(656c) Designing Hydrofluoroalkane- and Hydrofluoroolefine-Philic Moieties for Medical Aerosols

Hydrofluoroalkanes (HFAs) and Hydrofluoroolefins (HFOs) are widely used propellants in a variety of applications, including as medical aerosols in pressurized metered-dose inhalers, nasal sprays, topical sprays and medical foams.  A common problem associated with formulating therapeutic molecules in HFAs and HFOs medical aerosols is the fact that many therapeutics have low solubility in these propellants.  The need then arises to design moieties that are capable of imparting stability to formulations, which is also a challenge given the somewhat hydrophobic and lipophobic nature of these semi-fluorinated solvents.

In this work ab initio calculations are used to guide the design of HFA- and HFO-philic chemistries.  We investigate three propellants, namely HFA134a and HFA227, which are approved for use in metered-dose inhalers, and HFO-1234ze, whose potential in medical sprays in being currently evaluated – currently in use as refrigerants.  We determine the binding energy between the propellants and fragments of relevant chemistries including alkanes, ethers and esters.  The relative binding strength, that between propellant-fragment to that of fragment-fragment, which may serve as a better predictor of solubility and solvation of those chemistries is also discussed.  The effect of degree of branching of those chemistries are also studied, by varying pendant methyl group within each category.  The results show that ether and ester groups interact more favorably with HFAs/HFOs than their non-oxygenated analogs by participating in stronger bonds with the dipole of the propellant molecules.  Adding a pendant methyl group can decrease the self-interaction energy between fragments, thus indirectly enhancing HFA/HFO-philicity.