Assessing the efficiency of polymeric excipients by atomistic molecular dynamics simulations.

We have performed all-atom molecular dynamics simulations of aqueous solutions of model oligomers of hydroxypropyl methylcellulose (HPMC) and hydroxypropyl methylcellulose acetate succinate (HPMCAS) excipients interacting with a representative poorly soluble active pharmaceutical ingredient (API), phenytoin. Simulations reveal formation of excipient-API complexes for some of the oligomers, which results in a reduction of API aggregation. API aggregation and diffusivity decreased with an increase in excipient content. Excipients form a "gel-like" phase spanning the simulation box beyond ∼10 wt %; API diffusivity within this gel phase is much smaller than API diffusivity without excipient, and decreases exponentially, by 5 orders of magnitude, with increased polymer concentration. Substantial differences are observed with variations in methyl, hydroxypropyl, acetate, and succinate substitution levels in the model oligomers and with the deprotonation state of succinate groups, with strongest interactions with hydrophobic phenytoin observed in the case of acetate substitution. These are used to develop quantitative measures of excipient-API interactions and excipient efficiency in the inhibition of API aggregation. We also find that for model oligomers based on Methocel E (manufactured by Dow Pharma & Food Solutions) chemistry, oligomers of length 10 monomers and simulation boxes of size 7 nm give results similar to those for longer oligomers and bigger boxes. The quantitative measures developed in this study are expected to prove useful as computational screening tools in excipient design.