Langmuir 2006, 22, 8675-8683
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Surfactant Design for the 1,1,1,2-Tetrafluoroethane-Water Interface: ab initio Calculations and in situ High-Pressure Tensiometry Parthiban Selvam, Robson P. S. Peguin, Udayan Chokshi, and Sandro R. P. da Rocha* Department of Chemical Engineering and Materials Science, Wayne State UniVersity, 5050 Anthony Wayne DriVe, Detroit, Michigan 48202 ReceiVed April 13, 2006. In Final Form: July 25, 2006 In situ high-pressure tensiometry and ab initio calculations were used to rationally design surfactants for the 1,1,1,2-tetrafluoroethane-water (HFA134a|W) interface. Nonbonded pair interaction (binding) energies (Eb) of the complexes between HFA134a and candidate surfactant tails were used to quantify the HFA-philicity of selected moieties. The interaction between HFA134a and an ether-based tail was shown to be predominantly electrostatic in nature and much more favorable than that between HFA134a and a methyl-based fragment. The interfacial activity of (i) amphiphiles typically found in FDA-approved pressurized metered-dose inhaler (pMDI) formulations, (ii) a series of nonionic surfactants with methylene-based tails, and (iii) a series of nonionic surfactants with ether-based tails was investigated at the HFA134a|W interface using in situ tensiometry. This is the first time that the tension of the surfactant-modified HFA134a|W interface has been reported in the literature. The ether-based surfactants were shown to be very interfacially active, with tension decreasing by as much as 27 mN‚m-1. However, the methyl-based surfactants, including those from FDA-approved formulations, did not exhibit high activity at the HFA134a|W interface. These results are in direct agreement with the Eb calculations. Significant differences in interfacial activity are noted for surfactants at the 2H,3H-perfluoropentane (HPFP)|water and HFA134a|W interfaces. Care should be taken, therefore, when results from the mimicking solvent (HPFP) are extrapolated to HFA134a-based systems. The results shown here are of relevance in the selection of surfactants capable of forming and stabilizing reverse aqueous aggregates in HFA-based pMDIs, which are promising formulations for the systemic delivery of biomolecules to and through the lungs.
Introduction Over 40 years have elapsed since pressurized metered-dose inhalers (pMDIs) were first introduced as a convenient delivery system for targeting bronchodilator drugs, and later corticosteroids, directly into the lungs of patients with asthma.1 The lungs have also been recognized as an efficient pathway for drugs to the bloodstream due to their large adsorptive surface area2,3 and the lower activity of bound enzymes compared to those present in the liver and kidneys.4 pMDIs are the least expensive devices for inhalation therapy, accounting for more than 80% of the total prescribed aerosols. They represent over 2 billion dollars per year in revenue, and target over 70 million patients worldwide.5 Even though CFCs are still used as propellants in pMDI formulations, their complete phaseout is expected any time, as required by the Montreal Protocol.6,7 On the basis of its obligations with the Montreal Protocol, the FDA has amended its regulation on the use of ozone-depleting substances.8 The chosen replacements for CFC propellants in pMDI formulations are the nontoxic * To whom correspondence should be addressed. Phone: (313) 5774669. Fax: (313) 577-3810. E-mail:
[email protected]. (1) Freedman, T. Postgrad. Med. J. 1956, 20, 667-673. (2) Courrier, H. M.; Butz, N. Crit. ReV. Ther. Drug Carrier Syst. 2002, 19, 425-498. (3) Hollinger, M. A. Respiratory Pharmacology and Toxicology. W. B. Saunders: Philadelphia, 1985; pp 1-20. (4) Zheng, Y.; Marsh, K. C.; et al. Int. J. Pharm. 1999, 191, 131-140. (5) Terzano, C. Pulm. Pharm. Technol. 2001, 14, 351-366. (6) UNEP. The Montreal Protocol on Substances that Deplete the Ozone Layer; Secretariat for The Vienna Convention for the Protection of the Ozone Layer & The Montreal Protocol on Substances that Deplete the Ozone Layer, United Nations Environment Programme: Nairobi, Kenya, 1987; pp 1-48. (7) FDA recently issued a final rule for removal of CFC-containing albuterol products by Dec. 31, 2008: http://www.fdaadvisorycommittee.com/FDC/AdvisoryCommittee/Committees/Pulmonary-Allergy+Drugs/ 071405essentialuse/ 071405_EssentialP.html.
and non-ozone-depleting hydrofluoroalkanes (HFAs). Patients are tolerant to 1,1,1,2-tetrafluoroethane (HFA134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA227),9 which are nontoxic10 and noncarcinogenic.11 HFA134a is rapidly absorbed and eliminated from the body, with a half-life of approximately 5 min.12 HFAs also have densities and vapor pressures similar to those of CFCs.13 Meanwhile, propellants such as butane, isobutene, and propane are not compatible for pulmonary use.11 It is worth mentioning that while HFAs have an ozone-depleting potential (ODP) of zero, the global warming potential (100 year integrated time horizon) of HFA134a and HFA227 is 1300 and 2900, respectively.14 Although the operation of pMDIs with both CFCs and HFAs is similar, extensive reformulation work is currently taking place for the development of HFA-based pMDIs. To a large extent, reformulation is necessary due to the different solvent properties of HFAs and CFCs, some of which are shown in Table 1.15,16 (8) FDA. Use of Ozone-Depleting Substances; RemoVal of Essential-Use Designations; Final Rule; 2003P-0029; National Archives and Records Administration: College Park, MD, 2005; pp 17168-17192. (9) Kirby, S. M.; Smith, J.; et al. Thorax 1995, 50, 679-681. (10) Graepel, P.; Alexander, D. J. J. Aerosol Med. 1991, 4, 193-200. (11) Aiache, J. M. Ann. Pharm. Fr. 1997, 55, 62-68. (12) Harrison, L. I.; Soria, I.; et al. J. Pharm. Pharmacol. 1999, 51, 12351240. (13) Dalby, R. N.; Phillips, E. M.; et al. Pharm. Res. 1991, 8, 1206-1209. (14) O’Doherty, S.; McCulloch, A.; et al. Climate ChangesEmissions of Industrial Greenhouse Gases (HFCs, PFCs and Sulphur Hexafluoride); Environmental Protection Agency: Wexford, Ireland, 2000; p 81. (15) Dickinson, P. A.; Seville, P. C.; et al. J. Aerosol Med. 2000, 13, 179-186. (16) Rogueda, P. G. A. Drug DeV. Ind. Pharm. 2003, 29, 39-49. (17) Boggs, J. E.; Crain, C. M.; et al. J. Phys. Chem. 1957, 61, 682-684. (18) Lemmon, E. W.; McLinden, M. O.; et al. REFPROPsReference Fluid Thermodynamic and Transport Properties, version 7.0; 2002. (19) Meyer, C. W.; Morrison, G. J. Chem. Eng. Data 1991, 36, 409-413. (20) Solvay. HFA propellants for medical use. Solkane 227 pharma and Solkane 134a pharma; Solvay Fluor und Derivate GmbH: Hannover, Germany, 2003; p 43.
10.1021/la061015z CCC: $33.50 © 2006 American Chemical Society Published on Web 09/14/2006
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Table 1. Selected Properties of CFC14 (C2Cl2F2), HPFP (C5H2F10), and HFA134a (C2H2F4) property
CFC1417-19
HPFP16
HFA134a20 102.03 1.21 9.46 (at 4.5 bar) 2.06 8.7 33.5 ( 0.3a
molecular weight density (g‚cm-3) dielectric constant ()
170.92 1.46 0.46
dipole moment (D) surface tension (mN‚m-1) interfacial tension (mN‚m-1), purified interfacial tension (mN‚m-1), commercial water solubility (ppm) solubility in water (ppm) PEG 300 solubility (%, w/w)23 PPG 2000 solubility (%, w/w)23
0.66 12.0 4021
252.05 1.58 15.05 (at 18.66 kHz) 1.90 13.6 36.0 ( 0.1a
4021
33.7 ( 0.2a
31.8 ( 0.05a
90 N/A N/A N/A
390 ( 40 14022 ∼4.50 ∼0.70
2200 1200 ∼4.00 ∼2.00
a
This work.
HFAs a possess larger dipole moment (µ) and dielectric constant () than CFCs due to the presence of asymmetrically positioned H atoms in the molecules. This is reflected in the increased polarity of HFAs. Perhaps the most notable challenge in reformulating pMDIs is the fact that the FDA-approved surfactants traditionally employed with CFCs have very limited solubility in HFAs.24 The low solubility is related to the poor solvation of the hydrogenated tails by HFAs, as will be shown in this work. Surfactants are generally required in solution and dispersion formulations to improve dosage reproducibility.25 They are used both as solubilizing/dispersing agents and as valve lubricants.26 While drug delivery with HFA-based pMDIs can be as effective as that with pMDIs containing CFCs,12 cosolvents such as alcohols are generally required in HFA-based formulations to aid in the solubilization of surfactants.27 Ethanol is fully miscible with HFA134a, HFA227, and their mixtures.28 However, the presence of excipients such as ethanol affects the vapor pressure of the mixture and thus the aerosol respirable fraction.29 Moreover, it enhances the undesirable crystal growth of the drug particles.29 pMDI-based formulations are also prospective candidates for the delivery of pharmaceutically relevant biomolecules including peptides, DNA, proteins, and vitamins.30 However, polar molecules, including water, have extremely low solubility in HFAs. It has been suggested that reverse aqueous aggregates can be potentially utilized for the solubilization and delivery of biomolecules to and through the lungs using pMDIs.2,31,32 A large number of surfactants approved by the FDA for inhalation, oral, and intravenous routes of administration have been screened in the past (phase behavior measurements) with respect to their ability to form and stabilize reverse aggregates of water in HFAs.33 (21) Peguin, R. P. S.; Selvam, P.; et al. Langmuir, in press. (22) Duboisson, R. Physical Properties of HPFP; Synquest Laboratories: Alachua, FL, 2005. (23) Ridder, K. B.; Davies-CuttingIan, C. J.; et al. Int. J. Pharm. 2005, 295, 57-65. (24) Blondino, F. E.; Byron, P. R. Drug DeV. Ind. Pharm. 1998, 24, 935-945. (25) Cyr, T. D.; Duhaime, R. M.; et al. J. Pharm. Biomed. Anal. 1997, 15, 1709-1718. (26) Hickey, A. J. Pharmaceutical Inhalation Aerosol Technology. Drugs and the Pharmaceutical Sciences, 2nd ed.; Marcel Dekker: New York, 2004; Vol. 134, p 593. (27) Vervaet, C.; Byron, P. R. Int. J. Pharm. 1999, 186, 13-30. (28) Williams, R. O., III; Liu, J. Eur. J. Pharm. Sci. 1999, 7, 137-144. (29) Byron, P. R.; Patton, J. S. J. Aerosol Med. 1994, 7, 49-75. (30) Keller, M. Int. J. Pharm. 1999, 186, 81-90. (31) Evans, R. M.; Farr, S. J.; et al. Pharm. Res. 1991, 8, 629-635. (32) Sommerville, M.; Hickey, A. J. Respiratory Drug Delivery VI: Biological, Pharmaceutical, Clinical and Regulatory Issues Relating to Optimized Drug Delivery by Aerosol, the International Symposium, Hilton Head, SC, 1998. (33) Blondino, F. E. Ph.D. Thesis, Virginia Commonwealth University, Richmond, VA, 1995.
None of the studied amphiphiles, however, were shown to be capable of forming such aggregates within the conditions investigated.24,29,34,35 Some limited success has been achieved with surfactants containing fluorinated moieties.36-38 In those cases, either a very large amount of a non-FDA-approved amphiphile and cosolvent37,38 or pressures above saturation (at ambient temperature) were required.36 The results indicate a mismatch between the investigated surfactant tail groups and the semifluorinated propellant. On the other hand, copolymers of propylene and ethylene oxide have high solubility in HFAs and tend to form reverse aggregates in the absence of water.23 A recent patent also describes the formation of aggregates of an EO-PO-EO (EO ) ethylene oxide, PO ) propylene oxide) surfactant in HFA227.39 While proton correlation spectroscopy indicated that water-in-HFA227 (W/HFA227) aggregates were formed, the formulations again required surfactant in excess of 10% and cosolvent in excess of 20% (w/w). In addition, information on the amount of free water available to solubilize solutes of interest in the core of the reverse aggregates (vs water that is solvating the head group or molecularly solubilized due to added ethanol) could not be directly extracted. From the above discussion, it is clear that a fundamental understanding of the interaction between HFA propellants and candidate surfactant tail moieties is required to rationally design surfactants for HFA-based pMDIs. We approach this problem by calculating the nonbonded pair interaction (binding) energy (Eb) between the HFA propellant and candidate tail moieties. Information on energetically favorable solvent-solute complexes has been previously employed to help understand the solubility of moieties in compressible solvents.40-43 To accurately describe the nonbonded interactions of solvent-solute complexes, where dispersion forces are dominant, high levels of theory and large basis sets are generally required.44 As the nonbonded interactions become more electrostatic in nature, the Eb becomes less dependent on the basis set and the level of theory.44 For complexes with interactions that are less electrostatic in nature than for the systems of interest in this work, single-point energy calculations with the aug-cc-pVDZ basis set, from optimized geometries at second-order Møller-Plesset (MP2) perturbation theory with the 6-31+g(d) basis set, were shown to provide a reasonable approximation to the more accurate calculations, such as CCSD(T).42,43 On the basis of an appropriate level of theory and basis set, Eb values can provide detailed information on site-specific interactions and thus aid in the design of highly HFA-philic surfactant tail groups. Treating surfactant tails quantum mechanically is prohibitively expensive in terms of computer time. The problem can be approached by selecting a representative fragment of the tail moiety.42,43 In this work we investigate the Eb between HFA134a and fragments of poly(propylene oxide) (CH3CH(CH3)OCH2CH3, PO) and of a methyl-based tail (CH3CH(CH3)CH2CH2CH3, CH2) analogue. CH2 serves as a baseline (34) Leach, C. L. Aerosol Sci. Technol. 1995, 22, 328. (35) Krafft, M. P.; Riess, J. G. Biochimie 1998, 80, 489-514. (36) Steytler, D. C.; Thorpe, M.; et al. Langmuir 2003, 19, 8715-8720. (37) Patel, N.; Marlow, M.; et al. J. Colloid Interface Sci. 2003, 258, 345353. (38) Patel, N.; Marlow, M.; et al. J. Colloid Interface Sci. 2003, 258, 354362. (39) Meakin, B. J.; Lewis, D. A.; et al. Solubilization of drugs in HFA propellant by means of emulsions. Patent EP1369113, 2003. (40) Cece, A.; Jureller, S. H.; et al. J. Phys. Chem. 1996, 100, 7435-7439. (41) Diep, P.; Jordan, K. D.; et al. J. Phy. Chem. A 1998, 102, 2231-2236. (42) Baradie, B.; Shoichet, M. S.; et al. Macromolecules 2004, 37, 77997807. (43) Kilic, S.; Michalik, S.; et al. Ind. Eng. Chem. Res. 2003, 42, 6415-6424. (44) Rappe, A. K.; Bernstein, E. R. J. Phy. Chem. A 2000, 104, 6117-6128.
Surfactant Design for the HFA134a|Water Interface
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Table 2. Surfactant Structure and Activity at the HPFP|W and HFA134a|W Interfacesa surfactant
MW
oleic acid sorbitan trioleate (Span 85) lecithin PEG monooleyl ether (n ) 2) PEG monooleyl ether (n ) 7) PEG monooleyl ether (n ) 10) PEG monooleyl ether (n ) 20) PEG monooleyl ether (n ) 25) PPG2000f Pluronic L61f Pluronic L62 Pluronic L64 Pluronic P65 Pluronic F68 PEG300f
282 956 731 356 576 708 1148 1368 2000 2000 2500 2900 3500 8400 300
structureb
% EO
C17H33COOH C60H108O8 C40H77O8NP EO2C18H35 EO7C18H35 EO10C18H35 EO20C18H35 EO25C18H35 PO35 EO2.5PO31EO25 EO6PO34EO6 EO13PO30EO13 EO20PO30EO20 EO76PO30EO76 EO7
1.0d 1.8d 7.0d 25.0 53.5 62.0 76.5 80.5 0 10 20 40 50 80 100
γHPFP|Wc
ΠHPFP|Wc
γHFA|Wd
ΠHPA|Wd
14.1 15.9 19.8 23.4 18.6 15.1 10.9 9.0 11.8 11.1 5.9 7.9 8.8 10.5 18.0
19.5 17.7 13.8 10.2 15.0 18.5 22.7 24.6 21.8 22.5 27.7 25.7 24.8 23.1 15.6
12.5 18.6 14.9 24.1 19.7 16.3 9.6 8.9 7.5 6.6 5.9 5.2 4.4 8.5 14.7
19.3 13.2 16.9 7.7 12.1 15.5 22.2 22.9 24.3 25.2 25.9 26.6 27.4 23.3 17.1
a γHPFP|W ) interfacial tension of the HPFP|W interface (mN‚m-1), γHFA|W ) interfacial tension of the HFA143a|W interface (mN‚m-1), γHPFP|S|W ) interfacial tension of the surfactant-modified HPFP|W interface (mN‚m-1), γHFA|S|W ) interfacial tension of the surfactant-modified HFA143a|W interface (mN‚m-1), ΠHPFP|W ) surface pressure of the HPFP|W interface ) γHPFP|W - γHPFP|S|W (mN‚m-1), and ΠHFA|W ) surface pressure of the HFA134a|W interface ) γHFA|W - γHFA|S|W (mN‚m-1). b EOn and POm, where n and m represent the average number of repeat units. c At 1 mM surfactant concentration, 298 K, and atmospheric pressure. d At 1 mM surfactant concentration, 298 K, and saturation pressure (0.665 MPa). e Hydrophiliclipophilic balance (HLB). f Surfactant solubilized in HFA134a or HPFP.
fragment in our studies as it represents the surfactants (in FDAapproved pMDI formulations) that have limited solubility in HFA134a and have been shown not to form reverse microemulsions in the semifluorinated propellants.33 The PO fragment has been chosen because it possesses enhanced solubility in HFAs.23 Besides evaluating the tail-solvent interactions, surfactant interfacial activity/balance must also be addressed to design surfactants for fluid-fluid interfaces such as that of HFA134a and water. The surface tension of HFA134a has been the subject of several investigations.16,20,21,45-47 We have also recently reported a combined atomistic molecular dynamics simulation and tensiometric study of the bare HFA134a|W interface.21 However, there has been no previous report on the interfacial tension of the surfactant-modified HFA134a|W interface. Here we use in situ high-pressure tensiometry to study the effect of surfactant tail chemistry and surfactant balance (hydrophilic-HFA-philic balance, HFB) on the most fundamental property of the HFA134a|W interface, its interfacial tension (γ). Due to the low toxicity of EO head groups,48,49 we devote most of our attention to nonionic surfactants. Besides selected surfactants that are part of FDA-approved pMDI formulations, two other surfactant classes were investigated: surfactants with methylene-based (CH2) tails, the building blocks of the currently FDA-approved surfactants for inhalation therapy,49 and those with more polar PO tail groups. A systematic variation of the surfactant balance (HFB) was accomplished by varying the % EO in the molecule. The tensiometric study parallels the ab initio calculations described above in that the chemistries of the surfactant tails and tail fragments used in the Eb calculations are the same. Materials and Methods Binding Energy Calculations. Binding energies (Eb) were computed using the supermolecule approach: Eb ) Est - Es - Et
(1)
where Est is the total energy of the complex HFA134a + tail fragment and Es and Et are energies of the isolated HFA134a and tail fragment, respectively. More negative Eb values will be observed for more energetically favorable dimers. Both raw Est values and those corrected for basis set superposition error (BSSE) are reported. BSSE was determined using the counterpoise (CP) method of Boys and
Bernadi.50 Calculations were carried out using Gaussian 03.51 Complete geometry optimizations were done for each fragment and the complex at the MP2 level of theory with the 6-31+g(d,p) basis set. The results of these optimizations correspond to energy minima since no imaginary frequencies were observed.52 Single-point MP2 energy calculations have been carried out with the Dunning basis set, aug-cc-pVDZ.53 We used the average of the raw and counterpoisecorrected interaction energies to discuss the Eb results.42,43,54 Energies obtained this way have been shown to be a better approximation to the complete basis set limit, while avoiding computationally expensive calculations.42,43 Also, averaged Eb minimizes the overestimation of the energy at the MP2 level of theory.43,55 Partial charges on individual atoms were calculated by fitting the electrostatic potential using the CHELPG subroutine of Gaussian 03. CHELPG charges are more useful quantities in studying intermolecular interactions than Mulliken population analysis. The Mulliken analysis is known to be strongly affected by the basis set used and, therefore, does not reflect the details of the electron distribution.56 Materials. Pluronic L surfactants, with the general structure PEOb-PPO-b-PEO (EOnPOmEOn) (PEO ) poly(ethylene oxide), PPO ) poly(propylene oxide), were kindly provided by BASF. Poly(ethylene glycol) monooleyl ethers with general structure HO(EOn)(CH2)8CHdCH(CH2)7CH3 (EOnC18H35) and sorbitan trioleate (Span 85, >99%) were purchased from TCI America Inc. Poly(ethylene glycol) (300 g‚mol-1) (PEG300) and poly(propylene glycol) (2000 g‚mol-1) (PPG2000) were purchased from Acros Organics. Lecithin (refined, 100%) was purchased from Alfa Aesar. Oleic acid (>99%) was purchased from Sigma-Aldrich. All of the surfactants were used as received. Their commercial names and corresponding structures are shown in Table 2. Deionized water (NANOpureII, Barnstead), with a resistivity of 17.6 MΩ‚cm-1 and surface tension of 72.9 mN‚m-1 at 298 K, was used in all experiments. Commercial (pharma) grade HFA134a (>99.99%) was a gift from Solvay Fluor & Derivate (45) Chae, H. B.; Schmidt, J. W.; et al. J. Chem. Eng. Data 1990, 35, 6-8. (46) Heide, R. Int. J. Refrig. 1997, 20, 496-503. (47) Higashi, Y.; Shibata, T.; et al. J. Chem. Eng. Data 1997, 42, 438-440. (48) Malmsten, M. Surfactants and Polymers in Drug Delivery. Drugs and The Pharmaceutical Sciences; Marcel Dekker: New York, 2002; p 122. (49) Marti-Mestres, G.; Nielloud, F. Drug Pharm. Sci. 2000, 105, 1-18. (50) Gutowski, M.; Van Duijneveldt-Van de Rijdt, J. G. C. M.; et al. J. Chem. Phys. 1993, 98, 4728-4737. (51) Frisch, M. J.; Trucks, G. W.; et al. Gaussian 03, version A.1; Gaussian, Inc.: Pittsburgh, PA, 2003. (52) Foresman, J. B.; Frisch, A. Exploring Chemistry With Electronic Structure Methods: A Guide to Using Gaussian, 2nd ed.; Gaussian: Pittsburgh, PA, 1998; pp 70-72. (53) Dunning, T. H., Jr. J. Chem. Phys. 1989, 90, 1007-1023. (54) Feller, D.; Jordan, K. D. J. Phys. Chem. A 2000, 104, 9971-9975. (55) Hyla-Kryspin, I.; Haufe, G.; et al. Chem.-Eur. J. 2004, 10, 3411-3422. (56) Wiberg, K. B.; Rablen, P. R. J. Comput. Chem. 1993, 14, 1504-1518.
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Figure 1. Schematic diagram of the high-pressure pendant/hanging drop tensiometer. GmbH (Hanover, Germany). 2H,3H-Perfluoropentane (HPFP; 99.9%) was purchased from SynQuest Labs, Inc. Basic alumina (99%) was purchased from Fisher Scientific and was used as received. Purification of HFA134a and HPFP. Results for the tension of as-received and purified HPFP and HFA134a against water are discussed below. First, the commercial sample of HPFP was purified by mixing the solvent with basic alumina (up to 50 vol %) at room temperature. Subsequently, the sealed system was agitated using a magnetic stirrer for a period of 1 h. The mixture was then distilled at a temperature of 333-338 K. The purified liquid was then collected and refrigerated. The purification of the commercial HFA134a sample was done under pressure, following a procedure similar to that described above for HPFP. Initially, the commercial sample was loaded into a variable-volume high-pressure cell, which was filled with basic alumina (25 vol %). The contents in the cell were thoroughly mixed for 3 h using a magnetic stirrer. The alumina was then allowed to settle for 45-60 min. HFA134a was displaced into another pressure cell (measuring cell) via a 10 µm filter. Interfacial Tension Measurements. The interfacial tension (γ) measurements were performed using a high-pressure tensiometer, schematically depicted in Figure 1. The apparatus consisted of a variable-volume high-pressure cell equipped with a front window and two side windows, which allowed for the visualization of the system under pressure and extraction of the droplet profile. Temperature was monitored in the cell, close to the droplet. The temperature was controlled with a heating tape wrapped around the cell and a temperature controller (Cole Parmer, EW-89000-10) to (0.2 K. Pressure was also monitored in the front part of the pressure cell with a pressure transducer (Sensotec FP2000) to (0.07 MPa. The binary HFA134a|W interfacial tension (γHFA|W) and that of the surfactant-modified interface (γHFA|S|W) were determined using both the pendant and hanging drop techniques. A hanging/pendant drop was formed at the tip of a capillary connected to a six-port injection valve (Valco Instruments). The droplets were generated with the help of a high-pressure pump (manual high-pressure generator, HiP, for HFA; HPLC pump, Waters 501, for water). For water-soluble surfactants, the cell was initially filled with water-surfactant solution. A drop of HFA134a was injected into the system and allowed to equilibrate. For surfactants not soluble in water, the continuous phase was composed of HFA134a and surfactant, and the (hanging) drop phase was pure water. Several drops were formed within each experiment, and their equilibrium tension was determined. The experiment was repeated at least three times to determine the average value for the tension. The error bars are calculated from the deviation from these repeated measurements and are shown along with the results. The interfacial tension was determined using the Laplace equation ∆P ) γ
(
)
1 1 2γ + ) + ∆Fgz R1 R2 Ro
(2)
where ∆P is the pressure difference across the interface, R0 is the radius of curvature at the apex of the drop, and z is the vertical distance from the apex.57 The whole droplet profile was used for the (57) Harrison, K. L.; Da Rocha, S. R. P.; et al. Langmuir 1999, 15, 419-428.
Figure 2. Interfacial tension (γ) vs time for the commercial (a) HPFP|water interface at 298 K and ambient pressure and (b) HFA134a|water interface at 298 K and saturation pressure (0.665 MPa). Inset: Interfacial tension (γ) vs time for the purified (a) HPFP|water interface at 298 K and ambient pressure and (b) HFA134a|water interface at 298 K and saturation pressure (0.665 MPa). Error bars represent the deviation among three different measurements. fitting to the Laplace equation using an automated procedure.58 After the injection of each drop, several snapshots were taken with time. The droplets were imaged with a digital camera (jAi), with a 55 mm lens (Computar). The light source (Dolan-Jenner Fiber-Lite MI 150) was aligned to the camera via a mounting rail. It was assumed that equilibrium was attained after the variation in γ became less than the maximum expected experimental error.59
Results and Discussion InterfacialTensionoftheBareHPFP|WaterandHFA134a|Water Interfaces. The interfacial tension results for the commercial and purified HPFP and HFA134a are shown in parts a and b, respectively, of Figure 2. HPFP is a relevant hydrofluoroalkane (liquid at atmospheric pressure) in the context of novel pMDI formulations because it is considered to be a model for HFA134a and HFA227.15,16 The results reported for HPFP are obtained at atmospheric pressure and 298 ( 0.3 K. It is seen that the γ of a commercial HPFP|W interface decreases with time until it starts to fluctuate around the value of 33.7 mN‚m-1. The timedependent behavior of the tension is attributed to the presence of differing species (impurities) in HPFP. Equilibrium tension is reached after the different species have diffused to and rearranged at the interface. A different behavior is observed for the purified HPFP|W interface. The equilibrium interfacial tension value of 36.0 ( 0.1 mN‚m-1 is attained very shortly after drop formation. These results agree with previously reported γ values (58) KSV. CAM 200-Optical contact angle meter; KSV Instruments: Helsinki, Finland, 2001; p 8. (59) da Rocha, S. R. P.; Johnston, K. P. Langmuir 2000, 16, 3690-3695.
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Table 3. Average, Raw, and CP-Corrected Binding Energies (kcal‚mol-1) for the Tail Fragment-HFA134a Complexes Determined at the MP2/aug-cc-pVDZ Level of Theory binding energy complex
average
raw
CP-corrected
PO-HFA134a CH2-HFA134a
-6.36 -2.72
-8.07 -3.85
-4.65 -1.59
for commercial and purified HPFP of 33.3 mN‚m-1 (293 K, 1 atm) and 35.5 mN‚m-1 (295 K, 1 atm), respectively.16 The in situ γ for commercial and purified HFA134a, obtained at 298 K and saturation pressure (0.665 MPa),18 follows a trend similar to that observed for commercial and purified HPFP. The value for the commercial HFA134a|W tension decreases with time until it reaches a constant value of 31.8 mN‚m-1. However, time scales for equilibrium are much longer. This might be attributed to a difference in the type and concentration of impurities present in HFA134a. The purified HFA134a has an interfacial tension value of 33.5 ( 0.3 mN‚m-1, measured at 298 ( 0.2 K and 0.665 MPa. The observed γHFA|W value is lower than that of conventional60 and compressed alkanes such as ethane and propane (∼50 mN‚m-1).61 The results reflect the increased polarity of HFA134a due to the presence of asymmetric H and F in the molecule. HFA134a has a lower interfacial tension against water than HPFP. This result is in agreement with the higher mutual solubility between water and HFA134a and can be attributed to the more polar character of HFA134a, as indicated by its larger dipole moment, Table 1. The interfacial tension of perfluorohexane of 56.45 mN‚m-1 (298 K)61 is also higher than that of HPFP. The presence of the dipole in the semihydrogenated HPFP is also likely to contribute to the lower tension compared to that of perfluorohexane. Surfactant Tail-HFA134a Interaction. In an effort to understand the specific interactions between the HFA134a propellant and candidate surfactant moieties, we computed the interaction energies of HFA134a-tail fragment complexes. Table 3 summarizes the single-point MP2/aug-cc-pVDZ Eb values calculated from the optimized geometries at MP2/6-31g+(d,p). Both raw and counterpoise-corrected Eb values are listed. As described earlier, the results will be discussed on the basis of the average Eb values. The calculations reveal that the PO tail fragment interacts much more strongly with HFA134a (Eb ) -6.36 Kcal.mol-1) than the methyl-based fragment (-2.72 kcal‚mol-1). The presence of the ether oxygen appears as an important factor for the enhancement of the tail fragment-HFA134a interaction. The observed interaction energy of the PO-HFA134a complex is of much larger magnitude than those observed between CO2 and small hydrocarbons and fluorocarbon fragments.41 Large BSSE corrections are also observed. A decrease in the magnitude of the BSSE correction is expected on going from MP2/aug-ccpVDZ to aug-cc-pVTZ calculations (a larger basis set). However, calculations using the latter basis set are not feasible given the size and number of heavy atoms in the systems of interest. Nevertheless, binding energy calculations performed at MP2/ aug-cc-pVDZ with optimized geometries at MP2/6-31g+(d) have been shown to be satisfactory in describing the intermolecular interactions of complexes.42,43,62 Further insight into the nature of the interaction between HFA134a and the tail fragments can be obtained by analyzing (60) Freitas, A. A.; Quina, F. H.; et al. J. Phy. Chem. B 1997, 101, 7488-7493. (61) Handa, T.; Mukerjee, P. J. Phys. Chem. 1981, 85, 3916-3920. (62) Raveendran, P.; Wallen, S. L. J. Am. Chem. Soc. 2002, 124, 1259012599.
Figure 3. Optimized geometry of the (a) PO-HFA134a and (b) CH2-HFA134a complexes at the MP2/6-31g+(d,p) level of theory. Interatomic distances (in bold) are in angstroms.
the interatomic distances, reported here in angstroms. The interaction points between HFA134a and PO and CH2 are indicated by dashed lines in parts a and b, respectively, of Figures 3. In total, we can identify four interaction points between HFA134a and the PO moiety and five between HFA134a and CH2. Both complexes show interactions between the fluorine atoms and the hydrogen atoms of the tail fragments. All short C-F‚‚‚H distances and angles present in both complexes are inside the range (2.36-2.86 Å and 120.4-173.5°) observed in crystalline fluorobenzenes.63 The two longest C-F‚‚‚H interactions in the CH2-HFA134a complex are inside the range (2.182.98 Å) reported in complexes formed between fluorobenzene and N-methylformamide or benzene.64 On the basis of a distance criterion, C-F‚‚‚H interactions are within the typical range for weak H bonds.65 In the PO-HFA134a complex, the hydrogen atoms of HFA are directed toward the oxygen atom of the tail fragment, indicating a stronger electrostatic C-H‚‚‚O interaction. The observed H‚‚‚O distance of 2.21 Å is shorter than the distance (63) Thalladi, V. R.; Weiss, H.-C.; et al. J. Am. Chem. Soc. 1998, 120, 87028710. (64) DerHovanessian, A.; Doyon, J. B.; et al. Org. Lett. 1999, 1, 1359-1362. (65) Alonso, J. L.; Antolinez, S.; et al. J. Am. Chem. Soc. 2004, 126, 32443249.
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Table 4. Change in ESP Atomic Charges for the HFA134a Propellant and the Fragments of PO and CH2a CH2-HFA134a
PO-HFA134a HFA134a
PO
HFA134a
CH2
atom
charge
atom
charge
atom
charge
atom
charge
H19 C20 C21 H22 F23 F24 F25 F26
+0.059 -0.184 +0.048 +0.054 +0.052 -0.024 -0.004 +0.021
C1 C2 H3 H4 H5 H6 H7 C8 H9 C10 H11 H12 H13 C14 H15 H16 H17 O18
-0.055 +0.148 -0.011 +0.019 +0.033 -0.038 -0.041 +0.104 -0.023 -0.026 +0.007 -0.003 -0.002 -0.032 +0.008 +0.004 -0.006 -0.108
H19 C20 C21 H22 F23 F24 F25 F26
+0.004 +0.048 -0.079 -0.005 -0.045 +0.018 +0.016 +0.018
C1 C2 H3 H4 H5 H6 H7 C8 H9 C10 H11 H12 H13 C14 H15 H16 H17 C18 H27 H28
+0.031 -0.018 -0.006 -0.006 -0.002 +0.003 +0.012 -0.025 +0.014 -0.021 +0.010 +0.011 +0.001 -0.002 +0.005 +0.003 +0.004 +0.014 -0.004 0.001
a Charge ) ESP charges of isolated molecule - ESP charges in the complex.
reported for CO2-C2H6 and CO2-acetaldehyde complexes.40,66 Similar interaction was observed previously for the CO2-CH4 complex.66 Repulsion between fluorine and the oxygen atom is another factor that determines the optimized geometries of this complex. Different from PO-HFA134a, the CH2-HFA134a complex has weaker interactions. We have also examined the electrostatic potential (ESP) charge distribution of the HFA complexes with the tail fragments to determine the origin of the enhanced binding between HFA134a and PO. The changes in electrostatic charges from the individual components to the complexes are shown in Table 4 and follow the atom numbers shown in Figure 3. The actual charges are provided as Supporting Information. ESP charges were obtained at the MP2/aug-cc-pVDZ level of theory. When comparing the charge distribution of HFA134a as an isolated molecule and that in the complex, one can observe that the carbon charge at the hydrocarbon-fluorocarbon junction (CH2F) displays a marked sensitivity to the bonding environment (changing from +0.025 to +0.209). On the PO fragment, a significant change in atomic charge is observed for the ether oxygen (O18), which is interacting with the C-H group in HFA134a. The charges of C2 and C8 in PO are also very sensitive to the presence of the HFA134a molecule. The net effect is that the CH group of HFA134a becomes more positive in the presence of PO, while the group composed of the ether oxygen, C2, and C8 in the tail fragment becomes significantly more negative. H13 (+0.085) and H16 (+0.092) in PO have the highest charges among the H atoms. Both are interacting with the less electronegative fluorine of HFA. The charges are significantly larger than those of hydrogen atoms in the same positions in the CH2 fragment, which are about +0.056. These results indicate that the more acidic hydrogen atoms H13 and H16 in the PO complex help enhance the binding. Similar phenomena were also observed in 4,4,4-trifluoro-sec-butyl acetate at the CO2 complex.42 The interaction between F25 and H16 is also observed to be shorter (2.68 Å) in the PO-HFA134a complex than in the CH2HFA134a complex (2.72 Å). In this case, acidic hydrogens are (66) Raveendran, P.; Wallen, S. L. J. Phys. Chem. B 2003, 107, 1473-1477.
available on the moiety due to the addition of the oxygen atom, which enhanced the polarity of the tail. It is also noteworthy that the change in atomic charge distribution in the HFA134a molecule is higher in the presence of PO than CH2. Another distinction between the complexes is that when in contact with PO, the largest change in the charge distribution happens on the CH2F side of the molecule, while with CH2, the change is more significant on the CF3 side. Moreover, the highest variation in charge intensity in the presence of the propellant is seen in the PO fragment. It can be concluded, therefore, that the interactions between PO and HFA are predominantly electrostatic in nature. The rO‚‚‚H distance in the PO-HFA134a complex (2.21 Å) is shorter than those found in C2H4O‚‚‚HCF3 (2.37 Å),65 CO2‚‚‚ HCF3 (2.65 Å),66 and polycarbonyl moieties and CO2 (2.663.05 Å)62 complexes. The results indicate that the C-H‚‚‚O bond plays a significant role in the solute-solvent interaction between HFA134a and PO. While the C-H‚‚‚O interaction is the one contributing most to the observed binding between HFA and PO, the C-F‚‚‚H bonds with the more acidic C-H groups also contribute to the overall interaction between the propellant and both tail fragments. Overall, Eb values are shown to be sensitive enough to quantitatively discriminate the interaction between HFA and candidate tail fragments. Therefore, the approach described above can be utilized to guide the design of highly HFA-philic moieties that can be used as tail groups for surfactants for the HFA|W interface. Interfacial Tension of the Surfactant-Modified Interface. Surfactants Used in pMDI-Based, FDA-ApproVed Formulations. Design of pharmaceutically acceptable surfactants that are capable of forming and stabilizing reverse aqueous microemulsions in HFAs has proven to be a significant challenge.24,33 On the basis of solubility studies, several surfactants acceptable for use in both inhalation (pMDIs) and intravenous formulations were screened for the formation of reverse aqueous microemulsions in HFAs, with no success.33 However, phase behavior alone does not address surfactant interfacial activity. For example, the double-chained cationic surfactant didoceyldimethylammonium bromide, which is insoluble in both oil (alkanes) and water, is capable of forming water-in-oil microemulsions.67 The interfacial activity of three surfactants used in FDAapproved pMDI formulations68 was investigated at the HFA134a|W and HPFP|W interfaces. As can be seen from Figure 4, at 298 K and 1 mM concentration, the selected surfactants are capable of reducing the tension of both the HFA134a|W and HPFP|W interfaces by approximately 20 mN‚m-1. However, the final tension values are much higher than what is typically required for the formation of stable reverse aqueous aggregates in both conventional and compressible media.59,69-72 The low interfacial activity can be attributed to the weak solvation of methylenebased tails by HFA134a, as indicated by the small (not very negative) Eb calculated above. Table 2 also lists the surface pressure (Π) for the FDA-approved surfactants in both HPFP|W (ΠHPFP|W) and HFA134a|W (ΠHFA|W). The surface pressure is the difference between the interfacial tensions at the bare and surfactant-modified interfaces. Large Π (67) Ninham, B. W.; Mitchell, D. J.; et al. J. Phys. Chem. 1987, 91, 23202324. (68) Wang, Y. C.; Kowal, R. R. J. Parenter. Drug Assoc. 1980, 34, 452-462. (69) da Rocha, S. R. P.; Johnston, K. P.; et al. J. Phys. Chem. B 2002, 106, 13250-13261. (70) Danielsson, I.; Lindman, B. Colloids Surf. 1981, 3, 391-392. (71) Eastoe, J.; Steytler, D. C.; et al. J. Chem. Soc., Faraday Trans. 1 1994, 90, 3121-3127. (72) Jasper L.; Dickson, P.; Smith, G., Jr.; et al. Ind. Eng. Chem. Res. 2005, 44.
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Figure 4. Interfacial tension (γ) of the surfactant-modified HFA134a|water and HPFP|water interfaces as a function of the HLB of the surfactant. The amphiphiles investigated are approved by the FDA for use in pMDI-based formulations. Conditions: 1 mM surfactant concentration, 298 K, and ambient (HPFP) or saturation (HFA134a) pressure (0.665 MPa).
Figure 5. Interfacial tension (γ) of the surfactant-modified HFA134a|water and HPFP|water interfaces as a function of the hydrophilic-HFA-philic balance (HFB) for the EOnC18H35 surfactant class. In this case HFB is indicated as % EO. Conditions are: 1 mM surfactant concentration, 298 K and ambient (HPFP) or saturation (HFA134a) pressure (0.665 MPa).
indicates high interfacial activity of the surfactant. The concept of interfacial pressure is useful in that the differences in the bare interfacial tension between the two fluids (HPFP and HFA134a) are subtracted out when the interfacial activity of the surfactant is compared. In the case of oleic acid, ΠHPFP|W is approximately equal to ΠHFA|W, indicating that oleic acid has the same activity at both HFA134a|W and HPFP|W interfaces. Lecithin, on the other hand, is more interfacially active at the HFA134a|W interface, and the reverse is true for sorbitan trioleate. From Figure 4, it is clear that as the hydrophilic-lipophilc balance (HLB) decreases γHPFP|W decreases; i.e., the interfacial activity increases. However, in the case of HFA134a|W, interfacial activity goes through a maximum with the HLB, indicating a different behavior between the two classes of solvents. EOnC18H35 Surfactant Class. The interfacial activity of the nonionic surfactant class poly(ethylene glycol) monooleyl ether (EOnC18H35) was investigated at both HPFP|W and HFA134a|W interfaces. Conditions were 298 K, 1 mM surfactant concentration, and ambient (HPFP) or saturation (0.665 MPa) pressure (HFA134a). Besides in situ monitoring of the pressure, saturation conditions for HFA134a were guaranteed by keeping a vaporliquid meniscus in the high-pressure cell throughout the measurements. The results are summarized in Table 2 and plotted in Figure 5 as a function of the HFB. HFB, in this case, is represented by variations in the % EO in the surfactant molecule, while the hydrophobic chain length is kept constant. γ for the homopolymer PEG300 (EO7) is also reported. The CH2-based tail chemistry of this surfactant class is representative of the tail moieties present in the currently FDAapproved surfactants for pMDIs. The FDA-approved amphiphiles are known to have very limited solubility in HFAs24,28 and to not be capable of forming/stabilizing reverse aqueous microemulsions in HFA propellants.24 In a fashion similar to what has been reported for oil|water (O|W)73 and compressible CO2|W interfaces,74 a minimum in tension can be sought by varying the HFB. Both the absolute and minimum values of tension indicate that these amphiphiles behave similarly at the HFA134a|W and HPFP|W interfaces. The trend in the measured γ may be explained in part by the tail and head group solubility in the semifluorinated solvent and in water. A surfactant lowers γ the most when the partitioning
between the phases is balanced.73 For the surfactant class under consideration, however, we believe that there is no balanced state per se. Even though we may be tempted to identify an optimum balance at approximately 80% EO for both HFA134a and HPFP, when compared to the results for the PO-based surfactants shown below, a balance point at such high % EO seems unreasonable. We rationalize these results on the basis of the knowledge that the CH2-based tail interacts poorly with both water and HFAs. The effect of the CH2-based tail is, therefore, to drive the surfactant to the interfacial region due to a mismatch with both phases, and not due to enhanced interactions with the hydrophobic side of the interface. It is also interesting to note the relatively high interfacial activity of the homopolymer EO7. This is indicated by a reduction in tension of about 20 mN‚m-1, when compared to that of the binary HFA134a|W interface. Such high activity is in line with the fact that EO interacts well not only with water but also with HFAs, as indicated by the high solubility of PEG homopolymers, Table 1. PEG300 has more or less equal solubility in HPFP and HFA134a.23 Interfacial tension data, however, suggest that HFA134a interacts more strongly with EO than HPFP does. This is reflected by the more pronounced tension lowering of PEG300 at the HFA134a|W interface. The decrease in tension at the HFA134a|W interface is greater than what can be accounted for due to the lower tension of the binary HFA134a|W interface itself, as can be seen from the Π results in Table 2. EOnPOmEOn Surfactant Class. The interfacial activity of a series of EOnPOmEOn surfactants, with an approximately constant number of PO units, was also studied at the HFA134a|W and HPFP|W interfaces. Experimental conditions are the same as described above, except for the homopolymer PO35 and EO2.5PO31EO2.5, which were dissolved in HFA134a or HPFP. All other surfactants were solubilized in the aqueous phase. The results are summarized in Table 2 and plotted as a function of % EO in Figure 6. The results indicate that the PO-based surfactants are significantly more interfacially active than the CH2-based amphiphiles, in agreement with the binding energy calculations described above. Tension reductions of about 30 mN‚m-1 are observed. The typical V-shaped curve as a function of HFB is also observed for this system.74-78 Different from the CH2-based surfactants, however, here we identify a true balanced point at
(73) Aveyard, R.; Binks, B. P.; et al. J. Chem. Soc., Faraday Trans. 1990, 86, 3111-3115. (74) da Rocha, S. R. P.; Harrison, K. L.; et al. Langmuir 1999, 15, 419-428.
(75) Aveyard, R.; Binks, B. P.; et al. J. Chem. Soc., Faraday Trans. 1 1985, 81, 2155-2168.
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Figure 6. Interfacial tension (γ) of the surfactant-modified HFA134a|water and HPFP|water interfaces as a function of the hydrophilic-HFA-philic balance (HFB) for the EOnPOmEOn surfactant class. In this case HFB is indicated as % EO. Conditions are: 1 mM surfactant concentration, 298 K and ambient (HPFP) or saturation (HFA134a) pressure (0.665 MPa).
approximately 50% EO for the HFA134a|W interface. This balance can be contrasted with that observed for the same surfactant class when the CO2|W interface is modified.74 A balanced point at higher % EO at the HFA134a|W interface is indicative of stronger interaction between HFA134a and PO than between compressed CO2 and PO. Another important difference compared to the amphiphiles with CH2-based tails is the fact that the minimum for the HFA134a|W and HPFP|W interfaces happens at different % EO values. This result suggests that HPFP and HFA134a interact differently with the PO moiety. From a recent solubility study of EOnPOmEOn surfactants in HFAs, it was observed that the addition of the PO moiety (to the pure PEO) causes a much more pronounced decrease in solubility in HPFP than HFA134a.23 Moreover, pure PO has higher solubility in HFA134a than in HPFP.23 This is a strong indication that HFA134a interacts better with PO. A more cooperative interaction between HFA134a and PO is also supported by the surfactant balance at a higher % EO for HFA134a and the overall higher surface pressures. These observations seem to indicate that the higher dipole of HFA134a, and thus enhanced hydrogen bonding capability, apart from any possible size effects,59 may play a major role in the solvation of the surfactant tails. This interaction between HFA and the PO fragment was quantitatively described in the Eb studies described previously. It should be noted, however, that HFAs interact more strongly with the head group (EO) than conventional organic solvents do, making the understanding of surfactant balance at the HFA|W interface a more subtle issue when compared to that of conventional O|W systems. The minimum tension observed for the EOnPOmEOn series is of the same order of magnitude as those observed at the critical aggregation concentration for surfactants capable of forming and stabilizing reverse aqueous aggregates in compressed CO2. Surfactants with tension at the onset of aggregation (γcµc) of ∼4-6 mN‚m-1 (and below) have been shown to form stable water-in-CO2 microemulsions.59,72,74,79
Conclusions The tension of the commercial and purified HFA134a|W interface (γHFA|W) has been determined at 298 K and saturation (76) Becher, P. In Encyclopedia of Emulsion Technology; Becher, P., Ed.; Marcel Dekker: New York, 1987; p 521. (77) Binks, B. P. Langmuir 1993, 9, 25-28. (78) Harrison, K. L.; Johnston, K. P.; et al. Langmuir 1996, 12, 2637-2644. (79) Sagisaka, M.; Fujii, T.; et al. Langmuir 2004, 20, 2560-2566.
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pressure, using a high-pressure pendant drop tensiometer. Further purification of the commercial product is shown to affect the dynamics and final equilibrium γHFA|W value. γHFA|W after purification was 33.5 mN‚m-1, approximately 2.5 mN‚m-1 lower than that of HPFP, a model propellant. This trend may be explained by the enhanced interaction between HFA134a and water relative to that of HPFP and water, as indicated by their larger mutual solubility. This value is close to that of the compressed CO2|W interface.80 Low tension values of the compressible fluid/water interface have been shown to be associated with smaller surfactant coverages59 and also with greater attractive interaction between reverse aqueous aggregates in compressed fluids.81 Similar behavior might be expected for the compressed HFA|W interface. Pair interaction binding energies (Eb) from ab initio calculations are shown to provide a means for quantitatively relating the chemistry of candidate surfactant tail moieties to their HFAphilicity, thus guiding surfactant design. An Eb of -6.36 kcal‚mol-1 for the PO-HFA134a tail fragment complex indicates a significantly more favorable interaction (better solvation), compared to that of the CH2-HFA134a pair, Eb ) -2.72 kcal‚mol-1. A significant contribution to the larger (more negative) Eb observed for the HFA134a-PO complex arises from electrostatic contributions. The interatomic distance and angle of the C-H‚‚‚O bond (between the CH2F group in HFA134a and the ether oxygen in the PO moiety) are similar to those observed for strong hydrogen bonds. It is also observed that the C-F‚‚‚H bonds, where the H atoms are the more acidic hydrogens, also contribute to the overall energy of the complex, though to a lesser extent. This effect is more pronounced in the POHFA134a pair due to the enhanced acidity of certain H atoms in PO that arises due to the presence of the ether linkage. In summary, Eb values are shown to be a powerful tool for the selection of candidate tail moieties for HFA-based formulations. Even though the focus of this work is on the design of amphiphiles for the HFA|W interface, the Eb methodology and results shown here are also of relevance to traditional solution and dispersion pMDI formulations where surfactants are generally required excipients.33 For the first time, in situ high-pressure tensiometry is used to guide the design of amphiphiles for the HFA|W interface. As indicated by the lowering of the surfactant-modified interfacial tension (γHFA|S|W), surfactants with PO-based tails are shown to be more interfacially active at the HFA134a|W interface than those containing CH2-based moieties. The most interfacially active EOnPOmEOn surfactant is shown to reduce the tension to 4.5 mN‚m-1, compared to 9 mN‚m-1 observed for the most active EOnC18H35 surfactant. These results are in direct agreement with the Eb results described above. The surfactants present in FDAapproved formulations are shown to be somewhat interfacially active at the HFA134a|W interface, with tension reductions of up to 20 mN‚m-1. Oleic acid is the most interfacially active of the three FDA-approved surfactants investigated. The γHFA|S|W results as a function the HFB clearly demonstrate the importance of an appropriate balance in the surfactant molecule. While both surfactant classes show a typical V-shaped curve when γHFA|S|W is plotted vs % EO, it is argued that no true balanced state is found for the methyl-based system. On the other hand, a true balance point is found for the EOnPOmEOn surfactant class at approximately 50% EO at the HFA134a|W interface. It is also noteworthy that the balanced state for this surfactant class happens at a lower % EO at the HPFP|W interface. This result can be understood on the basis of the fact that the (80) Bharatwaj, B.; Wu, L.; et al. To be submitted for publication. (81) Lee, C. T.; Psathas, P. A.; et al. Langmuir 1999, 15, 6781-6791.
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more polar HFA134a is expected to interact more strongly with PO than HPFP does. These results suggest caution when the results obtained with this model propellant (HPFP) are extrapolated to HFA-based systems.
group at WSU for useful discussions related to the ab initio calculations, GRID/WSU for computer time, and the National Science Foundation (Grant NSF-CTS 0553537) for financial support.
Acknowledgment. We thank Wayne State University (WSU) for start-up funds and Ph.D. assistantships for R.P.S.P. and the Thomas C. Rumble Fellowship for P.S., Solvay Fluor und Derivate GmbH & Co., Hannover, Germany, for the HFA134a samples, BASF for the Pluronic surfactant samples, Dr. Schlegel’s
Supporting Information Available: ESP atomic charge distribution of the isolated molecules (HFA134a and the PO and CH2 fragments) and the complexes. This material is available free of charge via the Internet at http://pubs.acs.org. LA061015Z
