The Essential Synergy of MD Simulation and NMR in Understanding Amorphous Drug Forms

Molecular dynamics (MD) simulations and chemical shifts from machine learning are used to predict N, C and H chemical shifts for the amorphous form of the drug irbesartan. The local environments are observed to be highly dynamic well below the glass transition, and averaging over the dynamics is essential to understanding the observed NMR shifts. Predicted linewidths are about 2 ppm narrower than observed experimentally, which is hypothesised to largely result from susceptibility effects. Previously observed differences in the C shifts associated with the two tetrazole tautomers can be rationalised in terms of differing conformational dynamics associated with the presence of an intramolecular interaction in one tautomer. H shifts associated with hydrogen bonding can also be rationalised in terms of differing average frequencies of transient hydrogen bonding interactions.