Langmuir 2003, 19, 8715-8720
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Microemulsion Formation in 1,1,1,2-Tetrafluoroethane (R134a) David C. Steytler* and Matthew Thorpe School of Chemical Sciences and Pharmacy, University of East Anglia, Norwich, NR4 7TJ, United Kingdom
Julian Eastoe* and Audrey Dupont School of Chemistry, University of Bristol, Bristol, BS8 1TS, United Kingdom
Richard K. Heenan ISIS-CLRC, Rutherford Appleton Laboratory, Chilton, OXON OX11 0QX, United Kingdom Received June 5, 2003. In Final Form: August 5, 2003 Water solubilization by anionic perfluorinated surfactants has been examined in the condensed phase of the hydrofluorocarbon (HFC) gas 1,1,1,2-tetrafluoroethane (R134a) in the temperature range 15-55 °C and to pressures of 500 bar. The surfactant di(1H,1H,5H-octafluoro-n-pentyl) sodium sulfosuccinate (diHCF4) forms stable water-in-R134a microemulsions up to w > 60 (where w ) [H2O]/[surfactant]) with applied pressure and to w ) 50 at the vapor pressure of R134a. Solubilization levels for the related surfactant di(1H,1H,5H-octafluoro-n-pentyl) ammonium phosphate and the commercial grade anionic perfluoro poly(propylene oxide) carboxylate (CF3(CF2CF(CF3)-O-)3CF2CO2- NH4+) were lower. Structural features of the microemulsion systems formed have been examined by small-angle neutron scattering (SANS). The SANS data from all microemulsions examined were characteristic of spherical droplet structure and provided measurement of the mean radius and, for di-HCF4, the headgroup area at the water-R134a interface. When significant, attractive interactions between droplets were evident in the S(Q)ATT contribution to the SANS I(Q). The low level of this contribution for di-HCF4 confirmed the good compatibility of this surfactant with R134a under the conditions examined.
Introduction Due to ozone depletion and other environmental hazards, legislation has, for some time, been driving replacement of chlorinated refrigerant and propellant gases (chlorofluorocarbons, CFCs) with more environmentally compatible hydrofluorocarbons (HFCs).1 As a result, a range of “zero ozone depletion” fluorinated gases have been marketed of which 1,1,1,2-tetrafluoroethane or R134a (critical temperature Tc ) 101 °C) is being widely promoted as a refrigerant. More recently, attention has turned to examining the potential to exploit the solvent properties of such low vapor pressure HFC gases.2 One application in the pharmaceutical industry concerns replacement of dimethyl ether (DME) that is currently used as a “carrier” or “propellant” in inhalers. Owing to their low toxicity3 and nonflammability, alternative HFC propellants would be desirable.4 Since these liquefied gases are essentially hydrophobic solvents, accurate delivery of proteins or hydrophilic drugs may require suitable surfactants to provide either solid dispersions or solubilization of aqueous solutions within water-in-HFC emulsions5 or microemul* To whom correspondence should be addressed. David C. Steytler: Tel, UK + 1603 592033; fax, UK + 1603 25985; e-mail,
[email protected]. Julian Eastoe: Tel, UK + 117 9289180; fax, UK + 117 9250612; e-mail,
[email protected]. (1) Stone, R. Science 1992, 256, 22. (2) Abbott, A. P.; Eardley, C. A. J. Phys. Chem. B 1998, 102, 85748578. (3) Alexander, D. J.; Libretto, S. E. J. Aerosol. Med. 1995, 14, 715720. (4) Bousquet, J.; Cantini, L. Respir. Med. 2002, 96, S17-S27. (5) Butz, N.; Porte, C.; Courrier, H.; Krafft, M. P.; Vandamme, T. F. Int. J. Pharm. 2002, 238, 257-269.
sions.6,7 We here report formation of water-in-R134a (w/R134a) microemulsions using anionic fluorocarbon surfactants and believe this to be the first report of extensive water solubilization in this solvent. Although the surfactants examined are not approved for pharmaceutical use, the results contribute to a fundamental background to aid development of such applications. Using a range of hydrocarbon-based nonionic surfactants, George et al.6 have examined dispersion of smallparticle aerosols of the protein bovine γ-globulin in R134a and DME. Although not all protein was effectively dispersed, it was established that protein/surfactant particles first dispersed in DME and then diluted in R134a propellant produced respirable-sized protein aerosols. The approach represents an alternative to nebulized aqueous aerosols for delivering peptide-based pharmaceuticals to the respiratory tract. To examine water solubilization in propellants, solubilities of a group of 15 pharmaceutically and toxicologically acceptable surfactants have been determined7 in chlorine-free “alternative propellants” (n-butane, propane, DME, R134a, 1,1,1,2,3,3,3-heptafluoropropane (R227), and trichloromonofluoromethane (R11)). Surfactants with high hydrophilic-lipophilic balance (HLB) values showed appreciable solubility in R134a, but water solubilization was only evident in DME and in the hydrocarbons (HCs) n-butane and propane. Water-in-fluorocarbon emulsion formation in the HFC gases R227 and R134a has recently been reported by Krafft (6) Brown, A.; George, D. Pharm. Res. 1997, 14, 1542-1547. (7) Blondino, F. E.; Byron, P. R. Drug Dev. Ind. Pharm. 1998, 24, 935-945.
10.1021/la0302347 CCC: $25.00 © 2003 American Chemical Society Published on Web 09/18/2003
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Figure 1. Chemical structure of the perfluorinated phosphate and sulfosuccinate surfactants.
et al.5 using perfluoroalkylated dimorpholinophosphate (F8H11DMP) as the surfactant. The most stable dispersions were formed in R227 and showed much promise for applications in pressurized, metered dose inhalers. Using the surfactant sodium di(2-ethylhexyl) sulfosuccinate (Aerosol OT), Fulton et al.8 have examined microemulsion formation in chlorodifluoromethane (R22) and R134a. The extent of water solubilization in apolar media is commonly defined by the molar ratio of water to surfactant w ) [H2O]/[surfactant], and levels in R22 were significant, increasing with pressure from w ) 5 (100 bar) to w ) 50 (400 bar). However, stable microemulsions could not be formed in the more “ozone friendly” R134a. We have successfully developed surfactants for use with CO2 based on perfluoro sodium sulfosuccinates.9 From this range, di(1H,1H,5H-octafluoro-n-pentyl) sodium sulfosuccinate (or di-HCF4, see Figure 1) was found to be the best compromise between cost and efficiency for forming water-in-CO2 (w/c) microemulsions. It has since been adopted as a “benchmark” for similar studies.10 More recently, w/c microemulsion formation by related surfactants based on salts of dialkylperfluorophosphates has been examined.11,12 This paper reports phase behavior and structural features of w/R134a microemulsions formed by these surfactants (Figure 1) in R134a. A commercial surfactant, perfluoro poly(propylene oxide) carboxylate (PFPE) that is also successful at stabilizing w/c microemulsions13 was also examined. The solubilization capacity of the sulfosuccinate di-HCF4 is particularly impressive (wmax > 60) with substantial solubilization at ambient temperatures (w ) 40) at vapor pressure alone. Experimental Section Surfactant Synthesis and Purification. The synthetic procedures for the di-HCF414 and di(1H,1H,5H-octafluoro-npentyl) ammonium phosphate (di-HCF4-P)15 surfactants examined have been detailed elsewhere. In R134a (BOC 99.9%), as in CO2, we have noted a high sensitivity of the solubilization capacity (wmax) to trace quantities of inorganic material that may be carried through in the synthesis and is not always detected by routine analytical techniques (e.g., elemental analysis, NMR, surface tension). Removal of such material by two-phase extraction with (8) Jackson, K.; Fulton, J. L. Langmuir 1996, 12, 5289-5295. (9) Eastoe, J.; Downer, A.; Paul, A.; Steytler, D. C.; Rumsey, E.; Penfold, J.; Heenan, R. K. Phys. Chem. Chem. Phys. 2000, 2, 52355242. (10) Liu, Z. T.; Erkey, C. Langmuir 2001, 17, 274-277. (11) Steytler, D. C.; Rumsey, E.; Thorpe, M.; Eastoe, J.; Paul, A. Langmuir 2001, 17, 7948-7950. (12) Keiper, J. S.; Simhan, R.; DeSimone, J. M.; Wignall, G. D.; Melnichenko, Y. B.; Frielinghaus, H. J. Am. Chem. Soc. 2002, 124, 1834-1835. (13) Clarke, M. J.; Harrison, K. L.; Johnston, K. P.; Howdle, S. M. J. Am. Chem. Soc. 1997, 119, 6399-6406. (14) Yoshino, N.; Komine, N.; Suzuki, J.-I.; Arima, Y.; Hirai, H. Bull. Chem. Soc. Jpn. 1991, 64, 3262-3266. (15) Peppard, D. F.; Mason, G. W.; Giffin, G. J. Inorg. Nucl. Chem. 1965, 27, 1683-1691.
Figure 2. Schematic representation of the Soxhlet apparatus using R134a as the solvent for perfluorinated surfactant purification. water is routinely employed, but this presents practical difficulties due to emulsification and losses of surfactant through partitioning to the aqueous phase. These problems are further complicated with fluorocarbon surfactants where selection of a suitable waterimmiscible solvent is not straightforward. An efficient Soxhlet extraction procedure that overcomes these problems has been developed that is particularly amenable to removal of low levels of inorganic impurities from di-HCF4. The experimental configuration is illustrated schematically in Figure 2. The raw surfactant (typically 30 g) was placed in a filter paper in the upper chamber connected to a lower cylindrical reservoir (volume ∼ 100 mL) fitted with a removable toughened glass optical window. The temperature of the two compartments could be independently controlled by circulation of fluid from two thermostated baths. Liquid R134a (∼50 mL) was first introduced into the lower chamber, and a temperature differential of about 25 °C was then applied to drive continuous distillation through the apparatus. The extraction typically took a few hours during which time the surfactant solution deposited in the lower reservoir became increasingly viscous until precipitation occurred at the solubility limit. On depressurization, the purified surfactant could easily be removed physically, by opening the cell, or by flushing with a suitable carrier solvent (e.g., methanol). The PFPE ammonium carboxylate surfactant was made by neutralization of the precursor carboxylic acid PFPE (molecular weight, 650 g mol-1; Ausimont, Italy) with ammonium hydroxide.16 The material so formed was then thoroughly dried in a desiccator over P2O5. High-Pressure Cell. All reported experiments at elevated pressure were conducted using a variable-volume (
