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Tensioactive Properties of Poly([R,S]-β-malic acid-b-E-caprolactone) Diblock Copolymers in Aqueous Solution Olivier Coulembier,† Philippe Dege´e,† Philippe Gue´rin,‡ and Philippe Dubois*,† Laboratory of Polymeric and Composite Materials (LPCM), University of Mons-Hainaut, Place du Parc 20, B-7000 Mons, Belgium, and Laboratoire de Recherche sur les Polyme` res, UMR C7581 CNRS, Universite´ Paris Val-de-Marne, Rue Henry Durant 2-8, 94320 Thiais, France Received April 10, 2003. In Final Form: July 14, 2003 Well-defined amphiphilic poly(β-malic acid-b--caprolactone) diblock copolymers with tunable hydrophobic content have been synthesized. For the sake of comparison, amphiphilic R-lauryl, ω-methyl poly(β-malic acid) has been synthesized as well. The stability of the block copolymers in aqueous solutions against hydrolysis has been demonstrated, at least within a period of time long enough to rely on tensioactive measurements by the pendant drop method. The critical micellar concentration of such amphiphilic (co)polymers has been determined by dynamic light scattering. The effect of pH, temperature, salt (NaCl) addition, and copolymer composition has been investigated. Whatever the copolymer composition, it has been shown that increasing pH from 2.2 to 8.5 increases surface tension in water. In contrast, reducing the length of the hydrophobic block lowers the surface tension in water but also the mean diameter of micellar structures.
Introduction Micelles formed by amphiphilic block or graft copolymers belong to the family of colloidal polymers. This family is constituted by self-assembling and self-organizing macromolecular systems possessing colloidal properties and surface activity.1 In the late 1950s, researchers observed a stable turbidity when they tried to carry out fractional precipitation of amphiphilic block or graft copolymers.2-4 This observation was attributed to the presence of macromolecular micelles. Under selective solvent conditions (thermodynamically good solvent for one block and bad one for the other block), the copolymers adopt various organized structures. Multimolecular spherical micelles, having an inner core made up by the insoluble blocks and an outer shell constructed by the soluble blocks, represent the most frequent structure.5 In the past 10 years, several research activities have been focused on the preparation of macromolecular micelles based on amphiphilic block copolymers in an aqueous medium and on their characterization. These micelles have the advantages of having a fairly narrow size distribution and a low critical aggregation concentration which paves the way to different potential applications such as emulsifiers, dispersing and foaming agents, solubilizers, and drug carrier systems.7,8 With respect to this latter field, totally biocompatible and degradable amphiphilic diblock copolymers are of particular interest for temporary applications.8-14 * To whom correspondence should be addressed. E-mail: philippe.
[email protected]. † University of Mons-Hainaut. ‡ Universite ´ Paris Val-de-Marne. (1) Tuzar, Z. In Solvents and Self-organization of Polymers; Webber, S. E., Munk, P., Tuzar, Z., Eds.; NATO ASI Series E: Applied Sciences, Vol. 327; Kluwer: Dordrecht, 1996; p 1. (2) Merret, F. M. J. Polym. Sci. 1957, 24, 467. (3) Hartlay, F. D. J. Polym. Sci. 1959, 34, 397. (4) Schlick, S.; Levy, M. J. Phys. Chem. 1960, 64, 883. (5) Fisher, L. R.; Oakenful, D. G. Chem. Soc. Rev. 1977, 6, 25. (6) Cammas-Marion, S.; Be´ar, M.-M.; Harada, A.; Gue´rin, Ph.; Kataoka, K. Macromol. Chem. Phys. 2000, 201, 355. (7) Tuzar, Z. In Solvents and Self-organization of Polymers; Webber, S. E., Munk, P., Tuzar, Z., Eds.; NATO ASI Series E: Applied Sciences, Vol. 327; Kluwer: Dordrecht, 1996; p 309. (8) Lehtonen, J.; Kinnunnen, P. K. J. Biophys J. 1995, 68 (2), 525.
Poly(β-malic acid), PMLA, is an attractive water-soluble aliphatic polyester with carboxylic acid pendant groups that has proven to be biocompatible and to degradable in vivo into malic acid, a nontoxic molecule.15-17 Gue´rin et al. have synthesized amphiphilic block copolymers composed of a PMLA hydrophilic block and poly(butyl malate) or poly(butyl 3-methyl malate) hydrophobic segments through the sequential anionic copolymerization of benzyl β-malolactonate and butyl malolactonate derivatives, followed by selective hydrogenolysis of benzyl ester groups.6 The resulting copolymers formed stable micelles in physiological conditions. The critical micellar concentration (cmc) was dependent on the chain length of both blocks and on the chemical structure of the hydrophobic block.2 Recently, we reported on the controlled synthesis of well-defined biodegradable and biocompatible amphiphilic poly(β-malic acid-b--caprolactone) diblock copolymers (P(MLA-b-CL)) according to a three-step strategy (Scheme 1).18 This paper reports on the application of this three-step strategy for producing well-defined amphiphilic P(MLAb-CL) diblock copolymers with controlled composition and block length. Their tensioactive properties have been investigated in water by surface tension experiments. Micelles and their aggregates have been studied by dynamic light scattering measurements as well. The temperature dependence of the cmc has been particularly examined to evaluate the thermodynamic parameters of (9) Bromberg, L.; Magner, E. Langmuir 1999, 15, 6792. (10) Rapoport, N.; Marin, A.; Luo, Y.; Prestwich, G. D.; Muniruzzaman, M. J. Pharm. Sci. 2002, 91, 157. (11) Kabanov, A. V.; Nazarova, I. R.; Astafieva, I. V.; Batrakova, E. V.; Alakhov, V. Y.; Yaroslavov, A. A.; Kabanov, V. A. Macromolecules 1995, 28, 2303. (12) Alexandridis, P. Curr. Opin. Colloid Interface Sci. 1997, 2, 478. (13) La, S. B.; Okano, T.; Kataoka, K. J. Pharm. Sci. 1996, 85, 85. (14) Jeong, Y. I.; Nah, J. W.; Lee, H. C.; Kim, S. H.; Cho, C. S. Int. J. Pharm. 1999, 188, 49. (15) Vert, M. CRC Crit. Rev. Ther. Drug Carrier Syst. 1986, 2, 291. (16) Fournie´, Ph.; Dumurado, D.; Gue´rin, Ph.; Braud, C.; Vert, M.; Pontikis, R. J. Bioact. Compat. Polym. 1992, 7, 113. (17) Braud, C.; Vert, M. Polym. Bull. (Berlin) 1992, 29, 177. (18) Coulembier, O.; Dege´e, Ph.; Cammas-Marion, S.; Gue´rin, Ph.; Dubois, Ph. Macromolecules 2002, 35, 9896.
10.1021/la030151q CCC: $25.00 © 2003 American Chemical Society Published on Web 09/09/2003
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Scheme 1 . Three-Step Synthesis of Poly(β-malic acid-b-E-caprolactone) (P(MLA-b-CL)) Diblock Copolymers
micellization. The effect of pH, temperature, length of the hydrophobic block, and salt addition on the tensioactive properties in water has also been investigated as well. For comparison, lauric acid has been substituted for 11hydroxydodecanoic acid as the initiator, therefore leading to R-lauryl, ω-methyloxycarbonyl poly(β-malic acid) chains after consecutive controlled methylation of the carboxylic acid end-group of R-lauryl, ω-carboxylic acid poly(benzyl β-malolactonate) and selective removal of benzyloxy ester groups by hydrogenolysis (C11H23-PMLA). Experimental Section Materials. [R,S]-benzyl β-malolactonate (MLABz) was synthesized and purified starting from aspartic acid as published elsewhere.19 It was stored at -18 °C, distilled under reduced pressure, and dried by three successive azeotropic distillations of toluene just before use. -Caprolactone (CL) (across, 99%) was dried over calcium hydride at room temperature (RT) for 48 h and then distilled under reduced pressure. 11-Hydroxydodecanoic acid (Aldrich, 97%), lauric acid (Aldrich, 98%), and 18-crown-6 (Acros, 99%) were dried by three successive azeotropic distillations of toluene. Potassium (Acros, 98%), naphthalene (Acros, 99%), trimethylsilyldiazomethane (2 N in hexane from Aldrich), triethylaluminum (1.8 M in toluene from Fluka), NaOH (Acros, pellets p.a.), HCl (Acros, p.a. 37%), Pd/C (10 wt % from Aldrich), and hydrogen (Air Liquide, >99.999%) were used without further purification. Toluene (Labscan, 99%) and tetrahydrofuran (THF) (Labscan, 99%) were dried by refluxing over CaH2 and Na/ benzophenone complex, respectively. Just before use, THF was further dried over low molecular weight ω-lithium styryl polystyrene and then distilled under reduced pressure. Preparation of Micellar Solutions. A Millipore Milli-Ro 4 water purification system with resistance around 18 MΩ cm was used to purify water necessary to the preparation of the amphiphilic copolymer solutions. Stock amphiphilic (co)polymer solutions were prepared at room temperature by dissolving a known amount of (co)polymer in the appropriate volume of purified water (Cc ) 10 g L-1), sonicated for 1 h by using a Bransonic 2210 bath, and filtered through a 1.2 µm Acrodisk filter. Solutions of lower concentration were obtained by subsequent dilutions of the stock solutions. Just before measurements, the pH of the copolymer solutions was adjusted between 2 and 8.5 by adding small volumes of either an aqueous HCl (19) Cammas-Marion, S.; Renard, I.; Langlois, V.; Gue´rin, Ph. Polymer 1996, 37, 4215.
solution ([HCl]0 ) 1.02 mol L-1) or an aqueous NaOH solution ([NaOH]0 ) 0.1 mol L-1) to the initial copolymer solutions (pH ∼ 3 for a copolymer concentration of 2 g L-1). Characterization. 1H NMR spectra were recorded using a Bruker AMX-300 apparatus at RT in CDCl3 except as otherwise mentioned (30 mg/0.6 mL). Size exclusion chromatography (SEC) was performed in THF at 30 °C using a Polymer Laboratories liquid chromatograph equipped with a PL-DG802 degasser, an isocratic HPLC pump LC 1120 (flow rate ) 1 mL/min), a Rheodin manual injection (loop volume ) 200 µL, solution concentration ) 2 mg/mL), a PL-DRI refractive index detector, a Viscotek 270 dual detector (viscometer and right angle laser light scattering), and four columns: a PL gel 10 µm guard column and three PL gel Mixed-B 10 µm columns (linear columns for separation of MWPS ranging from 500 to 106 Da). A polystyrene standard was used for the equipment calibration (PS 90K, Mp ) 89 300, Mw ) 90 100, Mn ) 86 700, IV ) 0.439 dL g-1). Dynamic light scattering measurements were carried out using a BI-160 apparatus (Brookhaven Instruments Corp., USA) with a He-Ne laser source operating at 17 mW and delivering a vertically polarized light (λ ) 633 nm). The particle sizes and size distribution were calculated using CONTIN algorithms. The surface tensions were determined using a Drop Shape Analysis System DSA 10 Mk2 equipped with a thermostated chamber and a Circulator Thermo HAAKE DC 10. Synthesis of r-Lauryl, ω-Methyl Poly(β-malic acid). In a previously flamed and nitrogen-purged round-bottom flask, a 0.2 mol L-1 potassium naphthalene radical anion solution was prepared as reported elsewhere.17 In another previously flamed and nitrogen-purged round-bottom flask, 18-crown-6 ether (0.52 g, 1.97 mmol) and lauric acid (0.39 g, 1.97 mmol) were dissolved in THF (10 mL) and then added with a stoichiometric amount of the solution of potassium naphthalene radical anion (final concentration ) 0.1 mol L-1). The polymerization of MLABz (2.0 g, 9.7 mmol) was typically conducted in a previously flamed and nitrogen-purged round-bottom flask equipped with a three-way stopcock capped by a septum by initiation with the complex formed between potassium laurate and 18-crown-6 ether (2.0 mL, 0.2 mmol) in THF (44.5 mL) at 0 °C. After 120 min, the polymerization was stopped by adding a few drops of aqueous HCl (0.1 mol L-1). After evaporation of the solvent, the product was dissolved in dichloromethane (20 mL) and extracted three times with a saturated aqueous KCl solution (3 × 20 mL) and with deionized water (3 × 20 mL). Finally, the organic layer was poured into 8 volumes of cold heptane (160 mL). The polymer was recovered by filtration and dried under reduced pressure at 40 °C until constant weight (yield ) 79%). A number-average
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Table 1. Molecular Characteristics of C11H23-PMLA and P(MLA-b-CL) Diblock Copolymers and the Effect of Their Composition on the Surface Tension Measurements for 2 g L-1 Solutions in an Aqueous Medium entry
samples
MnPMLAblocka
1 2 3 4 5
C11H23-PMLA P(MLA-b-CL) 1 P(MLA-b-CL) 2 P(MLA-b-CL) 3 P(MLA-b-CL) 4
4400 3800 3800 3800 3800
MnPCLblocka 2500 5400 9000 11500
MnP(MLA-b-CL)
fPMLAb
γ (mN/m)
6300 9200 12800 15300
0.96 0.60 0.41 0.30 0.25
37.1 ( 0.6 42.4 ( 1.0 43.9 ( 1.0 45.3 ( 2.0 44.7 ( 2.3
a As determined by 1H NMR spectroscopy in CD COCD added with a few drops of D O (see Experimental Section). b f 3 3 2 PMLA is the weight fraction of PMLA in the copolymer.
molecular weight of 7700 was calculated by 1H NMR spectroscopy from the relative intensity of methine protons of the repetitive units at 5.45 ppm and R-methylenecarbonyl protons of the initiator moiety at 2.25 ppm (Mn ) [2I5.45/I2.25] × MWMLABz] + MWLA where MWMLABz and MWLA are the molecular weights of MLABz and lauric acid, respectively). SEC showed that the molecular weight distribution was monomodal with a polydispersity index of 1.28. After selective methylation of the carboxylic acid end-group of the resulting R-lauryl, ω-carboxylic acid poly(benzyl-β-malolactonate) (1.3 g, 0.17 mmol) by trimethylsilyldiazomethane17 (0.25 mL, 0.51 mmol), a catalytic hydrogenation of the benzyl ester function was realized by dissolving the R-methyl, ω-methyloxycarbonyl poly(benzyl β-malolactonate) (1.3 g, 0.17 mmol) into 200 mL of acetone at RT and then added with Pd/C 10 wt % (0.2 g). A continuous flow of hydrogen (0.15 bar) was bubbled into the solution for 7 h. After filtration through Celite, a clear solution was obtained. The solvent was evaporated under moderated reduced pressure (10 mmHg) before recovering the polymer by extensive drying at 40 °C in a vacuum oven (yield > 99%). 1H NMR (300 MHz, CD3COCD3 added with a few drops of D2O, δ ppm): 0.8-1.8 (m, 21H), 2.25 (t, 2H), 2.8 (m, 2H), 3.8 (s, 3H from -C(O)OMe), 5.45 (m, H). As determined by 1H NMR spectroscopy, Mn ) 4400. (Mn ) [2I5.45/I2.45 × MWMLA] + MWLA where MWMLA and MWLA are the molecular weights of MLA and lauric acid, respectively.) Synthesis of the Poly(β-malic acid-b-E-caprolactone). As previously reported,18 P(MLA-b-CL) was synthesized through a three-step strategy combining the anionic polymerization of MLABz with the coordination-insertion ring-opening polymerization (ROP) of CL, followed by the selective removal of benzyloxy protective groups. Typically, the anionic polymerization of MLABz was carried out for 120 min at 0 °C and with an initial monomer-to-potassium 11-hydroxydodecanoate initiator molar ratio of 49. A molar mass of 7900 was determined by 1H NMR spectroscopy from the relative intensity of methine protons of the repetitive units at 5.45 ppm and hydroxymethylene protons of the initiator moiety at 3.7 ppm. This value is in good agreement with the one determined by SEC (MnSEC ) 7800, Mw/Mn ) 1.23). After selective and quantitative methylation of the carboxylic end-group with trimethylsilyldiazomethane, the R-hydroxyl endgroup was reacted with 1.2 equiv of triethylaluminum in toluene at 50 °C for 2 h. After ethane evolution, the ROP of CL was carried out at RT for 48 h and with initial monomer-to-initiator molar ratios ranging from 22 to 88 ([CL]0 ) 0.5 mol L-1). The polymerization was stopped by the addition of a few drops of an HCl aqueous solution. After extraction of aluminum residues, the diblock copolymer was selectively recovered by precipitation in heptane (yield > 99%). Two minor resonances in the 1H NMR spectrum at 3.7 and 3.8 ppm, attributed to R-hydroxymethylene and ω-methyloxycarbonyl end-group protons, respectively, allowed for calculating the Mn of each block (MnPMLABz ) (I5.45/ (I3.7-3.8/5) × MWMLABz) + MWHDD ) 7700; MnPCL ) (I4.2/2)/(I3.7-3.8/ 5) × MWCL ) 2500, 5400, 9000, and 11 500 depending on the initial monomer-to-macroinitiator molar ratio). The molecular weight distribution remained quite narrow as determined by SEC (1.35 e Mw/Mn e 1.80). The final step consisted of the selective catalytic hydrogenolysis of benzylester groups all along the poly(benzyl malolactonate) block. It was carried out as previously described for R-lauryl, ω-methyl poly(β-malic acid) synthesis (yield > 99%). 1H NMR spectroscopy in CD3COCD3 added with a few drops of D2O allowed for calculating the molar mass of the P(MLA-b-CL): MnPMLA ) (I5.45/(I3.6/2) × MWMLA) + MWHDD ) 3800; MnPCL ) (I4.2)/(I3.6) × MWCL ) 2500, 5400, 9000,
and 11 500, respectively; Mn(PMLA-b-CL) ) MnPCL + MnPMLA (see Table 1).
Results and Discussion Synthesis of Poly(β-malic acid-b-E-caprolactone) and r-Lauryl, ω-Methyl Poly(β-malic acid). Welldefined P(MLA-b-CL) copolymers have been synthesized according to a three-step strategy combining the anionic polymerization of MLABz with the coordination-insertion ring-opening polymerization of CL from an asymmetric difunctional initiator, followed by the selective removal of benzyloxy protective groups (Scheme 1). Substituting potassium laurate for potassium 11-hydroxydodecanoate in the first step, that is, the anionic polymerization of MLABz, followed by the methylation of the polyester carboxylic acid end-group and the catalytic hydrogenolysis of benzyloxy protective groups, allows the controlled synthesis of R-lauryl, ω-methyl poly(β-malic acid) (C11H23PMLA). Table 1 gathers the molecular characteristics of C11H23-PMLA and various P(MLA-b-CL) diblock copolymers in which the length of the hydrophilic PMLA block is kept constant while the molar mass of the hydrophobic poly(-caprolactone) (PCL) block is continuously increased. As both PMLA and PCL are known to be sensitive to hydrolysis,20-24 the first question to be addressed before in-depth characterization of diblock copolymer behavior in aqueous solution is to check their stability within the time required to measure the tensioactive properties by surface tension and dynamic light scattering measurements. Even though each copolymer aqueous solution has been analyzed the day of its preparation, the possible evolution of the copolymer composition by some hydrolysis reactions has been recorded by 1H NMR spectroscopy. First, a selected block copolymer has been dissolved in water for 2 days at RT, followed by water volatilization under very mild conditions for 1 day and dissolution of the recovered solid product in CD3COCD3 added with a few drops of D2O. The 1H NMR spectrum of the copolymers attests that no signal corresponding to hydrolysis byproducts could be detected, for example, malic acid and caproic acid. Moreover, the molar mass of each block remains unchanged as determined from the relative intensity of protons of the repetitive units and the end-groups. In contrast, for the same block copolymer dissolved in water for 50 days, the 1H NMR spectrum clearly shows that polyester chain degradation by hydrolysis occurs leading to the formation of malic acid (δ HO-CH(COOH)-CH2COOH ) 4.45 (t) and δ -CH2-COOH ) 2.7 ppm (m)) and to the decrease of the PCL segment length as evidenced by reduction of the intensity ratio between PCL methylene (20) Braud, C.; Bunel, C.; Vert, M. Polym. Bull. 1985, 13, 293. (21) Braud, C.; Caron, A.; Francillette, J.; Gue´rin, Ph.; Vert, M. Polym. Prepr. (Am. Chem. Soc., Div. Polym. Chem.) 1988, 29 (1), 600. (22) Fujishige, S.; Morita, R.; Brewer, J. R. Makromol. Chem., Rapid Commun. 1993, 14, 163. (23) Yasin, M.; Tighe, B. J. Biomaterials 1992, 13, 9. (24) Ye, W. P.; Du, F. S.; Jin, W. H.; Yang, J. Y.; Xu, Y. React. Funct. Polym. 1997, 32, 161.
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Figure 2. Concentration dependence of the surface tension of an amphiphilic P(MLA-b-CL) diblock copolymer (entry 2, Table 1) in aqueous solution at different temperatures: ([) 283 K, (9) 293 K, (2) 310 K, and (×) 323 K. Table 2. Temperature Dependence of the cmc, the Surface Tension at the cmc (γcmc), and the Surface Pressure (πcmc) for an Amphiphilic Diblock Copolymer P(MLA-b-CL) (Entry 2, Table 1)
Figure 1. 1H NMR spectra of an amphiphilic diblock copolymer P(MLA-b-CL) (entry 3, Table 1, solvent ) CD3COCD3 added with a few drops of D2O) compared to the same sample after 50 days in water (solvent ) CD3COCD3).
protons at 3.95 ppm (Hm) and ω-hydroxy methylene endgroup protons at 3.45 ppm (Hn) (Figure 1). Interestingly, these observations are consistent with the concomitant increase of the surface tension of the copolymer solution in water at 20 °C from 43.9 mN/m (at t0) to 54.4 mN/m (at t0 + 50 days) (entry 3 in Table 1, concentration ) 2 g/L) and the slight decrease of the copolymer aqueous solution pH. As a conclusion, it can be stated that the PMLAbased compositions listed in Table 1 are stable against hydrolysis, at least, for 3 days, which is long enough to perform our measurements and rely on our data. The mechanism and kinetics of the hydrolytic degradation of the P(MLA-b-CL) copolymers are under current investigation and will be the topic of a forthcoming paper. Surface Tension Measurements. Figure 2 shows the semilogarithmic plot of the surface tension of a given P(MLA-b-CL) diblock copolymer (entry 2 in Table 1) versus its concentration in water (expressed in g L-1) at different temperatures. The cmc has been determined from the intersection between the tangents drawn from higher concentration portions of the sigmoidal plots.25,26 From Table 2, it comes out that the temperature dependence of the cmc passes through a minimum close to 299 K in perfect agreement with the value of 298 K expected for an ionic surface-active agent.27 The evolution of the cmc as a function of the temperature is also presented in Table 2, (25) Mukerjee, P.; Mysels, K. J. Critical Micelle Concentration of Aqueous Surfactant Systems; NSRDS-NBS 36; U.S. Government Printing Office: Washington, DC, 1971. (26) Garibi, H.; Palepu, R.; Tiddy, G. J. T.; Hall, D. G.; Wyne-Jones J. Chem. Soc., Commun. 1990, 2, 115. (27) Chen, L. J.; Lin, S. Y.; Huang, C. C.; Chen, E. M. Colloids Surf., A 1998, 135, 175.
T (K)
cmc (g L-1)
γcmc (mN/m)
πcmc (mN/m)
283 293 310 323
1.86 0.92 1.17 1.90
47.06 46.76 41.54 38.24
30.34 30.24 33.16 30.30
together with those of the surface tension at the cmc (γcmc) and the surface pressure (πcmc) which is defined as the difference between the surface tension of water at a given temperature (γ0) and γcmc (πcmc ) γ0 - γcmc). In contrast to the cmc, γcmc continuously decreases as a function of the temperature increase but without paralleling the decrease of γ0. The temperature dependence of the cmc is useful to calculate the standard enthalpy and entropy of micelle formation. Indeed, according to the phase separation28 and the mass action models,29 the standard Gibbs energy of micelle formation can be expressed by ∆G°m ) RT ln χcmc, where χcmc stands for the mole fraction of surfactant in aqueous solution at the cmc. Applying the Gibbs-Helmholtz equation, the standard enthalpy of micelle formation can be expressed by the following equation:
∆H°m ) -T2[δ(∆G°m/T)]/δT ) -RT2(δ ln χcmc/δT) (1) To solve this equation, the temperature dependence of ln χcmc can be estimated from the temperature dependence of the cmc using a polynomial fitting as follows:
ln χcmc ) a + bT + cT2 + dT3
(2)
The standard enthalpy of micelle formation is then obtained by combining eqs 1 and 2 such as ∆H°m ) -RT2(b + 2cT + 3dT2). Once both the standard Gibbs energy and enthalpy of micelle formation are obtained, the standard entropy parameter can be easily derived. Figure 3 shows the evolution of ∆G°m, ∆H°m, and -T∆S°m as a function of the temperature for an amphiphilic diblock copolymer P(MLA-b-CL) (entry 2, Table 1) in aqueous solution. At low temperature, the micelle formation is entropy driven, while the unfavorable enthalpy contribution only becomes negligible close to the cmc. Figure 4 shows the linear dependence between ∆H°m and ∆S°m in agreement with the enthalpy-entropy compensation theory,30 so that ∆H°m ) ∆H/m + TC∆S°m, where ∆H/m is the enthalpy (28) Matijevic, E.; Pethica, B. A. Trans. Faraday Soc. 1958, 54, 587. (29) Philips, N. J. Trans. Faraday Soc. 1955, 51, 561. (30) Frank, H. S.; Evans, M. W. J. Chem. Phys. 1954, 13, 507.
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Langmuir, Vol. 19, No. 21, 2003 8665 Table 3. Influence of Concentration and Composition of P(MLA-b-CL) Copolymers on the Size of Micellar Structures in Water
Figure 3. Temperature dependence of ∆G°m (9), ∆H°m (2), and -T∆S°m (() for an amphiphilic P(MLA-b-CL) diblock copolymer (entry 2, Table 1) in aqueous solution.
Figure 4. Standard enthalpy of micelle formation vs standard entropy of micelle formation for an amphiphilic P(MLA-b-CL) diblock copolymer (entry 2, Table 1) in aqueous solution.
Figure 5. Influence of the pH on the surface tension of 2 g L-1 amphiphilic P(MLA-b-CL) diblock copolymers with various compositions in solution: (() entry 2, (9) entry 3, (2) entry 4, and (×) entry 5 in Table 1.
variation for standard entropy equal to zero and TC is the compensation temperature. ∆H/m reflects solute-solute interactions, while TC is characteristic of hydrophobic interactions between water and solute.31 For the P(MLAb-CL) diblock copolymer with MnPMLAblock of 3800 and MnPCLblock of 2500 (entry 2, Table 1), TC reaches 293 K which is close to the value of 300-315 K usually observed for ionic surfactants in aqueous solutions.32 In the next series of experiments, the effect of pH and copolymer composition on the surface tension in an aqueous medium was investigated. P(MLA-b-CL) diblock copolymers with various compositions (entries 2-5, Table 1) were dissolved in water for a concentration of 2 g L-1, sonicated, and filtered through an Acrodisk filter with a 1.2 µm porosity, just before measurements. The copolymer aqueous solutions were added with small volumes of either HCl (1.02 mol L-1) or NaOH (0.1 mol L-1) aqueous solutions. Figure 5 shows that a linear relationship actually exists between the surface tension and the pH, at least for pH ranging from 2.2 to 8.5. Whatever the copolymer composition, the surface tension increases from (31) Lumry, R.; Rajender, S. Biopolymer 1970, 9, 1125. (32) Jolicoeur, C.; Philip, P. R. Can. J. Chem. 1974, 52, 1834.
entry
samples
concn (g L-1)
1 2 3 4
P(MLA-b-CL) 1 P(MLA-b-CL) 2 P(MLA-b-CL) 3 P(MLA-b-CL) 4
2.5 × 10-2 2.0 × 10-2 1.2 × 10-2 6.25 × 10-3
mean mean diameter diameter for a concn (nm) of 2 g L-1 (nm) 39 43 80 85
221 302 412 500
40 to 57 mN/m, indicating that the efficacy of P(MLA-bCL) diblock copolymers as surfactants decreases at higher pH. Such a behavior perfectly agrees with previously reported data for poly(butyl malate-b-malic acid) diblock copolymers.2 This can be explained by the formation of carboxylate pendant groups along the hydrophilic block which are responsible for electrostatic repulsions in the outer shell of the micelles and their destabilization. On another hand, decreasing the length of the hydrophobic PCL block while keeping the hydrophilic counterpart unchanged tends to lower the surface tension in an aqueous medium (Table 1). This effect is still more pronounced when R-lauryl, ω-methyl poly(β-malic acid) is compared to P(MLA-b-CL) diblock copolymers, at least at a concentration of 2 g L-1. In this case, the lauryl chain plays the role of the hydrophobic segment. Dynamic Light Scattering (DLS) Measurements. The size distribution of micelles and aggregates formed by P(MLA-b-CL) diblock copolymers in water has been investigated by dynamic light scattering. In an attempt to approach the mean diameter of the micelles formed by P(MLA-b-CL) copolymers with various compositions, DLS measurements were carried out starting from an initial copolymer concentration of 0.2 g L-1. When the copolymer concentration is decreased, it has been observed that the average size of the micelle aggregates sharply drops down when a given concentration is reached. Table 3 provides both mean diameters and concentrations at which such deaggregation occurs. The mean diameter of micellar structures increases (from 39 to 85 nm) with the molar mass of the hydrophobic PCL segments forming the inner core (from 2500 to 11 500) (Figure 6). When the copolymer concentration is much higher than the cmc (concentration ) 2 g L-1), the size distribution of the micelle/aggregate structures remains monomodal but characterized by higher mean diameters. Typical values range from 221 to 500 nm with increasing PCL molar mass from 2500 to 11 500 (Table 3). Such a behavior might find some explanations in the formation of micellar aggregates via hydrogen bonding between carboxylic groups in the corona and/or through electrostatic interaction (see the effect of ionic strength hereafter). As P(MLA-b-CL) copolymers are composed by a PMLA polyelectrolyte segment due to partial dissociation and ionization of carboxylic acid functions at a given pH, temperature, and concentration, we have studied the effect of added NaCl salt on both the surface tension and the mean diameter of micellar structures in water at 20 °C. Table 4 shows the influence of NaCl concentration on the properties of micellar aggregates formed by P(MLA-bCL) copolymer (entry 5, Table 1) for a constant copolymer concentration of 2 g L-1. Reaching a NaCl concentration of 4.2 mmol L-1 triggers a sharp decrease of the mean diameter of micellar aggregates from 413 to 286 nm, in perfect agreement with a decrease of long-range intermolecular interactions when the salt concentration increases.33 A further increase of NaCl concentration has no significant effect on either the mean diameter or the surface tension. A NaCl concentra-
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Figure 6. Size distribution of P(MLA-b-CL) micellar structures in water for various copolymer compositions: (a) entry 1 (at 2.5 × 10-2 g L-1), (b) entry 2 (at 2.0 × 10-2 g L-1), (c) entry 3 (at 1.2 × 10-2 g L-1), and (d) entry 4 (at 6.25 × 10-3 g L-1) in Table 3. Table 4. Influence of NaCl Concentration on the Properties of Micelle Aggregates Obtained by Direct Dissolution of P(MLA-b-CL) Diblock Copolymer (Entry 5, Table 1) in Aqueous Solutions ([P(MLA-b-CL)] ) 2 g L-1) [NaCl] (mmol L-1)
mean diameter (nm)
γ (mN/m)
0.0 2.0 4.2 50.0 100.0 200.0
500 413 286 294 302 289
44.7 ( 2.3 44.0 ( 0.4 42.4 ( 0.7 42.7 ( 0.4 42.1 ( 0.5 42.6 ( 0.3
tion of 4.2 mmol L-1 approximately corresponds to the total concentration of carboxylic groups in the diblock copolymer ([COOH] ) 4.3 mmol L-1). Furthermore, it must be emphasized that the salt concentration required to adjust the pH of P(MLA-b-CL) copolymer solutions from 2.2 to 8.5 (see Figure 5) is systematically higher than 4.2 mmol L-1. In other words, the surface tension is totally unaffected by NaCl concentration, at least in such a concentration range. This behavior strengthens the reliability on the pH dependence of the surface tension discussed above. (33) Stalgren, J. J. R.; Pamedytyte, V.; Makuska, R.; Claesson, P. M.; Brown, W.; Jacobsson, U. Polym. Int. 2003, 52, 399.
In conclusion, this work reports on the tensioactive properties and micellization behavior in aqueous solution of well-defined amphiphilic diblock copolymers. The effect of pH, temperature, salt addition, and copolymer composition has been investigated. Since such amphiphilic diblock copolymers can find applications in the biomedical area, for example, as drug carriers in controlled release (nano)systems, their hydrolytic degradation (by polyester chain cleavage) which takes place at longer periods of time is of additional interest and needs to be more understood and tailored. Such a study actually carried out by direct observation of the copolyester micelle structure by atomic force microscopy will be reported soon. Acknowledgment. This work was partially supported by both the Re´ gion Wallonne and Fonds Social Europe´ en in the frame of the Objectif 1-Hainaut: Materia Nova program. O.C. is grateful to F.R.I.A. for his Ph.D. grant. LPCM thanks the “Service Fe´de´raux des Affaires Scientifiques, Techniques et Culturelles” for general support in the frame of the PAI-5/03. LA030151Q
