(601f) Understanding the Role of Ethanol As Co-Solvent in Hydrofluoroalkane Propellants

Oral inhalation (OI) is not only the preferred route for the regional delivery of therapeutics to the lungs, but it may also offer opportunities for targeting the systemic circulation due to the lungs ample surface area, good epithelial permeability, and the extensive vascularization.  Pressurized metered-dose inhalers (pMDIs) are the most common portable OI devices for the delivery of therapeutics to the lungs.  Hydrofluoroalkanes (HFAs) are used as both solvent and propellants in pMDIs.  There are many challenges in the development of excipients required for particle stabilization and valve lubrication in HFA-based pMDIs that arise due to the somewhat hydrophobic and lipophobic nature of HFAs.  Ethanol has been widely used to enhance the solubility of HFA excipients, but little is understood about the ability of ethanol (co-solvent) to enhance the solvation of such chemistries in the propellants.

In this work we use chemical force microscopy (CFM) to evaluate the effect of ethanol as co-solvent for HFAs.  We determine the interaction forces between various chemically modified tip/surface combinations in 2H,3H-perfluoropentane (HPFP), a model HFA, which is liquid at ambient conditions.  The effect of varying volume fraction of ethanol on the resulting forces was also evaluated.  Johnson–Kendall–Roberts (JKR) theory was used to model the results.  Our results demonstrate that while the presence of ethanol indeed helps reduce the cohesive forces between the various chemistries, including those representatives of excipients commonly used in particle stabilization in HFAs, the reduction in cohesive forces within ethanol concentrations relevant for commercial pMDIs is relatively small.  Ethanol, therefore, while enhancing the solubility of excipients, has limited effect in terms of solvation forces in HFAs, fact which is corroborated by the poor stability of colloidal particles in HFAs even in the presence of ethanol.