morphology (small vesicles and tubules, tubules, and larger vesicles). Various morphologies can also be obtained by changing the temperature or the concentration. In propanol, vesicles and large compound vesicles (LCVs) were obtained at 140 °C, whereas interconnected vesicles appeared at 160 °C. In butanol, only spheres are seen at 160 °C, but experiments carried out at 115 °C showed the presence of vesicles along with spheres. From previous studies,13 we know that the better the solvent for the core block (the solvent quality improves as the temperature increases), the more likely it is to form spherical aggregates. Temperature is a necessary parameter, the solubility of the copolymer in low alkanols at room temperature has been evaluated, and no dissolution has been observed even after several days of stirring. At temperatures below 120 °C, no recognizable morphologies could be obtained in either ethanol or methanol. It was also found that, while interconnected vesicles were obtained at a concentration of 0.10% (w/w) copolymer, multiplying the concentration by a factor of 3 leads to the formation of mainly spheres and rods (figures not shown). The success of the present single-solvent method relies on changes in the polymer/solvent interaction parameters with temperature. Gu¨ndu¨z and Dinc¸ er19 determined the solubility parameter of polystyrene (M h n ) 20 000 ( 5000) in low alkanols. They showed that, upon heating from 162 to 229 °C, χPS/alcohol decreases from 2.19 to 0.44 in methanol, from 1.8 to 0.43 in ethanol, from +1.74 to -0.15 in propanol, and from 1.47 to 0.82 in butanol. The solvent thus becomes better for the long PS block. On cooling, χPS/solv will obviously increase while the PAA block will remain in solution,20 thus stabilizing the aggregates. The use of high temperatures requires elevated pressures. It is worth inquiring whether it is the temperature or the pressure that has the major effect on the phenomena reported here. Changes in morphology of crew-cut aggregates have been analyzed through the relative values of the solubility parameters of the solvents and copolymer13 and can also be related to the dielectric constants. Consequently, because a significant change in the dielectric constant of ethanol or butanol requires several hundred atmospheres21 (e.g., approximately one unit for 500 atm for ethanol), pressure is not expected to have a great influence on the micellization. By contrast, in the
(17) Ylitalo, D. A.; Frank, C. W. Polymer 1996, 37, 4969; Polym. Prepr. (Am. Chem. Soc., Div. Polym. Chem.) 1991, 32, 503. (18) Handbook of Chemistry and Physics, 60th ed.; CRC Press Inc.: Boca Raton, FL, 1979-80; pp D203-219.
(19) Gu¨ndu¨z, S.; Dinc¸ er, S. Polymer 1980, 21, 1041. (20) Polymer Handbook, 2nd ed.; Wiley-Intersciences Publication: New York, p IV 243. (21) Danforth, W. E., Jr. Phys. Rev. 1931, 38, 1224.
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Figure 1. Morphological changes in different solvents: (A) methanol at 165 °C, 0.10% (w/w), (B) ethanol at 165 °C, 0.07% (w/w), (C) propanol at 160 °C, 0.10% (w/w), (D) butanol at 170 °C, 0.07% (w/w).
temperature range considered, has been shown to change appreciably as a function of temperature22 (e.g., several units for temperature changes of a few degrees); therefore, temperature is expected to play a major role in micellization. In addition, because the relative coil dimensions of each block are known to be an important parameter for the micellization process, morphologies will also depend strongly on the type of solvent. In addition to the temperature and the nature of the solvent, the initial copolymer concentration, and other parameters described elsewhere,15 can also be used to control the morphologies. In summary, it has been shown that crew-cut aggregates can be obtained from the amphiphilic block copolymer PS386-b-PAA79 through a single-solvent method. An interesting feature of this method is the use of low alkanols, including ethanol, a pharmacologically acceptable solvent. Because polystyrene is insoluble in alcohols at room temperature, high temperatures have been used to dissolve the copolymer, while cooling induces the formation of micelles. This shows that low alkanols can become reasonably good solvents for PS at high temperatures. The success of the method is based on the change of the polymer/solvent χ parameters with temperature. The low boiling point of the solvents, along with the relatively high (22) Åkerlo¨f, G. J. Am. Chem. Soc. 1932, 54, 4125.
temperatures reached, makes the use of a pressure vessel necessary. However, pressure by itself is not believed to have a major influence on the aggregation process. The morphologies can be controlled by changing, among others, the temperature, the nature of the solvent, and the copolymer concentration; we anticipate that the use of mixed solvents and the addition of salts will also be relevant. Interconnected vesicles may be intermediates between tubules and vesicles, resulting from the kinetically controlled aggregation which is stopped at different stages during the long cooling process. The micelles formed are very stable at room temperature. In addition to the possible use of crew-cut aggregates in pharmaceutical applications, this method is very promising because it involves a single parameter, i.e., temperature, to control the aggregation process. Acknowledgment. The authors thank the Natural Sciences and Engineering Research Council of Canada (NSERC) for financial support of this research. Thanks are also due to Dr. L. Zhang for providing the block copolymer and for useful discussions and to Mr. F. Kluck for the design of the equipment. LA980632N
