Elucidating the Structure of Ranitidine Hydrochloride Form II: Insights from Solid-State Spectroscopy and Ab Initio Simulations
- Kacper Drużbicki*Kacper Drużbicki*E-mail: [email protected]. Phone: +48 618 295 205.Department of Radiospectroscopy, Faculty of Physics, Adam Mickiewicz University, Umultowska 85, 61-614, Poznan, PolandFrank Laboratory of Neutron Physics, Joint Institute for Nuclear Research, 141980, Dubna, Russian FederationMore by Kacper Drużbicki
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- Aleksandra PajzderskaAleksandra PajzderskaDepartment of Radiospectroscopy, Faculty of Physics, Adam Mickiewicz University, Umultowska 85, 61-614, Poznan, PolandMore by Aleksandra Pajzderska
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- Dorota ChudobaDorota ChudobaDepartment of Radiospectroscopy, Faculty of Physics, Adam Mickiewicz University, Umultowska 85, 61-614, Poznan, PolandFrank Laboratory of Neutron Physics, Joint Institute for Nuclear Research, 141980, Dubna, Russian FederationMore by Dorota Chudoba
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- Jacek JenczykJacek JenczykNanoBioMedical Centre, Adam Mickiewicz University, Umultowska 85, 61-614, Poznan, PolandMore by Jacek Jenczyk
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- Marcin JarekMarcin JarekNanoBioMedical Centre, Adam Mickiewicz University, Umultowska 85, 61-614, Poznan, PolandMore by Marcin Jarek
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- Jadwiga MielcarekJadwiga MielcarekDepartment of Inorganics and Analytical Chemistry, Poznan Univeristy of Medical Sciences, Grunwaldzka 6, 60-780 Poznan, PolandMore by Jadwiga Mielcarek
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- Jan Wa̧sickiJan Wa̧sickiDepartment of Radiospectroscopy, Faculty of Physics and NanoBioMedical Centre, Adam Mickiewicz University, Umultowska 85, 61-614, Poznan, PolandMore by Jan Wa̧sicki
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 the previously proposed model, such an arrangement is found to be highly energetically favorable, disclosing the source of the high stability of form II. An improved atomistic model has been proposed, successfully accounting for all available spectroscopic data. In particular, 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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