Block Copolymers of Ethylene Oxide and Phenyl Glycidyl Ether

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Langmuir 2005, 21, 5263-5271

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Block Copolymers of Ethylene Oxide and Phenyl Glycidyl Ether: Micellization, Gelation, and Drug Solubilization Pablo Taboada,† Gemma Velasquez,‡ Silvia Barbosa,† Valeria Castelletto,§ S. Keith Nixon,| Zhuo Yang,|,⊥ Frank Heatley,| Ian W. Hamley,§ Marianne Ashford,∇ Victor Mosquera,† David Attwood,*,‡ and Colin Booth| Department of Physics of Condensed Matter, University of Santiago de Compostela, E-15706 Santiago de Compostela, Spain, Schools of Pharmacy and Pharmaceutical Sciences and Chemistry, University of Manchester, Manchester M13 9PL, United Kingdom, School of Chemistry, University of Leeds, Leeds LS2 9JT, United Kingdom, and Pharmaceutical & Analytical R & D, AstraZeneca, Macclesfield, Cheshire SK10 2NA, United Kingdom Received February 10, 2005. In Final Form: March 18, 2005 Three triblock copolymers of ethylene oxide and phenyl glycidyl ether, type EmGnEm, where G ) OCH2CH(CH2OC6H5) and E ) OCH2CH2, were synthesized and characterized by gel-permeation chromatography, matrix-assisted laser desorption ionization time-of-flight mass spectrometry, and NMR spectroscopy. Their association properties in aqueous solution were investigated by surface tensiometry and light scattering, yielding values of the critical micelle concentration (cmc), the hydrodynamic radius, and the association number. Gel boundaries in concentrated micellar solution were investigated by tube inversion, and for one copolymer, the temperature and frequency dependence of the dynamic moduli served to confirm and extend the phase diagram and to highlight gel properties. Small-angle X-ray scattering was used to investigate gel structure. The overall aim of the work was to define a block copolymer micellar system with better solubilization capacity for poorly soluble aromatic drugs than had been achieved so far by use of block copoly(oxyalkylene)s. Judged by the solubilization of griseofulvin in aqueous solutions of the EmGnEm copolymers, this aim was achieved.

1. Introduction Recently we have prepared a range of block copoly(oxyalkylene)s, combining hydrophilic poly(ethylene oxide) with hydrophobic blocks formed from propylene oxide (PO), 1,2-butylene oxide (BO), or styrene oxide (SO), including diblock, triblock, and cyclic architectures.1 A major interest has been their aqueous solution properties, including micellization and gelation, and, building on that work, the application of the micellar solutions to drug solubilization.2,3 It is known that values of the critical micelle concentration (cmc) of block copoly(oxyalkylene)s are particularly sensitive to the composition of the hydrophobic block, and on the basis of values of the cmc in molar units, the hydrophobicities per repeat unit of the three types of block rank in the approximate ratio P:B:S ) 1:6:12.1,4 Here P denotes oxypropylene, OCH2CH(CH3); B denotes oxybutylene, OCH2CH(C2H5); and S denotes oxyphenylethylene, OCH2CH(C6H5) (S from styrene oxide). Given that hydrophobic blocks constitute the micelle core and that †

University of Santiago de Compostela. School of Pharmacy and Pharmaceutical Sciences, University of Manchester. § University of Leeds. | School of Chemistry, University of Manchester. ⊥ Present address: School of Materials, University of Manchester, Manchester M60 1QD, U.K. ∇ AstraZeneca. ‡

(1) Booth, C.; Attwood, D. Macromol. Rapid Commun. 2000, 21, 501. (2) (a) Rekatas, C. J.; Mai, S.-M.; Crothers, M.; Quinn, M.; Collett, J. H.; Attwood, D.; Heatley, F.; Martini, L.; Booth, C. Phys. Chem. Chem. Phys. 2001, 3, 4769. (b) Chaibundit, C.; Ricardo, N. M. P. S.; Crothers, M.; Booth, C. Langmuir 2002, 18, 4277. (3) Crothers, M.; Zhou, Z.-Y.; Ricardo, N. M. P. S.; Yang, Z.; Taboada, P.; Chaibundit, C.; Attwood, D.; Booth, C. Int. J. Pharm. 2005, 293, 91. (4) Crothers, M.; Attwood, D.; Collett, J. H.; Yang, Z.; Booth, C.; Taboada, P.; Mosquera, V.; Ricardo, N. M. P. S.; Martini, L. Langmuir 2002, 18, 8685.

a poorly soluble drug is solubilized in the micelle core, the availability of a wide range chemical compositions for the core is advantageous. Most alkylene oxides are readily polymerized anionically, and as reviewed by Boileau,5 it has long been established that phenyl glycidyl ether (PGE, 2,3-epoxypropyl phenyl ether) is no exception. As in our previous work,1 we have found that the sequential polymerization in bulk of PGE followed by ethylene oxide (EO), or vice versa, starting from mono- or difunctional hydroxy-ended initiators with potassium activator, gives ready access to water-soluble diblock and triblock copolymers with narrow block-length distributions. The laboratory procedure is robust, being related to that used industrially to prepare block copoly(oxyalkylene)s, which, in various compositions, are used as emulsifiers and de-emulsifiers, foaming and antifoaming agents, etc.6 In this paper we describe the preparation and aqueous solution properties of triblock copolymers of ethylene oxide and phenyl glycidyl ether with a central hydrophobic block. As noted above, we have found it convenient to use the notation P, B, and S for the repeat units of our copolymers. To this we add E to represent an oxyethylene unit, OCH2CH2, and for present purposes, G to represent an oxy(phenyloxymethylene)ethylene unit, OCH2CH(CH2OC6H5), derived from polymerization of PGE. With this notation, a triblock copolymer with a central G block is denoted EmGnEm, where m and n are number-average block lengths in chain units. (5) Boileau, S. In Comprehensive Polymer Science, Chain Polymerization, Vol. 3; Eastmond, G. C., Ledwith, A., Russo, S., Sigwalt, P., Eds.; Pergamon: Oxford, U.K., 1989; Chapt. 32. (6) Edens, M. W. In Nonionic Surfactants, Poly(oxyalkylene) Block Copolymers; Surfactant Science Series Vol. 60: Nace, V. M., Ed.; Marcel Dekker: New York, 1996; Chapt. 5.

10.1021/la0503808 CCC: $30.25 © 2005 American Chemical Society Published on Web 05/03/2005

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Our interest in PGE arose from the possibility that micellar solutions of EmGnEm block copolymers might prove successful as solubilizers of poorly soluble aromatic drugs. For this purpose it is desirable to have an aromatic micelle core. In principle, block copolymers of EO and styrene should be suitable. However, the high glass transition temperature of polystyrene, ca. 100 °C for a lengthy chain, means that the cores of micelles formed even from relatively short chains are immobile (so-called frozen micelles) in the temperature range of interest for drug solubilization and release, 10-40 °C.7,8 Micelles with mobile cores are available if poly(styrene oxide) is the core-forming block, the hydrophobicity being equivalent to that of a polystyrene block of equal length but the glass transition temperatures being some 60 °C lower.9 The glass transition temperatures of poly(phenyl glycidyl ether) chains are even lower, ca. 18 °C for Mn ≈ 6000 g mol-1 (G40),10 making the investigation of micellar solutions of EmGn and EmGnEm block copolymers an attractive proposition. So far as we have ascertained, there are no other reports of the preparation and association properties of copolymers of the type described here. 2. Experimental Section 2.1. Copolymers. Copolymers E71G7E71, E62G8E62, and E38G12E38 were prepared and used to investigate micellization and micelle properties in dilute aqueous solution and the gelation of concentrated micellar solutions. They were also used to explore the solubilization of griseofulvin, a poorly soluble aromatic drug,11 in their micellar solutions. Copolymers E71G7E71 and E62G8E62 were essentially repeat preparations of the same copolymer, which gave us sufficient material to adapt conventional methods to the new situation. Copolymer E38G12E38 was prepared to provide a material with a significantly larger G/E ratio. 2.1.1. Preparation. Vacuum line and ampule methods were used throughout. The general method has been described previously.12 Type 4A molecular sieve was used to dry the PGE, and potassium hydride was used to dry the EO. The initiator was 1-phenyl-1,2-ethanediol, partly in the form of its potassium salt (mole ratio OH/OK ≈ 10), prepared by reaction of the diol with a specified quantity of KOH followed by evaporation of water under high vacuum. At the first stage a known weight of dry PGE was added to an ampule under dry nitrogen by syringe, and after completion of that polymerization at 80 °C, a known weight of dry EO was distilled into the ampule through the vacuum line. For safety in glass apparatus, polymerization of EO was started at 20 °C and the temperature was increased in 20 °C intervals to 80 °C as polymerization proceeded. Completion of polymerization was determined by cooling the neck of the ampule and observing no condensation of monomer. Polymerization of PGE was slow, taking several weeks, while that of EO was completed in a few days. 2.1.2. Gel-Permeation Chromatography. The conventional GPC system comprised three 30-cm columns (Waters Styragel, HR 1, 2, and 3) eluted with tetrahydrofuran (THF, 1 cm3 min-1) at 25 °C, combined with a refractive index detector. Solutions of concentration 0.5-1.0 wt % were injected (volume 0.1 cm3), and the flow rate was monitored with dodecane as marker. Calibration was with poly(oxyethylene) standards. For each copolymer the GPC curve showed a narrow peak with a low-M tail: as an example, the curve obtained for copolymer E38G12E38 is shown (7) Jada, A.; Hurtrez, G.; Siffert, B.; Riess, G. Macromol. Chem. Phys. 1996, 197, 3697. (8) Hurtrez, G.; Dumas, P.; Riess, G. Polym. Bull. 1998, 40, 203. (9) Allen, G.; Booth, C.; Hurst, S. J.; Price, C.; Vernon, F.; Warren, R. F. Polymer 1967, 8, 406. (10) Sunder, A.; Tu¨rk, H.; Haag, R.; Frey, H. Macromolecules 2000, 33, 7682. (11) Yalkowsky, S. H.; He, Y. Handbook of Aqueous Solubilities, CRC Press: Boca Raton, FL, 2003. (12) Yang, Z.; Crothers, M.; Ricardo, N. M. P. S.; Chaibundit, C.; Taboada, P.; Mosquera, V.; Kelarakis, A.; Havredaki, V.; Martini, L.; Valder, C.; Collett, J. H.; Attwood, D.; Heatley, F.; Booth, C. Langmuir 2003, 19, 943.

Figure 1. Gel-permeation chromatography of copolymer E38G12E38. (a) THF eluent; low-M tail in the range 1000-2000 g mol-1 (PEO calibration). (b) Water eluent; low-M peak at ca. 2800 g mol-1 (PEO calibration). Note that the volume scale differs for the two GPC systems. in Figure 1a. Separate integration over the peak and its tail gave the following results: (i) For each copolymer, the ratio of massto number-average molar mass obtained for the narrow peak alone was Mw/Mn ≈ 1.05 without correction for instrumental spreading, 1.03 after correction. (ii) The low-M material had an average molar mass (Mw) about half that of the major component. (iii) Assuming the two components to have similar refractive indices, the proportion of low-M polymer in the copolymers was estimated from the areas of peak and tail to be ca. 10 wt %. Copolymers E71G7E71 and E38G12E38 were also investigated by GPC with THF solvent and a dual detection system, refractive index and ultraviolet absorption. Comparison of the UV and RI signals indicated that the low-M material in E38G12E38 was essentially poly(oxyethylene), while that in E71G7E71 contained a proportion of copolymer. To assess the amount of low-M polymer more accurately, the samples were reexamined by aqueous GPC. This GPC system comprised two 30-cm columns (TSK-PW gel 3000 and 4000), eluted with water at temperatures in the range 25-45 °C, and a refractive index detector. Solutions of concentration 5 g dm-3 were injected (volume 0.1 cm3). In water the copolymer forms micelles (see section 3 for details) and the associated GPC peak is moved to low elution volume, away from that of any nonmicellizable material. If the cmc of the copolymer at the temperature of the experiment is very low, and if the concentration of the injected solution is relatively high, then the micelles elute through the system essentially unchanged. These conditions held for solutions of copolymer E38G12E38: the cmc is no higher than 0.01 g dm-3 (see section 3.1), 500 times lower than the injected solution. An aqueous GPC curve obtained for a solution at 35 °C is illustrated in Figure 1b. The peak originating from nonmicellized polymer is clearly resolved from the micelle peak, and relative areas for the two peaks, with allowance for the different specific refractive index increments of PEO and E38G12E38 in water (see section 2.3 for the latter) indicate ca. 13 wt % low-M polymer in the sample. Similar results were obtained at other temperatures. Adsorption of unimers on the packing ruled out use of this method for copolymers E71G7E71 and E62G8E62, micelles of which dissociate more readily: cmc ≈ 0.1 g dm-3. However, inclusion of copolymer in the eluent (1 g dm-3) led to acceptable results for copolymer E71G7E71. As discussed elsewhere,13 this procedure indicates the state of micellization in the eluent, and our experiments showed 9 wt % nonmicellizable polymer with the eluent at 45 °C, slightly higher with the eluent at 25 °C. Copolymer E62G8E62 was not

Ethylene Oxide-Phenyl Glycidyl Ether Copolymers studied in this way, but given the fair agreement between the GPC methods for copolymers E38G12E38 and E71G7E71, we accepted the estimate of 10 wt % from the GPC curves obtained with THF eluent. 2.1.3. MALDI-TOF Mass Spectrometry. Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry was also used to investigate the copolymers and their precursors. The matrix material was dithranol plus potassium. The precursors showed narrow signals corresponding to number-average chain lengths G7 and G8, with a repeat of 150 g mol-1. The precursor of G12 was not investigated in this way. Investigation of the copolymers gave the following results: (i) major distributions corresponding to Mn ≈ 6000 g mol-1 (E71G7E71 and E62G8E62) or 4500 g mol-1 (E38G12E38), with 44 g mol-1 spacing complicated by the 150 g mol-1 spacings of the inner block; and (ii) minor distributions, not well resolved from the background, corresponding to Mn about half that of the major distribution. These signals had a repeat of 44 g mol-1 and were assigned to chains with a very high proportion of poly(oxyethylene). Because the minor peaks were not well resolved from their backgrounds, it was not possible to estimate the proportion of low-M polymer with accuracy. 2.1.4. Nuclear Magnetic Resonance Spectroscopy. 13C NMR spectra were obtained by use of a 10 mm broadband probe on a Varian Associates Unity 500 spectrometer operating at 125.7 MHz. Solutions in CDCl3 contained ca. 100 mg cm-3. A pulse interval of 11 s was used to ensure complete relaxation of all relevant peaks, and 1H decoupling was applied continuously; a trial nuclear Overhauser effect (NOE) measurement for one of the copolymers showed that both E and G blocks gave almost maximal enhancements. Peak assignments for G homopolymers were taken from ref 14; peaks from backbone CH2, side-chain OCH2, and terminal CHOH carbons were sufficiently well resolved to permit the reasonably accurate determination of Mn. Peak assignments for E blocks, including end groups, are well established.15 In the copolymer spectra, the absence of a terminal CHOH resonance from the G block confirmed the successful addition of the E blocks. The intense peak from E-block interior CH2 carbons partially overlapped the G-block backbone CH2 peaks. However, the G side-chain OCH2 peak remained well resolved, and this integral was used in the quantitative analysis. The integrals of the intensities of carbon resonances from backbone and end groups of the G-block precursors indicated average block lengths of G7.3, G8.1, and G12.1. As MALDI-TOF provided the chain length at the peak of the distribution, while NMR gave the number-average chain length, the near agreement between the two method was satisfactory. The spectra of the three copolymers indicated an excess of E ends (-OCH2CH2OH) over the number expected for EmGnEm copolymers on the basis of the signal from the side-chain OCH2 carbons of the central G block. This excess was assigned to the low-M fraction detected by GPC and MALDI-TOF. The evidence from MALDI is that the low-M material is largely poly(oxyethylene), and the evidence from GPC is that the low-M material is about half the length of the copolymer. The integral of the signal from all backbone carbons relative to that from the side-chain OCH2 carbons of the G units gave the overall ratio of E to G groups, which upon correction for the fraction of low-M poly(oxyethylene) gave the rounded formulas for the copolymers used throughout the paper. The molecular characteristics of the copolymers are listed in Table 1. 2.2. Surface Tension. Surface tensions (γ) of dilute aqueous solutions of copolymer E71G7E71 were measured at 20, 30, and 40 °C by the Wilhelmy plate method on a Kruss K-12 instrument equipped with a processor to acquire the data automatically. The instrument was connected to a circulating water bath with a proportional temperature controller to keep the temperature constant to (0.1 °C. The plate was cleaned by washing with doubly distilled water followed by heating in an alcohol flame. (13) (a) Wang, Q.-G.; Yu, G.-E.; Deng, Y.; Price, C.; Booth, C. Eur. Polym. J. 1993, 29, 665. (b) Wang, Q.-G.; Brown, D.; Huang, J.-M.; Nixon, S. K.; Gorry, P. A.; Price, C.; Booth, C. Polymer 2002, 43, 3621. (14) Ronda, J. C.; Serra, A.; Manteco´n, A.; Ca´diz, V. Polymer 1995, 36, 471. (15) See, for example, Heatley, F.; Luo, Y.-Z.; Ding, J.-F.; Mobbs, R. H.; Booth, C. Macromolecules 1995, 21, 2713.

Langmuir, Vol. 21, No. 12, 2005 5265 Table 1. Molecular Characteristics of the Copolymer Samples

samples E71G7E71 E62G8E62 E38G12E38

Mn/ Mpka/ g mol-1 g mol-1 Mwb/ wt % low-M (NMR) (GPC) g mol-1 wt % G (nonmicellizable) 7300 6700 5200

6000 5800 4100

7600 6900 5300

15 18 35

9c 10d 13c

a Molar mass as if the copolymer were poly(oxyethylene). b M w from Mn (NMR) and Mw/Mn (GPC) ≈ 1.05. c From aqueous GPC. d From GPC with THF eluent.

A stock solution (1.0 g dm-3) was prepared with distilled water and diluted as required. In the measurements a solution was equilibrated at 20 °C and the surface tension was recorded at 15 min intervals until a constant value was reached, a process that took 12-36 h depending on concentration. The temperature was then raised and the process was repeated. The accuracy of measurement was checked by frequent determination of the surface tension of pure water. 2.3. Light Scattering. All solutions were optically clear to the eye. They were clarified by filtration through Millipore Millex filters (Triton-free, 0.22 µm porosity) directly into the cleaned scattering cell. Dynamic and static light scattering (DLS and SLS) intensities were measured for solutions at temperatures in the range 20-50 °C by means of an ALV-5000F (ALV-GmbH, Germany) instrument with vertically polarized incident light of wavelength λ ) 532 nm supplied by a CW diode-pumped Nd: YAG solid-state laser supplied by Coherent Inc. and operated at 400 mW. The intensity scale was calibrated against scattering from toluene. Measurements were made at a scattering angle θ ) 90° to the incident beam. Solutions were equilibrated at each chosen temperature for 30 min before a measurement was made. Experiment duration was in the range 3-5 min, and each experiment was repeated two or more times. The correlation functions from DLS were analyzed by the CONTIN method to obtain intensity distributions of decay rates (Γ).16 The decay rate distributions gave distributions of apparent diffusion coefficient [Dapp ) Γ/q2, q ) (4πns/λ) sin (θ/2), ns ) refractive index of water] and integration over the intensity distribution gave the intensity-weighted average of Dapp. Values of the apparent hydrodynamic radius (rh,app, radius of hydrodynamically equivalent hard sphere corresponding to Dapp) were calculated from the Stokes-Einstein equation:

rh,app ) kT/(6πηDapp)

(1)

where k is the Boltzmann constant and η is the viscosity of water at temperature T. The basis for analysis of SLS was the Debye equation:

K*c/(I - Is) ) 1/Mw + 2A2c + ...

(2)

where I is the intensity of light scattering from solution relative to that from toluene, Is is the corresponding quantity for the solvent, c is the concentration (in grams per cubic decimeter), Mw is the mass-average molar mass of the solute, A2 is the second virial coefficient (higher coefficients being neglected), and K* is the appropriate optical constant, which includes the specific refractive index increment, ν ) dn/dc. Values of ν ) 0.131, 0.142, and 0.149 cm3 g-1 were obtained for solutions at 20 °C of copolymers E71G7E71, E62G8E62, and E38G12E38, respectively, with a temperature increment of -4 × 10-4 cm3 g-1 K-1. Other quantities used were the Rayleigh ratio of toluene for vertically polarized light, Rv ) 2.57 × 10-5[1 + (3.68 × 10-3)(t - 25)] cm-1 (t in degrees Celsius), and the refractive index of toluene, n ) 1.4969[1 - (5.7 × 10-4)(t - 20)].17 The possible effect of the different refractive indices of the blocks on the derived molar masses of micelles has been considered for closely related EmSn copolymers and found to be negligible.18 The Debye equation taken to the second term (A2 only, as in eq 2) could not be used to analyze all the SLS data as micellar interaction could cause curvature of the Debye plot across the (16) Provencher, S. W. Makromol. Chem. 1979, 180, 201.

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concentration range investigated. The fitting procedure used for the curves was based on scattering theory for hard spheres,19 whereby the interparticle interference factor (structure factor S) in the scattering equation

K*c/(I - Is) ) 1/SMw

(3)

was approximated by

1/S ) [(1 + 2φ)2 - φ2(4φ - φ2)](1 - φ)-4

(4)

where φ is the volume fraction of equivalent uniform spheres. Values of φ were conveniently calculated from the volume fraction of copolymer in the system by applying a thermodynamic expansion factor δt ) vt/va, where vt is the thermodynamic volume of a micelle (i.e., 1/8 of the volume, u, excluded by one micelle to another) and va is the anhydrous volume of a micelle (va ) Mw/ NAFa, where NA is Avogadro’s constant and Fa is the liquid density of the copolymer solute calculated with the assumption of mass additivity of specific volumes.20) The fitting parameter, δt, applies as an effective parameter for compact micelles irrespective of their exact structure. The method is equivalent to using the virial expansion for the structure factor of effective hard spheres taken to its seventh term19c but requires just two adjustable parameters, that is, Mw and δt. 2.4. Tube Inversion. Solutions (concentration range 0-80 wt %) were prepared by weighing copolymer and water into small tubes and were mixed in the mobile state whenever possible before being stored at low temperature (T ≈ 5 °C). Tubes (10 mm internal diameter) containing 0.5 cm3 solution were immersed in a water bath, which was heated (or cooled) at approximately 0.2 °C min-1 from 5 to 95 °C. The change from a mobile to an immobile system (or vice versa) was determined by inverting the tube at 1 min intervals. 2.5. Rheometry. Rheological properties of solutions of copolymer E71G7E71 were determined on a Bohlin CS10 rheometer with water bath temperature control. Couette geometry (bob, 24.5 mm diameter, 27 mm height; cup, 26.5 mm diameter, 29 mm height) was used, with 2.5 cm3 of sample being added to the cup in the mobile state. Samples of very high modulus were investigated by use of cone-and-plate geometry (diameter 40 mm, angle 4°). A solvent trap maintained a water-saturated atmosphere around the cells, and evaporation was not significant for the temperatures and time scales investigated. Frequency scans of storage and loss moduli were recorded for selected copolymer concentrations and temperatures with the instrument in oscillatory-shear mode and with the strain amplitude (A) maintained at a low value (A < 0.5%) by means of the autostress facility of the Bohlin software. This ensured that the values of the moduli were measured in the linear viscoelastic range and so were essentially independent of strain. Temperature scans were recorded for selected copolymer concentrations at a frequency f ) 1 Hz. The samples were heated at ca. 1 °C min-1 in the range 5-85 °C. The strain amplitude was not closely controlled during the T scans, and the changes in modulus were used only to indicate the temperatures at which gel formed and dispersed. 2.6. Small-Angle X-ray Scattering. SAXS experiments on an aqueous gel of copolymer E62G8E62 were conducted on beamline 16.1 at the Synchrotron Radiation Source, Daresbury Laboratory, (17) (a) El-Kashef, H. Rev. Sci. Instrum. 1998, 69, 1243. (b) Lui, T.; Schuch, H.; Gerst, M.; Chu, B. Macromolecules 1999, 32, 6031. (c) The temperature dependence of the Raleigh ratio was not found in the literature and, as a working approximation, values of Rv for toluene were adjusted relative to those published for benzene: Gulari, E.; Chu, B. Biopolymers 1999, 32, 2943. The adjustment is small over the temperature range involved. (18) (a) Mai, S.-M.; Ludhera, S.; Heatley, F.; Attwood, D.; Booth, C. J. Chem. Soc., Faraday Trans. 1998, 94, 567. (b) Mai, S.-M.; Booth, C.; Kelarakis, A.; Havredaki, V.; Ryan, A. J. Langmuir 2000, 16, 1681. (19) (a) Percus, J. K.; Yevick, G. J. J. Phys. Rev. 1958, 110, 1. (b) Vrij, A. J. Chem. Phys. 1978, 69, 1742. (c) Carnahan, N. F.; Starling, K. E. J. Chem. Phys. 1969, 51, 635. (20) (a) Mai, S.-M.; Booth, C.; Nace, V. M. Eur. Polym J. 1997, 33, 991. (b) The value of δt is insensitive to specific volume and it was sufficient for our purposes to assume that specific volumes for poly(G) could be represented by those reported for poly(S): Kern, R. J. Makromol. Chem. 1965, 81, 261.

U.K., details of which have been provided elsewhere.21 Samples were loaded into 1 mm thick brass cells, with an inner spacer ring to hold the gel sealed between mica windows. Scattering patterns were obtained at 30 s intervals as the temperature was raised at 2 °C min-1 from 25 °C. They were recorded on a quadrant multiwire detector that provided the scattered intensity on a linear scale. The q scale (q ) 4π sin θ/λ, where λ ) 1.41 Å and 2θ is the scattering angle) was calibrated with a specimen of wet collagen (rat tail tendon). 2.7. Drug Solubilization. The aromatic drug griseofulvin (1) was selected for assessment of the solubilization capacity of the EGE block copolymers.

Griseofulvin has very low water solubility (less than 1 mg/100 cm3) and has been used as a comparative standard by many laboratories, including our own. Stock aqueous solutions containing 1 wt % copolymer were prepared. A portion of stock solution (9.9 g) was added to 0.1 g of finely ground (1 mm2 mesh) griseofulvin powder (Sigma-Aldrich, Poole, Dorset, U.K.). The mixture was stirred at constant temperature (25 or 37 °C) for 5 days before being filtered (0.45 µm Millipore) to remove unsolubilized drug. A UV/vis spectrometer (Cecil CE1020) was calibrated by recording the absorbance (wavelength range 200-350 nm) of methanol solutions of griseofulvin (2-20 mg dm-3) against a solvent blank. The strong absorbance at 292 nm gave a satisfactory Beer’s law plot. The sample was then diluted with methanol to enable analysis by UV spectroscopy. The water content after dilution was low enough to allow the calibration for methanol solutions to be used without correction. The absorbance of the copolymer solution at the same dilution was measured as a blank: the correction was 10-20% of the total absorbance. The absorbance for griseofulvin in water was also measured. All measurements were carried out in triplicate and the results were averaged.

3. Results and Discussion No attempt was made to purify the copolymers. However, wherever relevant the overall composition of the materials was taken into account. 3.1. Critical Micelle Concentration. Solutions of copolymer E71G7E71 were investigated by surface tensiometry. Plots of surface tension against log concentration are shown in Figure 2. The concentration at which the surface tension departed from its steady value served to the define the value of log cmc to (0.05. As is clear from Figure 2, values of the cmc were independent of temperature over the range examined: cmc ≈ 0.13 g dm-3 (1.8 × 10-5 mol dm-3). This insensitivity of the cmc to temperature means that the enthalpy of micellization (∆micH°) is approximately zero over that range. A zero value is consistent with the similarly low values of ∆micH° obtained for copolymers with S blocks,4,12,22 and the effect can be attributed to the hydrophobic G and S blocks being tightly coiled in the dispersed unimer state so that the hydrophobic interaction with water is small, as discussed in detail for copolymer S13E60 in ref 22. (21) Bliss, N.; Bordas, J.; Fell, B. D.; Harris, N. W.; Helsby, W. I.; Mant, G. R.; Smith. W.; Towns-Andrews, E. Rev. Sci. Instrum. 1995, 66, 1311. (22) Kelarakis, A.; Havredaki, V.; Rekatas, C. J.; Booth, C. Phys. Chem. Chem. Phys. 2001, 3, 5550.

Ethylene Oxide-Phenyl Glycidyl Ether Copolymers

Langmuir, Vol. 21, No. 12, 2005 5267 Table 2. Micelle Properties from DLS and SLSa

Figure 2. Concentration dependence of surface tension of aqueous solutions of copolymer E71G7E71 at the temperatures indicated.

T/°C

D/10-11 m2 s-1

rh /nm

Mw/105 g mol-1

Nw

20 30 40 50

3.7 4.8 6.3 7.7

E71G7E71 5.8 5.8 5.6 5.6

1.15 1.21 1.24 1.32

15 16 16 17

20 30 40 50

3.4 4.3 5.4 6.6

E62G8E62 6.4 6.4 6.5 6.6

1.32 1.38 1.49 1.60

19 20 22 23

20 30 40 50

3.0 3.9 4.9 6.0

E38G12E38 7.1 7.2 7.2 7.2

3.91 4.25 4.51 4.17

74 80 85 79

a

Estimated uncertainty in D and rh, (4%; in Mw and Nw, (10%.

Figure 3. Concentration dependence of diffusion coefficient for micelles in aqueous micellar solutions at 20 °C of copolymers (b) E71G7E71, (O) E62G8E62, and (9) E38G12E38.

An attempt was made to measure the cmc of copolymer E38G12E38 by the same method. The surface tension was constant down to concentrations of ca. 0.01 g dm-3 but it was difficult to obtain reproducible results at lower concentrations, no doubt a consequence of slow diffusion leading to long equilibration times. However, that work allowed us to set the value for the cmc of copolymer E38G12E38 at 0.01 g dm-3 or less. Values of the cmc have been reported for aqueous solutions of triblock copolymers of ethylene oxide and styrene oxide (EmSnEm) with block lengths in the range n ) 8-15.12 By use of values smoothed by plotting the logarithm of cmc in molar units against S-block length, the block length corresponding closely to cmc ) 1.8 × 10-5 mol dm-3 is S9; that is, a G7 block has a similar cmc to an S9 block. Of course this comparison is for one EmGnEm copolymer alone, and we hope to confirm the relation between the two chain units in future work. However, the conclusion that G and S chain units have similar hydrophobicity is consistent with their chemical similarity, OCH2CH(CH2OC6H5) and OCH2CH(C6H5). Provided that the block-length dependence of the cmc is similar to that of the EmSnEm copolymers, the predicted value of the cmc of copolymer E62G8E62, 0.09 g dm-3, is little different from that of copolymer E71G7E71. 3.2. Hydrodynamic Radius. Intensity fraction distributions of log rh,app obtained for copolymers E71G7E71, E62G8E62, and E38G12E38 contained narrow peaks (not illustrated) with average values of rh,app in the approximate range 3-7 nm (c ) 10-60 g dm-3, T ) 20-50 °C) and were assigned to spherical micelles formed by a closed association process. The intercepts at c ) 0 of linear plots of the apparent diffusion coefficients of the spherical micelles against concentration (see Figure 3 for examples) gave the intrinsic

Figure 4. Debye plots for aqueous micellar solutions of EmGnEm copolymers. (a) Copolymer E62G8E62 at (0) 20 and (9) 40 °C and copolymer E38G12E38 at (b) 40 °C. The curves for copolymer E62G8E62 were calculated by use of theory for hard spheres (see section 2.3). (b) Expansion of the data for copolymer E38G12E38 at (b) 40 and (O) 50 °C. In both figures the straight lines for micelles of copolymer E38G12E38 are least-squares fits.

values of rh listed in Table 2. Within experimental error, temperature had very little effect on rh, as is usually found for block copoly(oxyalkylene)s.1,23 The positive slopes of the plots in Figure 4 are consistent with the micelles acting effectively as hard spheres. This behavior is usually accommodated by introducing a diffusion second virial coefficient (kd) in the equation of the straight line:

Dapp ) D(1 + kdc + ...)

(5)

The coefficient kd is related to the thermodynamic second virial coefficient A2 by24 (23) Chu, B.; Zhou, Z.-K. In Nonionic Surfactants, Poly(oxyalkylene) Block Copolymers; Surfactant Science Series Vol. 60; Nace, V. M., Ed.; Marcel Dekker: New York, 1996; Chapt. 3. (24) Vink, H. J. Chem. Soc., Faraday Trans. 1 1985, 81, 1725.

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kd ) 2A2Mw - kf - 2v

Taboada et al.

(6)

where kf is the friction coefficient and v is the specific volume of the micelles in solution. As is clear from Figure 4, the positive term in eq 6 is dominant for all three copolymers. Relating A2 to the effective hard-sphere volume of the micelles, vhs (A2 ) 4NAvhs/Mw2, where NA is Avogadro’s constant),25 shows that the first term depends on the ratio vhs/Mw. We have no direct measure of vhs, but it will be closely related to the hydrodynamic volume, and the hydrodynamic radii in Table 2 are similar for all three copolymers. Accordingly, the insensitivity of the apparent diffusion coefficient of micelles of copolymer E38G12E38 to change in concentration is attributed to their high molar mass (see section 3.3 and Table 2). 3.3. Association Number. For the present micellar solutions, the dissymmetry (I45/I135) in SLS was less than 1.01, consistent with micelles with small radii of gyration (rg); a value of rg ≈ 5 nm can be estimated from rg ) 0.775rh (with rh ≈ 7 nm) by treating the micelles as uniform spheres. Consequently, scattering intensities measured at 90 °C were used without correction for intraparticle interference. Examples of Debye plots are illustrated in Figure 4, which shows data for aqueous solutions of copolymer E62G8E62 at 20 and 40 °C and for aqueous solutions of copolymer E38G12E38 at 40 °C. The curves drawn through the data points are based on scattering theory for hard spheres, as described in section 2.3. Similarly curved plots were found for solutions of copolymer E62G8E62 at other temperatures (30 and 50 °C) and for copolymer E71G7E71 at all temperatures (20-50 °C). Plots for copolymer E38G12E38 were adequately fitted by straight lines at all temperatures considered (20-50 °C). This difference in behavior is discussed below. Weight-average association numbers, Nw, are listed in Table 2. These were calculated by use of values of Mw for the micelles found from the intercepts of the Debye plots and the values of Mw listed for the copolymers in Table 1. Small corrections were made for the low-M fraction that did not micellize (ca. 10%; see section 2.1). As expected for micelles of block copoly(oxyalkylene)s,1,23 it was found that values of Nw increase with increasing length of the hydrophobic block. For copolymers E71G7E71 and E62G8E62, values of Nw increase only slightly with increasing temperature while, within the scatter of results, those for copolymer E38G12E38 are independent of temperature. This insensitivity to temperature can be rationalized as follows. Allowing 0.36 nm/chain unit,26 the average lengths of the fully stretched G8 and G12 blocks are 2.9 and 4.4 nm, respectively. As the central G block is looped in the micelle core, the effective lengths are 1.5 and 2.2 nm. Assuming spherical micelle cores with no penetration of water, representative values of Nw of 20 (E62G8E62) and 80 (E38G12E38) imply core radii of ca. 2.1 and 3.7 nm, respectively, equivalent to fully stretched chains of length G12 and G21, respectively. Assuming that the G blocks have Poisson distributions, as expected in an ideal polymerization of an alkylene oxide,27 10% of the G blocks in copolymer E62G8E62 will have length G12 or greater, whereas less than 1% of the G blocks in E38G12E38 will have length G21 or greater. Thus, (25) Flory, P. J. Principles of Polymer Chemistry; Cornell University Press: Ithaca, NY, 1953; p 532. For spheres the excluded volume is 8 times the hard-sphere volume. (26) Flory, P. J. Statistical Mechanics of Chain Molecules; Interscience: New York, 1969; p 165. (27) Flory, P. J. Principles of Polymer Chemistry; Cornell University Press: Ithaca, NY, 1953; p 336.

Table 3. Comparison of the Properties of Micelles of EmGnEm and EmSnEm Copolymers in Aqueous Solution at 25 °Ca hydrophobe block length n 7 8 12 a

Nw

rh/nm

E80GnE80

E80SnE80

E80GnE80

E80SnE80

16 18

10 12 22

6.5 7.2

7.0 7.2 8.0

Values are adjusted to a common E-block length, m ) 80.

given the range of block lengths, we see that spherical (or near-spherical) micelles are possible for copolymer E62G8E62, although further stretching of the G blocks in the core will act against any substantial increase of Nw with temperature. However, this geometry is effectively prohibited for micelles of copolymer E38G12E38 and the micelles must be substantially elongated, probably cylinders. A weak dependence of Nw on T for this geometry is expected, as the negative temperature coefficient of solubility of the copolymers in water, which favors an increase in Nw, will be opposed by the effect of thermal agitation in limiting cylinder length.28 This difference in micelle geometry provides an explanation for the different concentration dependences of the Debye function illustrated in Figure 4. That found for micelles of copolymers E71G7E71 and E62G8E62 is typical of spherical (or near-spherical) micelles, the pronounced curvature being a result of interference from micelles reducing the scattering intensity as concentration is increased. However, mass action ensures that cylindrical micelles of copolymer E38G12E38 increase in length as concentration is increased,28 an effect that progressively increases the scattering intensity and so opposes the effect of micelle interaction. 3.4. Comparison with EmSnEm Copolymers. Values of Nw and rh obtained for copolymers E71G7E71 and E62G8E62 can be compared with values reported for EmSnEm copolymers in aqueous solution at 25 °C (see Figures 7 and 8 of ref 12 for details). As seen in Table 2, the values of rh and Nw found for present copolymers are not strongly dependent on temperature, and representative values of the properties of their micelles at 25 °C could be readily estimated. The micelles considered here all have spherical geometry. As discussed above, micelles of copolymer E38G12E38 are a special case and are not included. The E-block length of the EmSnEm copolymers considered in ref 12 is 80 units compared with ca. 60 for the present copolymers, but it is known that Nw scales approximately as m-0.5 and that the corresponding scaling exponent for rh is approximately 0.4,29 so it is a simple matter to adjust values in Table 3 to a common E-block length (E80). Within the uncertainty of the comparison, values of rh are the same for the two sets of micelles, as would be expected as hydrodynamic volume is sensitive to coronal thickness (E-block length) and insensitive to the much smaller core radius. Association numbers do differ, values for the micelles of the EmGnEm copolymers being considerably higher. The comparison shows that micelles of copolymer E80G7E80 would have the same association number as micelles of E80S10E80, which, bearing in mind experimental uncertainties, is consistent with the comparison of values of the cmc made in section 3.1. 3.5. Gels. The gelation of aqueous solutions of the copolymers was investigated, including the rheological (28) See, for example, Cates, M. E.; Candau, S. J. J. Phys. Condens. Matter 1990, 96, 6869. (29) Chaibundit, C.; Mai, S.-M.; Heatley, F.; Booth, C. Langmuir 2000, 16, 9645.

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Figure 6. Frequency dependence of (b) storage and (O) loss modulus (log-log plot) for a 35 wt % aqueous gel of copolymer E71G7E71. T ) 25 °C, A ) 0.5%.

Figure 5. Hard-gel boundaries established by tube inversion for aqueous solutions of copolymers (b) E71G7E71, (O) E62G8E62, and (9) E38G12E38. Symbols ] and [ indicate the low-T and high-T boundaries of the viscous phase of copolymer E38G12E38. (0) Limiting temperature of the SAXS pattern characteristic of a bcc phase observed for a 20 wt % solution of copolymer E62G8E62.

behavior of dilute solutions of copolymer E71G7E71 and a SAXS study of a hard gel of copolymer E62G8E62. 3.5.1. Hard Gels. Tube-inversion experiments were used to define immobile and viscous regions of the phase diagrams. Immobility implies no detectable flow over a period of hours or days. To a good approximation, immobility in the test (details in section 2.4) requires the gel to have a yield stress higher than 30 Pa.30 Qualitatively, we distinguish a mobile fluid, which flows immediately and freely on tube inversion, from a viscous fluid, which flows very slowly on tube inversion. The gel boundaries found for aqueous micellar solutions of the copolymers E71G7E71 and E62G8E62 are shown in Figure 5a. Adopting the notation used by Hvidt and co-workers,31,32 this immobile phase is referred to as hard gel. As expected following work on other systems, for example, EmSnEm,12 the micellar gels formed from the copolymer with the longest G block are more stable at high temperatures. Also as found for EmSnEm copolymers,12 there is no lowtemperature boundary to the hard gel, a feature attributed to the stability of the micelles of these copolymers in water at low temperatures. Solutions of other copolymers (e.g., EmBnEm and EmPnEm) characteristically have a low-T mobile/immobile boundary as well as a high-T boundary.32,33 The gel diagram found for solutions of copolymer E38G12E38 (Figure 5b) is very different. The high concentration needed to form the immobile phase is consistent with packing of cylindrical micelles, while the formation (30) Kelarakis, A.; Mingvanish, W.; Daniel, C.; Li, H.; Havredaki, V.; Booth, C.; Hamley, I. W.; Ryan, A. J. Phys. Chem. Chem. Phys. 2000, 2, 2755. (31) Hvidt, S.; Jørgensen, E. B.; Brown, W.; Schille´n, K. J. Phys. Chem. 1994, 98, 12320. (32) Almgren, M.; Brown, W.; Hvidt, S. Colloid Polym. Sci. 1995, 273, 2. (33) Hamley, I. W.; Mai,S.-M.; Ryan, A. J.; Fairclough, J. P. A.; Booth, C. Phys. Chem. Chem. Phys. 2001, 3, 2972.

Figure 7. SAXS pattern obtained for the 20 wt % gel of copolymer E62G8E62 at 25 °C. Intensity is plotted against q/q*, where q* is the value of q at the first-order maximum. The arrows point to the readily measured reflections.

of a viscous phase at high temperatures has been observed for micellar solutions of other copolymers that form cylindrical micelles, notably E28P48E28 (commonly denoted P94).31 Overall, the gel diagrams confirm the conclusions drawn from the light scattering experiments: spherical (or near-spherical) micelles are formed from copolymers E71G7E71 and E62G8E62, and cylindrical micelles are formed from copolymer E38G12E38. Figure 6shows a frequency scan obtained for a 35 wt % hard gel of copolymer E71G7E71 at 25 °C, that is, well within the hard-gel region. The high values the storage modulus (G′ ≈ 5 kPa at f ) 1 Hz) in the linear viscoelastic region, the almost constant value of log G′, and the minimum in log G′′ are all characteristic of a hard gel formed by cubic packing of spherical micelles.34 These features are also seen in the frequency scans of microphase-separated block copolymer melts with body-centered cubic (bcc) structures35 and in those of colloidal hard spheres near the fluid-solid transition.36 SAXS was used to confirm the body-centered cubic structure of a 20 wt % hard gel of copolymer E62G8E62. As an example, the SAXS pattern obtained at 25 °C is shown in Figure 7. Intensity is plotted against q/q*, where q* ) 0.05908 Å-1 is the value of q at the first-order maximum. The reflections in the sequence q/q* ) 1, 21/2, 31/2, and (possibly) 2 provide evidence of a bcc structure formed from packed spherical micelles. The cell parameter corresponding to q* is a ) 150 Å, giving a cell volume (34) Kelarakis, A,; Yuan, X.-F.; Mai, S.-M.; Yang, Y.-W.; Booth, C. Phys. Chem. Chem. Phys. 2003, 5, 2628. (35) Zhao, J.; Majumdar, B.; Schulz, M. F.; Bates, F. S.; Almdal, K.; Mortensen, K.; Hadjuk, D. A.; Gruner, S. M. Macromolecules 1996, 29, 1204. (36) Mason, T. G.; Weitz, D. A. Phys. Rev. Lett. 1995, 75, 2770.

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Figure 8. Temperature profiles of the logarithm of storage modulus (f ) 1 Hz) for aqueous micellar solutions of copolymer E71G7E71. Copolymer concentrations (wt %) are indicated. For clarity, the curves are shifted to separate them on the ordinate scale.

Taboada et al.

Figure 10. Temperature profiles of storage (G′) and loss (G′′) modulus (f ) 1 Hz, A ≈ 50%) for a 17.5 wt % aqueous micellar solution of copolymer E71G7E71.

Figure 9. (b) Hard-gel boundary defined by tube inversion and (O) soft-gel boundary defined by rheometry for aqueous solutions of copolymer E71G7E71.

3.4 × 106 Å3. Assuming that the value of rh ) 64 Å (Table 2) approximates the hard-sphere radius of a micelle in the bcc structure, then the volume fraction of micelles in the bcc structure (2 micelles/unit cell) is 0.65, in reasonable agreement with the expected value 0.68. The bcc SAXS pattern was found at temperatures up to 43 °C, with a single broad peak at temperatures higher than 48 °C, characteristic of a disordered phase. Patterns in the interval 44-47 °C were characteristic of defective bcc structures, a feature noted previously for soft micellar gels of block copolymers near the hard-gel boundary.37 As seen in Figure 5, the limiting temperature of the bcc SAXS pattern (43 °C) is in fair agreement with the hard-gel boundary defined by tube inversion. 3.5.2. Soft Gel. Rheometry was used to investigate solutions of copolymer E71G7E71 at concentrations below the hard-gel boundary. The temperature dependences of storage modulus (f ) 1 Hz) recorded for selected concentrations of E71G7E71 are shown in Figure 8. The temperatures bounding the regions of raised modulus, together with similar results for other copolymer concentrations, are plotted in Figure 9. As illustrated in Figure 10, within the region of raised modulus, the storage modulus was higher than the loss modulus, and it is this characteristic that justifies the convenient term soft gel for the fluid in order to distinguish it from sol. Under the conditions used and within the considerable scatter of the data, the ratio G′′/G′ ) tan δ was constant across the plateau region of the scans, with values in the range 0.3-0.5 independent of concentration. As noted in section 2.5, the strain amplitude was not closely controlled in these experiments. The values of G′ obtained with high values of A ≈ 50% (37) Castelletto, V.; Caillet, C.; Fundin, J.; Hamley, I. W.; Yang, Z.; Kelarakis, A. J. Chem. Phys. 2002, 116, 10947.

Figure 11. Frequency dependence of (b) storage and (O) loss modulus (log-log plot) for aqueous solutions of copolymer E71G7E71 in the soft-gel region: (a) 20 wt % solution at 45 °C and (b) 10 wt % solution at 60 °C. For both scans A ) 0.5%.

(see, for example, Figure 10, 17.5 wt % gel) were low compared with values obtained in the linear viscoelasticity region (A e 0.5%; see Figure 11, 20 wt % gel). Values of tan δ ≈ 0.08 were measured at f ) 1 Hz, A e 0.5%. Temperatures at the soft-gel boundary were not sensitive to this change in A. However, for a dilute solution the value of G′ can be sensitive to frequency, and an increase in modulus, characteristic of the formation of a soft gel, may be recognized at a lower temperature when the frequency is increased from, say, 1 to 10 Hz. Thus our division of micellar solutions into sol, soft gel, and hard gel is based on our arbitrary choices of frequency (1 Hz) and yield stress (30 Pa). Near the hard-gel boundary it is accepted that the soft gel is a defective version of the hard-gel phase.37-39 A frequency scan obtained for a 20 wt % solution of copolymer E71G7E71 at 45 °C (see Figure 11a) is consistent with this. The concentration of this solution is 13 wt % lower than the hard-gel boundary at this temperature. Although the values of the moduli are low (G′ ≈ 250 Pa and G′′ ≈ 20 Pa at f ) 1 Hz, A ) 0.5%) compared with the corresponding values for the 35 wt % gel (G′ ≈ 5.0 kPa and G′′ ≈ 130 Pa; see Figure 6), log G′ is approaching a constant value while log G" shows a shallow minimum. A frequency scan obtained for a 10 wt % solution at 60 °C (see Figure 11b) (38) Prud’homme, R. K.; Wu, G.; Schneider, D. K. Langmuir 1996, 12, 4651. (39) Li, H.; Yu, G.-E.; Price, C.; Booth, C.; Fairclough, J. P. A.; Ryan, A. J.; Mortensen, K. Langmuir 2003, 19, 1075.

Ethylene Oxide-Phenyl Glycidyl Ether Copolymers Table 4. Solubilization Capacities at T ) 25 °C for Griseofulvin in Micellar Solutions of Block Copolymers with G or S Hydrophobic Cores copolymer

sCP/mg g-1

wH

sH/mg g-1

E71G7E71 E62G8E62 E38G12E38 E82S8E82 E66S13E66 E67S15E67

6.0 8.0 17.8 2.7 4.0 5.6

0.15 0.18 0.35 0.12 0.21 0.23

40 44 51 21 18 22

shows yet lower values of G′ (G′ ≈ 50 Pa and G′′ ≈ 4 Pa at f ) 1 Hz, A ) 0.5%). The indication of a crossover of moduli at low frequency is consistent with a more fluid system, corresponding to, at most, localized cubic order. This is understandable; the concentration of this solution is only 4 wt % higher than the soft-gel boundary. Weak attraction in dilute solution of spherical micelles in water, leading to limited clustering and to G′ exceeding G′′, occurs at high temperatures where water is a poor solvent for the micelles. The transition from sol to soft gel may well occur when aggregates of spherical micelles reach a percolation threshold yielding sufficient structure to cause the characteristic rheological effect.39,40 Soft gels have been identified in aqueous micellar solutions of a wide range of triblock copolymers, including our own work on EmBnEm39,41 and EmSnEm12 copolymers, as well as work on EmPnEm copolymers by Hvidt and co-workers, who have ascribed the effect in certain systems to the intervention of the sphere-to-rod micellar transition,31,32 and by Mallamace and co-workers,42 who have identified mechanisms of percolation and packing (structural arrest), depending on temperature and concentration, in solutions of copolymer E13P30E13. 3.6. Drug Solubilization in Micellar Solution. Solubilization capacity per gram of copolymer in solution (sCP) was recorded as the amount of griseofulvin dissolved at 25 °C in 100 cm3 of solution in excess of that dissolved in an equivalent volume of water, divided by the copolymer concentration in weight percent. Values of sCP found for the present copolymers are listed in Table 4. Also in Table 4 are values of sH, the solubilization capacity per gram of hydrophobic block, calculated from the listed values of the mass fraction of the hydrophobic block (wH) with a small correction for solubilization in the E-block corona as described elsewhere.3 This quantity gives a direct measure of the efficiency of solubilization of the drug in the micelle core. The higher value found for micelles of copolymer E38G12E38 is consistent with cylindrical micelles.2b Considering all sources of error, we estimate a maximum uncertainty of 1 mg g-1 in sCP and (4 mg g-1 in sH. Comparable results reported for EmSnEm are listed in Table 4. Comparison of values of sH indicates that, on average, the solubilization capacity of a spherical G core (average sH ) 42 mg g-1) is more than twice that of a spherical S core (average sH ) 20 mg g-1). This we attribute in part to the slightly higher hydrophobicity of G units (see section 3.1) but mainly to the high mobility of G blocks in a micelle core compared to S blocks, a possibility (40) Li, H.; Yu, G.-E.; Price, C.; Booth, C.; Hecht, E.; Hoffmann, H. Macromolecules 1997, 30, 1347. (41) Kelarakis, A.; Castelletto, V.; Chaibundit, C.; Fundin, J.; Havredaki, V.; Hamley, I. W.; Booth, C. Langmuir 2001, 17, 4232. (42) (a) Lobry, L.; Micail, N.; Mallamace, F.; Liao, C.; Chen, S.-H. Phys. Rev. E 1999, 60, 7076. (b) Mallamace, F.; Gambaduaro, P.; Micail, N.; Tartaglia, P.; Liao, C.; Chen, S.-H. Phys. Rev. Lett. 2000, 84, 5431. (c) Chen, S.-H.; Chen, W.-R.; Mallamace, F. Science 2003, 300, 619.

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discussed in section 1. Mobility of blocks in the micelle core facilitates the solubilization process at room temperature. Results are available for the solubilization of griseofulvin at 25 °C in aqueous micellar solutions of EmBn and EmBnEm copolymers.2,3 For these copolymers the average solubilization capacity in the B core (sH) is 10 mg g-1. For EmPnEm copolymers the values of sH are even lower.2a,43 The results reported in ref 2a were not analyzed in the same way as the present results; in particular, no allowance was made for griseofulvin dissolved in the aqueous phase and that solubilized in the micelle corona. The correction is relatively small, and sH is increased if it is omitted. Ignoring these details, we believe that the ranking of sH,

G > S > B >> P broadly reflects the ranking of the hydrophobicities of the core-forming blocks,

G ≈ S > B >> P with the value of sH for S cores modified by the relative immobility of the chains. 4. Conclusions Triblock copolymers of ethylene oxide and phenyl glycidyl ether, type EmGnEm, in aqueous solution have low values of the cmc that are independent of temperature, the latter indicating that the standard (van’t Hoff) enthalpy of micellization is near zero. In this respect its association properties are similar to those of triblock copolymers of ethylene oxide and styrene oxide, type EmSnEm. On the basis of values of the cmc and the micelle association number, we rank the hydrophobicity of a G chain unit [OCH2CH(CH2OC6H5)] slightly higher than that of an S unit [OCH2CH(C6H5)]. Concentrated solutions of the copolymers form highmodulus gels. Gel structure depends on copolymer composition, but in the case of the gel investigated by smallangle X-ray scattering, the mesophase structure was bodycentered cubic. Griseofulvin, a poorly soluble aromatic drug, is more soluble in micelle cores of EGE copolymers than in those of ESE copolymers. Over the range of block copoly(oxyalkylene)s investigated, the solubilization capacity for griseofulvin ranks in the order

G > S > B >> P where B ) OCH2CH(C2H5) and P ) OCH2CH(CH3). The ranking order is very similar to that of hydrophobicity. However, compared with a poly(styrene oxide) core, solubilization of griseofulvin in a poly(phenyl glycidyl ether) core is aided by the lower glass transition temperature of the polymer. Acknowledgment. We thank AstraZeneca and the Engineering and Physical Science Research Council (U.K.) for financial support. The project was supported by the Ministerio de Ciencia y Tecnologia through Project Grant MAT2004-02756 and the Xunta de Galicia. P.T. thanks the Ministerio de Ciencia y Tecnologia for his Ramo´n y Cajal position. LA0503808 (43) For a recent view of the potential of EmPnEm copolymers for solubilization see Oh, K. T.; Bronich, T. K.; Kabanov, A. V. J. Controlled Release 2004, 94, 411.