Elucidating the Structure of Ranitidine Hydrochloride Form II: Insights from Solid-State Spectroscopy and Ab Initio Simulations

Abstract

We present a complex, computationally supported solid-state spectroscopy study, elucidating the local order in a blockbuster anti-ulcer drug, ranitidine hydrochloride form II. To this end, dispersion-corrected periodic density functional theory calculations were combined with powder X-ray diffraction, solid-state nuclear magnetic resonance, and low-frequency vibrational spectroscopy, delivering a refined structural model. We found that a competition of nearly iso-energetic substructures, formed by enamine-type species, gives rise to the formation of several potential polymorphs. The considered models were critically examined in terms of both the stabilization energy and the spectral response. While previous studies left the crystal structure considered to be conformationally disordered at a molecular level, we found that the disorder is realized far beyond the local molecular arrangement, elucidating formation of infinite nets of hydrogen-bonded chains, linking both Z and E enamine fragments. Contrary to ...