Langmuir 2006, 22, 7465-7470
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Articles Micellization and Drug Solubilization in Aqueous Solutions of a Diblock Copolymer of Ethylene Oxide and Phenyl Glycidyl Ether Pablo Taboada,† Gemma Velasquez,‡ Silvia Barbosa,† Zhuo Yang,‡,§ S. Keith Nixon,| Zhengyuan Zhou,‡ Frank Heatley,| 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, School of Pharmacy and Pharmaceutical Sciences, UniVersity of Manchester, Manchester, M13 9PL, U.K., School of Chemistry, UniVersity of Manchester, Manchester M13 9PL, U.K., and AstraZeneca, Pharmaceutical & Analytical R & D, Macclesfield, Cheshire SK10 2NA, U.K. ReceiVed March 13, 2006. In Final Form: June 9, 2006 The aim of this study was to define a block copolymer micellar system with a high solubilization capacity for poorly soluble aromatic drugs. Ethylene oxide and phenyl glycidyl ether were sequentially polymerized to form the diblock copolymer G5E67 (G ) phenyl glycidyl ether, OCH2CH(CH2OC6H5); E ) oxyethylene, OCH2CH2; subscripts denote number-average block lengths in repeat units). The association properties in aqueous solution over the range 20-50 °C were investigated by surface tensiometry and light scattering, yielding values of the cmc, hydrodynamic radius, and association number; gel boundaries in concentrated micellar solution were investigated by tube inversion. The solubilization capacity of G5E67 for the poorly water-soluble drug griseofulvin was higher than that of a triblock EGE copolymer of longer G block length and considerably higher than that achieved with poloxamers (EmPnEm, P ) oxypropylene).
1. Introduction We have prepared block copoly(oxyalkylene)s which combine hydrophilic poly(ethylene oxide) with hydrophobic blocks formed from propylene oxide, 1,2-butylene oxide, or styrene oxide, 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 their micellar solutions to drug delivery.2 Given that hydrophobic blocks constitute the micelle core and that a poorly soluble drug is solubilized in the micelle core, the availability of a range of chemical compositions for the core is advantageous. Copolymers with a wide range of hydrophobic blocks have been examined for their potential for solubilizing poorly soluble drugs3,4 in attempts to overcome the problems arising from the poor aqueous solubility of many potentially useful drug candidates, which frequently lead to poor or erratic * To whom correspondence should be addressed. † University of Santiago de Compostela. ‡ School of Pharmacy and Pharmaceutical Sciences, University of Manchester. § Present address: School of Materials, University of Manchester, Manchester M60 1QD, U.K. | School of Chemistry, University of Manchester. ∧ 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. (c) 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. (3) Allen, C.; Maysinger, D.; Eisenberg, A. Colloid Surf. B 1999, 16, 3. (4) Kabanov, A. V.; Batrakova, E. V.; Alakhov, V. Y. J. Controlled Release 2002, 82, 189.
absorption characteristics. Very recently,5 we prepared triblock copolymers of ethylene oxide (EO) and phenyl glycidyl ether (PGE, 2,3-epoxypropyl phenyl ether), denoted EmGnEm, where E denotes oxyethylene, OCH2CH2, G denotes oxy(phenyloxymethylene)ethylene, OCH2CH(CH2OC6H5) (G from phenyl glycidyl ether), and the subscripts denote number-average block lengths in chain units. For solubilization of aromatic drugs, in particular for griseofulvin, the poorly soluble drug used as the comparative standard in this work (see Scheme 1), aqueous solutions of triblock copolymers forming micelles with G-block cores proved advantageous.5 In this paper we describe the aqueous solution properties of a diblock copolymer, G5E67 prepared in our laboratory, and also the solubilization of griseofulvin in its micellar solution. As indicated by the formula, the order of sequential polymerization was PGE followed by EO. To our knowledge there are no other reports of the preparation and association properties of a diblock copolymer of this type. 2. Experimental Section 2.1. Copolymers. 2.1.1. Preparation and Characterization. The sequential oxyanionic polymerization of PGE followed by EO followed closely that described for the preparation of the corresponding triblock copolymers5 but with 2-phenylethanol as a monofunctional initiator. Vacuum-line and ampule techniques were used throughout. The preparation of diblock copolymers with longer precursor blocks (G10-G20) was undertaken, but gel permeation chromatography showed that their longer precursors had broadened chain length distributions, probably a result of chain transfer,6 and further work was disregarded. (5) Taboada, P.; Velasquez, G.; Barbosa, S.; Castelletto, V.; Nixon, S. K.; Yang, Z.; Heatley, F.; Hamley, I. W.; Ashford, M.; Mosquera, V.; Attwood, D.; Booth, C. Langmuir 2005, 21, 5263. (6) Stolarzewicz, A. Makromol. Chem. 1986, 187, 745.
10.1021/la060684+ CCC: $33.50 © 2006 American Chemical Society Published on Web 08/01/2006
7466 Langmuir, Vol. 22, No. 18, 2006 Scheme 1
2.1.2. Gel Permeation Chromatography (GPC). Three Waters Styragel HR columns with tetrahydrofuran (THF) eluent and refractive index detection were used. Calibration was with poly(oxyethylene) standards. The GPC curve showed two narrow peaks corresponding to diblock copolymer (major peak, 88 wt %, Mn ) 3100 g mol-1, Mw/Mn ) 1.03) and triblock copolymer (minor peak, 12 wt %, Mn ) 6000 g mol-1, Mw/Mn ) 1.02). The overall value of Mw/Mn was 1.08. Number- (Mn) and weight-average (Mw) molar masses are as if the solute were poly(oxyethylene). The additional use of dual detection, refractive index and ultraviolet absorption, served to show that that the composition was the same for both peaks, confirming their assignment to diblock and triblock copolymer, the latter assumed to be the result of initiation by a small residue of moisture in the PGE monomer. 2.1.3. Nuclear Magnetic Resonance (NMR) Spectroscopy. 13C NMR spectra were obtained for the G5 precursor and the copolymer using 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. Peak assignments were taken from refs 7 and 8. The operating conditions and assignments are discussed in more detail in ref 5. The integrals of the intensities of carbon resonances from backbone and end groups of the G-block precursors indicated an average block length of G5.2, the block length being calculated per OH end group. The spectrum indicated an excess of OH ends consistent with formation of bifunctional polymer, this being the initiator of the triblock copolymer detected by GPC. In the copolymer spectrum, the absence of a terminal CHOH resonance from the G block confirmed the successful addition of the E blocks. 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. This gave the proportion of G as 21 wt %, and, when combined with the precursor block length, an E-block length of 67 units, a rounded formula G5E67, and Mn ) 3730 g mol-1 . The triblock copolymer was included in the NMR analysis as if it were two diblock copolymers of one-half length. A value of Mw ) 4030 g mol-1 was calculated from Mn (NMR) and overall Mw/Mn (GPC). 2.2. Surface Tension. Surface tensions (γ) of dilute aqueous solutions of copolymer G5E67 were measured by the Wilhelmy plate method using a Kruss K-12 instrument, as described previously.5 In the measurements the solution was equilibrated at 20 °C, and the surface tension was recorded at 15 min intervals until a constant value was reached, a process which took 12-36 h depending on the concentration. The temperature was then raised and the process repeated. The solutions were covered with a plastic lid to prevent water evaporation. The accuracy of measurement was checked by frequent determination of the surface tension of pure water. 2.3. Isothermal Titration Calorimetry. Heats of dilution were measured using a VP-ITC titration microcalorimeter from MicroCal Inc., Northampton, MA. Small aliquots (5-10 µL) of stock solution of copolymer at a concentration well above the cmc were injected into a known volume of water (ca.1 cm3) held in the cell of the calorimeter, initially to produce a solution below the cmc. Repeated additions of the stock solution gave the heat evolved as a function of copolymer concentration. 2.4. Light Scattering. Solutions were clarified by filtering through Millipore Millex filters (Triton free, 0.22 or 0.10 µm porosity) directly (7) Ronda, J. C.; Serra, A.; Manteco´n, A.; Ca´diz, V. Polymer 1995, 36, 471. (8) Heatley, F.; Luo, Y.-Z.; Ding, J.-F.; Mobbs, R. H.; Booth, C. Macromolecules 1995, 21, 2713.
Taboada et al. 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 instrument with vertically polarized incident light of wavelength λ ) 532 nm supplied by a CW diode-pumped Nd:YAG solid-state laser (Coherent Inc.) 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 making a measurement. 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 method9 to obtain intensity distributions of decay rates (Γ) and, thereby, distributions of the apparent (concentration dependent) diffusion coefficients (Dapp) of the micelles. The Stokes-Einstein equation was then used to obtain distributions of apparent hydrodynamic radius (rh,app, the radius of the hydrodynamically equivalent hard sphere), i.e. rh,app ) kT/(6πηDapp)
(1)
where k is the Boltzmann constant and η is the viscosity of water at temperature T. The Debye equation was the basis of the analysis of the SLS data, i.e. K*c/(I - Is) ) 1/Mw,mic + 2A2c + ...
(2)
where I is the intensity of light scattering from solution relative to that from toluene, Is is the corresponding quantity for toluene, c is the mass concentration, Mw,mic is the weight-average molar mass of the micellar 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. Measured values of ν for solutions at 30 °C combined with those obtained previously for related EmGnEm copolymers5 gave ν/(cm3 g-1) ) 0.132 + 0.040wG
(3)
where wG is the weight fraction of G. The temperature increment was -4 × 10-4 cm3 g-1 K-1. In practice, the Debye plots were curved and a fitting procedure based on scattering theory for hard spheres was employed. Details of this procedure and of the quantities used in calculating K* are given in ref 5. 2.5. Tube Inversion. Solutions (within the concentration range 0-55 wt %) were prepared by mixing in the mobile state 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. 2.6. Drug Solubilization. The aromatic drug griseofulvin was used to measure the solubilization capacity of micellar solutions of the copolymer. Griseofulvin has a low water solubility (less than 10 mg dm-3)10 and has been used as a comparative standard by many laboratories, including our own.2,5 The method, which follows closely one of the methods which is widely used in the pharmaceutical industry for characterizing the solubilization of drugs in micellar solutions,11 has been described previously.5 Briefly, finely powdered griseofulvin and 1 wt % copolymer solution were mixed at 25 °C for 5 days before being filtered to remove unsolubilized drug. A sample was diluted with methanol to enable analysis by UV spectroscopy, the strong absorbance at 292 nm giving a satisfactory Beer’s law plot. The (9) Provencher, S. W. Makromol. Chem. 1979, 180, 201. (10) Yalkowsky, S. H.; He, Y. Handbook of Aqueous Solubilities; CRC Press: Boca Raton, 2003. (11) See, for example: Huskeson, J.; Salo, M.; Taskinen, J. J. Chem. Int. Comput. Soc. 1998, 38, 450.
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Figure 1. Concentration dependence of surface tension of aqueous solutions of copolymer G5E67 at the temperatures indicated. Figure 3. Intensity fraction distribution of log(rh,app) for 10 and 65 g dm-3 solutions at 30 °C of copolymer G5E67.
Figure 2. ITC determination of the enthalpy of demicellization of copolymer G5E67 in water at 30 °C. In this experiment a stock solution of concentration 10 g dm-3 was added at intervals of 300 s to the water in the calorimeter cell using 40 injections each of 6 µL. See text for explanation of the straight lines. absorbance of the copolymer solution at the same dilution was used as a blank. In the same way, the absorbance from griseofulvin equilibrated with water alone was used to correct for the water solubility of griseofulvin and of any UV-active impurities contained in the sample. Measurements were carried out in triplicate, and the results were averaged. The method has been checked against analyses using NMR spectroscopy2c and, more recently, liquid chromatography. In each case, agreement was satisfactory.
3. Results and Discussion It has been shown previously12 that mixtures of diblock and triblock copolymers with closely related composition comicellize to form micelles with characteristics (association number, radius) essentially identical with those of diblock copolymer alone. Accordingly, we are comfortable with our description of the copolymer as a diblock. 3.1. Critical Micelle Concentration. Solutions of copolymer G5E67 at 20-40 °C were investigated by surface tensiometry. Plots of surface tension against log(concentration) are shown in Figure 1. 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 1, values of the cmc were only weakly dependent on temperature over the range examined, varying from 0.065 g dm-3 at 20 °C to 0.050 g dm-3 at 40 °C. The value of 0.055 g dm-3 obtained for the cmc of copolymer G5E67 at 30 °C, equivalent to 1.4 × 10-5 mol dm-3, is similar to the smoothed value for E50S7 indicated in Figure 2 of ref 13a, consistent with a G unit being slightly more hydrophobic than an S unit. We use S to denote an oxyphenylethylene, OCH2(12) Mingvanish, W.; Chaibundit, C.; Booth, C. Phys. Chem. Chem. Phys. 2002, 4, 778. (13) (a) 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. (b) 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.
CH(C6H5) derived from polymerization of styrene oxide. A similar difference in cmc values was reported for copolymers EmG7Em and EmS9Em.5 The insensitivity to temperature of the cmc means that the standard enthalpy of micellization (∆micH°) is very low: a van’t Hoff plot of log(cmc) against reciprocal temperature gave an approximate value of ∆micHvH ≈ 10 kJ mol-1. This low value is consistent with similarly low values of ∆micHvH obtained for copolymer E71G7E715 and for related copolymers with S blocks.13,14 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 14. The low value obtained for the enthalpy of micellization was checked by use of isothermal titration calorimetry (ITC): see Figure 2. The initial dilution was to the cmc at 30 °C. The linear relationship between Q and concentration at high concentration (c > 0.7 g dm-3) relates to the enthalpy of dilution of intact micelles. Defining the enthalpy of demicellization (∆demicH) as the difference in values of Q corresponding to the lowest concentration for a completely micellar solution and the highest concentration for a completely molecular solution15 leads to ∆micHcal ≈ 1.7 kJ mol-1 at 20 °C. Assuming that the linear relationship between Q and concentration would hold if the micelles were intact down to c ) 0, the difference between the ordinate intercepts of the straight lines in Figure 2 leads to ∆micHcal ≈ 1.3 kJ mol-1 for the micellization process at infinite dilution. Because the enthalpy of dilution of the micellar solution is not large, the two values are similar. Values of ∆micHcal differ from those of ∆micHvH, since ∆micHcal relates to real conditions whereas ∆micHvH relates to hypothetical standard conditions, and may well contain a small contribution from the difference in heat capacity between unimers and micelles in solution (∆Cp∆T). In fact, ∆micHcal is almost always found to be the smaller quantity.16,17 3.2. Hydrodynamic Radius. Intensity fraction distributions of log rh,app obtained for copolymer G5E67 were narrow peaks (c ) 10-65 g dm-3, T ) 20-50 °C) and were assigned to spherical micelles formed by a closed association process. Examples are shown in Figure 3. Peak values of rh,app were in the range 5-7 nm. (14) Kelarakis, A.; Havredaki, V.; Rekatas, C. J.; Booth, C. Phys. Chem. Chem. Phys. 2001, 3, 5550. (15) Raju, B. B.; Winnik, F. M.; Morishima, Y. Langmuir 2001, 17, 4416. (16) Chu, B.; Zhou, Z.-K. In Nonionic Surfactants, Poly(oxyalkylene) Block Copolymers; Nace, V. M., Ed.; Surfactant Science Series; Marcel Dekker: New York, 1996; Vol. 60, Chapter 3. (17) Taboada, P.; Mosquera, V.; Attwood, D.; Yang, Z.; Booth, C. Phys. Chem. Chem. Phys. 2003, 5, 2625. Nixon, S. K.; Hvidt, S.; Booth, C. J. Colloid Interface Sci. 2004, 280, 219.
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Figure 4. Concentration dependence of diffusion coefficient for micelles of copolymer G5E67 in aqueous solutions at (9) 20, (0) 30, (b) 40, and (O) 50 °C. Table 1. Micelle Properties from DLS and SLSa
a
T/°C
D/10-11 m2 s-1
rh/nm
Nw
20 30 40 50
2.7 3.5 4.6 5.7
7.8 7.9 7.6 7.6
47 53 55 56
Figure 5. Debye plots for aqueous micellar solutions of copolymer E5G67 at the temperatures indicated. The curves were calculated using theory for hard spheres. Similarly curved plots were found for solutions at 30 and 40 °C.
Estimated uncertainty in D and rh (4%; Mw and Nw (10%.
The intercepts at c ) 0 (essentially c ) cmc) of average values of the apparent diffusion coefficient of the micelles (Dapp) plotted against concentration (see Figure 4) gave intrinsic values of D and, from eq 1, the intrinsic values of rh listed in Table 1. Within experimental error temperature had very little effect on rh, as is usually found for block copoly(oxyalkylene)s.1,16 The positive slopes of the lines in Figure 3 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
Dapp ) D(1 + kdc + ...)
(4)
The coefficient kd is related to the thermodynamic second virial coefficient A2 by18
kd ) 2A2Mw,mic - kf - 2V
(5)
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 5 is dominant. 3.3. Association Number. As the micelle radii were small, scattering intensities measured at 90° were used without correction for intraparticle interference. Examples of Debye plots are shown in Figure 5. The curves drawn through the data points require additional terms in eq 2, and the method used, equivalent to expanding eq 2 to the seventh virial coefficient, was based on scattering theory for hard spheres, as described in detail in ref 5. Association numbers, Nw, are listed in Table 1. These were calculated using values of Mw,mic, found from the intercepts of the Debye plots, and the value of Mw noted for copolymer G5E67 in section 2.1.3. Values of Nw increase only slightly with an increase in temperature. This insensitivity to temperature arises because the G blocks in the micelle core are stretched. Allowing 0.36 nm per chain unit,19 the average length of a fully stretched G5 block is 1.8 nm. Assuming spherical micelle cores with no penetration of water or poly(oxyethylene), a representative value of Nw ) 50 implies a core radius of ca. 2.4 nm. Assuming that (18) Vink, H. J. Chem. Soc., Faraday Trans. 1 1985, 81, 1725. (19) Flory, P. J. Statistical Mechanics of Chain Molecules; Interscience: New York, 1969; p 165.
Figure 6. Hard-gel boundary established by tube inversion for aqueous solutions of G5E67.
the G blocks have Poisson distributions, as expected in an ideal polymerization of an alkylene oxide,20 some 25% of the G blocks will be long enough to reach the center of the micelle cores if fully stretched. Therefore, spherical (or near spherical) micelles are possible, although the entropic penalty involved in stretching the G blocks in the core will act against any substantial increase of Nw with temperature. 3.4. Gelation. Tube inversion was used to define the immobile regions of the phase diagram: see Figure 6. To a good approximation, immobility in the test (details in section 2.5) requires the gel to have a yield stress higher than 30 Pa.21 Adopting the notation used by Hvidt et al.,22 the immobile phase is referred to as ‘hard gel’. As found for related copolymers,5,13 there is no low-temperature boundary to the hard gel, a feature attributable to the stability of the micelles of these copolymers in aqueous solution at low temperatures. Solutions of other diblock copolymers (e.g., EmBn and EmPn)23 characteristically have a low-T fluid/gel boundary as well as a high-T boundary. Such solutions have potential for use in the fabrication of thermally reversible drug delivery systems; a sol-gel transition between ambient and body temperature would in principle allow the formation of a gel depot in situ by the administration of a mobile copolymer solution containing solubilized drug. Although the copolymers of the present study do not exhibit a low-temperature boundary, we have shown that it is possible to design a drug delivery system having desirable gelation and solubilization characteristics by (20) Flory, P. J. Principles of Polymer Chemistry; Cornell UP: Ithaca, NY, 1953; p 336. (21) See, for example: Li, H.; Yu, G.-E.; Price, C.; Booth, C.; Fairclough, J. P. A.; Ryan, A. J.; Mortensen, K. Langmuir 2003, 19, 1075. (22) (a) Hvidt, S.; Jørgensen, E. B.; Brown, W.; Schillen, K. J. Phys. Chem. 1994, 98, 12320. (b) Almgren, M.; Brown, W.; Hvidt, S. Colloid Polym. Sci. 1995, 273, 2. (23) See, for example: (a) Hamley, I. W.; Mai, S.-M.; Ryan, A. J.; Fairclough, J. P. A.; Booth, C. Phys. Chem. Chem. Phys. 2001, 3, 2972. (b) Kelarakis, A.; Havredaki, V.; Booth, C. Macromol. Chem. Phys. 2003, 204, 15.
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Table 2. Solubilization Capacities for Griseofulvin in Micellar Solutions of Block Copolymers with G or S Hydrophobic Cores: T ) 25 °C copolymer
sCP/mg g-1
wH
sH/mg g-1
G5E67 E62G8E62 E45S8
12.4 8.0 7.5
0.21 0.18 0.33
54 44 22
combining highly solubilizing copolymers, such as G5E67, with block copolymers having the required low-temperature gelation properties.24 The results in sections 3.2 and 3.3 indicate that the micelles of G5E67 are spherical in dilute aqueous solution. Given the same geometry in more concentrated solutions, which is usually the case, the micelles would be expected to pack in a cubic array in the gel which is formed first as concentration is increased.16,23a It has been demonstrated that the micelles of block copoly(oxyalkylene)s with long E blocks, in particular micelles of copolymers with high values of the ratio m/n, form high-modulus gels with body-centered cubic (bcc) structures, i.e., the structure characteristic of particles with soft interaction potentials.23a,25 For copolymer G5E67, the ratio m/n is 13.4, and a gel with bcc structure will be formed in the concentration and temperature ranges involved. 3.5. Drug Solubilization. The solubilization capacity per gram of copolymer in solution (sCP) was calculated 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. Values are listed in Table 2. Also in Table 2 are values of sH, the solubilization capacity per gram of hydrophobic block, calculated using the mass fraction of the hydrophobic block (wH) and making a small correction for solubilization in the E-block corona as described elsewhere.2c This quantity gives a direct measure of the efficiency of solubilization of the drug in the micelle core irrespective of copolymer concentration, block lengths, and overall composition. Considering all sources of error, we estimate a maximum uncertainty of 1 mg g-1 in sCP and (4 mg g-1 in sH. Results reported2c,5 for micellar solutions of copolymers E62G8E62 and E45S8 are also listed in Table 2. Comparison of the results for G5E67 and E62G8E62 shows a higher solubilization capacity for the diblock despite its shorter hydrophobic block. The lower solubilization capacity of the triblock is a consequence of the block architecture; the maximum possible diameter of spherical micelles formed from a linear diblock copolymer will be approximately twice that of a micelle formed from the corresponding triblock copolymer because of the looping of the central block in the core.1 The core volume of E62G8E62 (Nw )19)5 is considerably smaller than G5E67, and this is reflected in its ability to solubilize the hydrophobic drug, presumably related to penetration of the surface region of the core by E blocks and water. As seen in Table 2, the solubilization capacity sH of a G core is twice (or more) that of an S core. A similar two-to-one ratio was found for micellar solutions of triblock EmGnEm and EmSnEm copolymers.5 Considering the similar chemical nature of the G and S units, OCH2CH(CH2OC6H5) and OCH2CH(C6H5), respectively, this difference is surprising. NMR spectroscopy has been used to provide evidence of the mobility of S blocks in micelle cores at room temperature.2a The glass-transition temperature reported for poly(PGE) of number-average molar mass Mn ≈ 6000 g mol-1 is Tg )18 °C,26 which can be compared (24) Ricardo, N. M. P. S.; Pinho, M. E. N.; Yang, Z.; Attwood, D.; Booth, C. Int. J. Pharm. 2005, 300, 22. (25) Hamley, I. W.; Daniel, C.; Mingvanish, W.; Mai, S.-M.; Booth, C.; Messe, L.; Ryan, A. J. Langmuir 2000, 16, 2508.
with Tg ≈ 33 °C for poly(S) of similar average chain length.27 This indicates that G blocks are more flexible and, consequently, that the material of a G core will be less viscous at room temperature than that of an S core. Different rates of solubilization resulting from differences in viscosity provide a possible explanation for our results. For comparison, a value of Tg ≈ 85 °C has been reported for poly(styrene) of Mn ≈ 6000 g mol-1,28 and it has been noted that the cores of micelles of poly(ethylene oxide)/poly(styrene) block copolymers may be glassy at room temperature, albeit for somewhat longer poly(styrene) blocks than the S and G blocks considered in our work.29 Results are also available for the solubilization of griseofulvin at 25 °C in aqueous micellar solutions of EmBn, EmBnEm, and EmPnEm copolymers. Here, P denotes oxypropylene, OCH2CH(CH3), and B denotes oxybutylene, OCH2CH(C2H5). The average solubilization capacity for B cores (sH) is ca.10 mg g-1,2 while values of sH for P cores are very low.2a Chain mobility is not a problem for micelles with B-block and P-block cores as values of Tg for these polymers are below -70 °C.27b On the basis of values of the cmc in molar units, the hydrophobicities per repeat unit of the four types of block rank in the approximate ratio1,5,13 G:S:B:P ≈ 15:12:6:1. In Flory-Huggins theory values of the interaction parameter (χ) are best compared for segments of given volume. Specific volumes are known for the hydrophobic copolymers,5,29 and the hydrophobicities per segment of given volume rank as G:S: B:P ≈ 6:6:5:1. For the solubilization of griseofulvin in aqueous micellar solutions, the ranking of values of sH, i.e., G > S > B . P, broadly reflects the ranking of the hydrophobicities of the core-forming blocks but with the value of sH for S cores reduced by the lower immobility of the chains at room temperature. Theoretical studies of solubilization in micellar solutions31 have focused mainly on EmPnEm copolymers, particularly on the solubilization of liquid solutes, thus removing the enthalpy of melting of a highly crystalline solute, such as griseofulvin, from consideration. Our results are not suited to quantitative consideration in these terms because we have no secure values for the interaction parameters required. Rather we emphasize the importance of compatibility of the blocks of the micelle core with the drug. In this respect, we can relate our results to those of Kabanov et al.32 and Wilhelm et al.33 which, as pointed out by Allen et al.,3 indicate a 1000-fold difference in the partition coefficient of pyrene between water and micelles with poly(propylene oxide) or poly(styrene) cores.
4. Concluding Remarks Our current interest is in the potential use of micellar solutions of block copolymers for the solubilization of aromatic drugs of low aqueous solubility. Comparison of the solubilization properties of copolymers of ethylene oxide and phenyl glycidyl ether (26) Sunder, A.; Tu¨rk, H.; Haag, R.; Frey, H. Macromolecules 2000, 33, 7682. (27) (a) Allen, G.; Booth, C.; Hurst, S. J.; Price, C.; Vernon, F.; Warren, R. F. Polymer 1967, 8, 406. (b) Allen, G.; Booth, C.; Price, C. Polymer 1976, 8, 414. (28) An, L.; He, D.; Jing, J.; Wang, Z.; Yu, D.; Jiang, B.; Jiang, Z.; Ma, R. Eur. Polym. J. 1997, 33, 1523. (29) (a) Jada, A.; Hurtrez, G.; Siffert, B.; Riess, G. Macromol. Chem. Phys. 1996, 197, 3697. (b) Hurtrez, G.; Dumas, P.; Riess, G. Polym. Bull. 1998, 40, 203. (30) (a) Mai, S.-M.; Booth, C.; Nace, V. M. Eur. Polym. J. 1997, 33, 991. (b) Kern, R. J. Makromol. Chem. 1965, 81, 261. (31) See, for example: (a) Hurter, P. N.; Scheutjens, J. M. H. M.; Hatton, T. A. Macromolecules 1993, 8, 5592 and 5030. (b) Nagarajan, R. Colloid Surf. B 1999, 16, 55. (32) Kabanov, A. V.; Nazarov, I. R.; Astafieva, E. V.; Batrakova, E. V.; Alakhov, V. Y.; Yaroslavov, A. A.; Kabanov, V. A. Macromolecules 1995, 28, 2303. (33) Wilhelm, M.; Zhao, C. L.; Wang, Y.; Xu, R.; Winnik, M. A. Macromolecules 1991, 24, 1033.
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with those of a range of copoly(oxyalkylene)s shows that solubilization capacities in milligram per gram of hydrophobe for griseofulvin rank in the order G > S > B . P, where G ) OCH2CH(CH2OC6H5), S ) OCH2CH(C6H5), B ) OCH2CH(C2H5), and P ) OCH2CH(CH3). The results also show that solubilization of griseofulvin by the diblock copolymer G5E67 is enhanced compared to that of a triblock EGE copolymer with a longer G block. Acknowledgment. We thank AstraZeneca and the Engineering and Physical Science Research Council (U.K.) for financial
Taboada et al.
support. This 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 Educacio´n y Cultura for his Ramo´n y Cajal position. Supporting Information Available: Justification of eq 3; dependence of dn/dc on chemical composition. This material is available free of charge via the Internet at http://pubs.acs.org. LA060684+
