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

Rok publikacji: 2018
Wydawca:  Cryst. Growth Des., 2018, DOI: 10.1021/acs.cgd.8b00639
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K. Drużbicki, A. Pajzderska, D. Chudoba, J. Jenczyk, M. Jarek, J. Mielcarek, J. Wąsicki
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 sub-structures, formed by enamine type species, give rise to the formation of several potential polymorphs. The considered models were critically examined both in terms of the stabilization energy and the spectral response. While previous studies left the crystal structure considered as a 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 \textit{Z} and \textit{E} enamine fragments. On the contrary to the previously proposed model, such an arrangement is found to be highly energy favorable, disclosing the source of a high-stability of the form II. An improved atomistic model has been proposed, successfully accounting for all available spectroscopic data. Particularly, we examine the presented structural arrangement to perfectly describe both optical and neutron terahertz fingerprints, representing string and robust assessment of the validity of the crystal structure with its sensitivity to the crystal packing and the intermolecular forces present therein.

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