(291f) Molecular Approach for the Design of Hydrofluoroalkane-Philes for Pressurized Metered-Dose Inhaler Formulations

Pressurized metered-dose inhaler (pMDI) formulations are prospective candidates for the delivery of pharmaceutically relevant biomolecules to and through the lungs. Since polar molecules, including water, have extremely low solubility in hydrofluoroalkanes (HFAs), it has been suggested that reverse aqueous aggregates can be potentially utilized for the solubilization and delivery of biomolecules using pMDIs. A large number of alkyl-based surfactants for inhalation, oral and intravenous routes, have been screened in the past with respect to their ability to form and stabilize water in HFA microemulsions. However, none of the studied amphiphiles were shown capable of forming such aggregates within the conditions investigated. Some limited success has been achieved with surfactants containing fluorinated-based moieties. The results indicate a mismatch between the investigated surfactant tail groups and the semi-fluorinated propellants. A fundamental understanding of these interactions is thus required in order to rationally design surfactants for HFA-based pMDIs. Besides being highly soluble in HFAs, potential surfactant candidates need also contain moieties that are well solvated by the propellant, and are thus capable of stabilizing dispersions in HFAs. In this work, we use ab initio calculations to quantitatively relate the chemistry of candidate surfactant tail groups to their HFA-philicity. HFA-philes are initially screened by calculating the nonbonded pair interaction (binding) energy between the propellant and a representative fragment of the candidate tail. Interaction energies between HFAs and hydrogenated, fluorinated and selected polar tails are reported at increasing levels of theory. One particularly interesting and novel aspect of the proposed approach is the definition of a new molecular-based parameter called the ?enhancement factor'. This factor serves as a better indicator of the solubility, solvation and dispersion ability of the candidate tails in HFAs than the binding energy of the solvent-fragment alone. The enhancement factor also takes into account both solvent-solute to solute-solute interactions. The proposed methodology is broad and expected to be applicable to any solvent-solvophile system. The results are expected to be applicable to all pMDI-based formulations, which generally require amphiphiles as excipients.

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