Pressurized metered-dose inhalers (pMDIs) have been recognized as potential devices for the delivery of systemically acting drugs, including biomolecules, to and through the lungs. The development of excipients capable of imparting stability to suspension formulations in hydrofluoroalkane (HFA) propellants is, therefore, of great relevance. This is especially true in this case since many of the drug molecules of interest are poorly soluble in HFAs and need to be formulated as dispersions. Steric stabilization is one possible mechanism for stabilizing colloidal dispersions in low dielectric media such as HFAs. Effective surface active agents will have an anchor moiety that interacts favorably with the dispersed phase (active drug), and a stabilizing group that is well solvated by the propellant medium (HFA). Understanding the interaction between HFAs and candidate stabilizing moieties is, therefore, crucial for the design of novel excipients for suspension-based pMDIs.

In this work we use ab initio calculations and chemical force microscopy (CFM) to quantitatively quantify the HFA-philicity of the biodegradable and biocompatible ester moiety. The complementary information obtained form the binding energy calculations and adhesion force measurements are used to gain microscopic insight on the relationship between the chemistry of the moiety of interest and its solvation in HFA. A lactide-based copolymer surfactant was synthesized and characterized, and its ability to stabilize a dispersion of micronized budesonide in situ in HFA227 (1,1,1,2,3,3,3-heptafluoropropane) was demonstrated. These results corroborate the ab initio calculations and CFM, and show that the ester-based moiety is a suitable candidate for enhancing stability of dispersions in HFA-based pMDIs.

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