(321b) Chemical Force Microscopy and Ab Initio Calculations: a Molecular Approach for the Design of Surfactants for Pressurized Metered-Dose Inhalers

Perhaps the most notable challenge in the transition from CFC- to hydrofluoroalkane (HFA)-based pressurized metered-dose inhalers (pMDIs) is the extremely low solubility of the FDA-approved surfactants (oleic acid, sorbitan trioleate, and phosphatidyl choline) in HFAs. Such problem arises due to the mismatch between the hydrogenated tails of the surfactants and the polar and semi-fluorinated nature of the propellants. Amphiphiles are used in most solution and dispersion formulations to improve dosage reproducibility and for valve lubrication. Co-solvents are generally required in order to enhance the solubility of the FDA-approved surfactants. However, co-solvents not only alter the vapor pressure of the mixture, thus affecting the aerosol respirable fraction, but also decrease the overall chemical and physical stability of the formulation. Such problems have sparked a recent surge in the search for new surfactants for pMDIs. In order to overcome the existing reformulation problems, one should be able to quantitatively relate the chemistry of the surfactant tail group to its HFA-philicity, which in turn dictates its solubility and ability to stabilize aggregates in HFAs. In this work, we propose a general molecular-based approach for the design of solvophiles. Microscopic information obtained from ab initio calculations and chemical force microscopy (CFM) is used to address surfactant design for HFAs. Binding energies for HFAs and perhydrogenated, perfluorinated and polar tail chemistries are reported. The same tail moieties are investigated by CFM in 2H,3H-perfluoropentane (HPFP), a model hydrofluoroalkane. The complementary ab initio calculations and CFM results provide quantitative information that allows one to discriminate candidate HFA-philic tails based on their chemistry. The results are expected to be applicable to all pMDI-based formulations, which generally require amphiphiles as excipients.

Keywords: ab initio calculations; chemical force microscopy; hydrofluoroalkanes; inhalers; pressurized metered-dose inhalers (pMDIs); surfactants; drug delivery.