Solvent-solute interactions in hydrofluoroalkane propellants

Understanding solvation in hydrofluoroalkane (HFA) propellants is of great importance for the development of novel pressurized metered-dose inhaler (pMDI) formulations. HFA-based pMDIs are not only the most widely used inhalation therapy devices for delivering small drug molecules to the respiratory tract, but they also hold promise as vehicles for the delivery of therapeutic biomolecules to and through the lungs. In this work we use binding energy calculations to determine the degree of interaction between HFA propellants and candidate HFA-philes, including a methyl-based tail (isohexane, ISO), and fragments of poly(ethylene oxide) (EO), poly(propylene oxide) (PO), and poly(lactide) (LA). The distinct nature of solvation forces of the two HFA propellants approved by the FDA for use in pMDIs, 1,1,1,2-tetrafluoroethane (HFA134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA227), is also studied. Binding energy (E-b(st)) calculations demonstrated that an increase in tail polarity through the addition of oxygen atoms in the fragment backbone provides for sites capable of interacting with the HFA propellant molecules, thus enhancing the stabilization energy of the complexes. The interaction energy between HFA227 and LA(E-b(HFA227-LA) = -247 kJ center dot mol(-1)).is significantly more favorable than that between HFA227 and its hydrocarbon analog (E-b(HFA227-ISO) = -10.0 kJ center dot mol(-1)). However, it was shown that not only the fragment polarity is of relevance in stabilizing the complexes. The accessibility of the oxygen atoms in the fragments of interest is also relevant. Cluster studies indicate that although both oxygen atoms in the LA fragment are available to form H-bonds with the propellant molecules, the ether oxygen in PO is accessible to only one propellant molecule, thus decreasing significantly the stabilization energy of the cluster. The results shown here serve as a guide for the design of novel HFA-philes for HFA-based pMDIs.