Surfactant Design for the 1,1,1,2-Tetrafluoroethane−Water Interface: ab initioCalculations andin situHigh-Pressure Tensiometry

Abstract

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 (E(b)) 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 E(b) 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.

Core–shell Particles for the Dispersion of Small Polar Drugs and Biomolecules in Hydrofluoroalkane Propellants

“…A fluid cell was used to conduct the CPM experiments in liquid HPFP at 298 K. HPFP has been proposed as a mimicking solvent to propellant HFAs. (29)(30)(31)(32)36,37) Drug particles were initially deposited onto a silicon wafer from HPFP. The adhesive force between the particles and the substrate is stronger than that between particles, so that the particles remain bound to the substrate during the measurements.…”

“…The interfacial tension (g) between water (saturated with ethyl acetate) and ethyl acetate (saturated with water) in the presence of LA-g-CS was measured using a pendant drop tensiometer (KSV 2001) as described previously (37). Measurements were carried out inside a sealed cuvette at 298 K. The results shown represent the average of three independent measurements that have a standard deviation of 0.05 mN m j1 or less.…”

“…3. Since no experimental density values of the mutually saturated phases are available in the literature, we use the density of pure water and ethyl acetate to calculate g, once the droplet profile was digitized (37). While this assumption might affect the absolute values of the reported tension, the relative (trend) effect of the copolymer on the tension is expected to remain unchanged.…”

“…CPM has been used to investigate several systems of relevance in pharmaceutical applications (35), including drugs suitable for inhalation therapy in vehicles such as DPIs and pMDIs (14,15,31,32). In this work, the interaction between core-shell particles (particles with the surface modified by the LA-g-CS copolymer) was determined by CPM in liquid HPFP, a mimic to HFA propellants (29)(30)(31)36,37), at 298 K. Figure 5a is an SEM image of an AFM cantilever modified with a single SS particle. A similar micrograph was observed for the core-shell particle (not shown).…”

Templated Open Flocs of Anisotropic Particles for Pulmonary Delivery with Pressurized Metered Dose Inhalers

“…The poor solvation has resulted in low surfactant solubilities and poor steric stabilization of drug particles coated by these surfactants. 10,12,[22][23][24] Consequently, pMDI formulations are often constrained by low mass loadings (<5%, w/w) and fine particle fractions (FPFs) between 5% and 30%. 25 The FPF is the percentage of delivered particles estimated to deposit in the deep lungs.…”