Comparison between the intermolecular interactions in the liquid and solid forms of propellant 1,1,1,2-Tetrafluoroethane

A multitude of metered dose inhaler (MDI) formulation properties, such as permanent particle growth or sep-aration, can affect the device's drug delivering performance. 1,1,1,2 - Tetrafluoroethane (HFA-134a) is a liquid propellant commonly employed in MDIs. Here molecular modelling approaches are reported to evaluate the effect weak hydrogen bonding and steric repulsions have on its solid and liquid state molecular-scale structure. Molecular dynamics (MD) simulations of pure liquid HFA-134a were completed for a range of temperatures (203 - 323 K) and intermolecular interactions were analysed using the molecular trajectory files generated. Empirical force fields were used to calculate the strength of interactions seen in the low-temperature crystal structure, and these were compared to the liquid. The solid-state intermolecular structure arranges to maximise attractive interactions between permanent di-poles which enables the formation of 'weak hydrogen bonds', these were found to guide the transition from body centred cubic to its low temperature, monoclinic phase. Reducing HFA-134a's liquid phase temperature increases its resemblance to the believed body centred cubic structure, with improved similarity between intermolecular radial distribution functions and vector angles. Weak hydrogen bonds in the liquid occurred more frequently at lower temperatures but the minimisation of steric repulsions is identified as the main cause of structural ordering, this shows liquid propellant is relatively non-polar. Understanding the structure of pure propellant is useful when evaluating the variation in wetting between different formulation materials and has the potential to be a useful resource for digital drug product design.