Molecular Modelling Particulate Interactions in Metered Dose Inhaler Suspension Formulations

In this study, predominantly molecular modelling was employed to investigate intermolecular interactions affecting a metered dose inhaler (MDI) suspension formulations two core ingredients, its liquid propellant and solid drug particle. Taking a first principles approach has potential to help explain the cause of formulation issues at a molecular scale. In turn, it could be a valuable tool during development and contribute to a digital drug design approach. A previously determined solid-state structure of propellant 1,1,1,2-Tetrafluoroethane, known commercially as HFA-134a, provided a reference point of favoured interactions at low temperatures. Its intermolecular interaction strength was predicted using molecular mechanics techniques. This identified that its dipole moment, caused by the asymmetric distribution of fluorine atoms, was responsible for the formation of ‘weak hydrogen bonds’ in the low temperature structure. These were believed to promote structural change from the higher temperature cubic phase. The disordered liquid propellant structure was modelled at different temperatures using molecular dynamics. Structural resemblance to the solid-state increased as liquid temperature was reduced. For instance, the liquid’s local density arranged in a similar manner to the body centred cubic phase. Plus, weak hydrogen bond interactions appeared in the liquid, like those seen in the solid-state. However, steric repulsions were the largest influence on the liquid packing. Two polymorphs of corticosteroid fluticasone propionate (FP) had previously been determined, these were visualised, and empirical force fields were applied to predict the strength of their intermolecular interactions. Intermolecular interactions were mostly non-polar in nature in both polymorphs. However, Form I showed better stability due to its favoured interactions. FP’s external morphology was predicted and surface analysis showed mostly non-polar functional groups were exposed.