The essential synergy of MD simulation and NMR in understanding amorphous drug forms

Abstract

Molecular dynamics (MD) simulations and chemical shifts from machine learning are used to predict ¹⁵N, ¹³C and ¹H chemical shifts for the amorphous form of the drug irbesartan. The molecules are observed to be highly dynamic well below the glass transition, and averaging over this dynamics is essential to understanding the observed NMR shifts. Predicted linewidths are consistently about 2 ppm narrower than observed experimentally, which is hypothesised to result from susceptibility effects. Previously observed differences in the ¹³C shifts associated with the two tetrazole tautomers can be rationalised in terms of differing conformational dynamics associated with the presence of intramolecular interaction in one tautomer. ¹H shifts associated with hydrogen bonding can also be rationalised in terms of differing average frequencies of transient hydrogen bonding interactions.