Elucidating an Amorphous Form Stabilization Mechanism for Tenapanor Hydrochloride: Crystal Structure Analysis Using X-ray Diffraction, NMR Crystallography, and Molecular Modeling

Molecular Pharmaceutics
Sten O Nilsson LillLyndon Emsley

Abstract

By the combined use of powder and single-crystal X-ray diffraction, solid-state NMR, and molecular modeling, the crystal structures of two systems containing the unusually large tenapanor drug molecule have been determined: the free form, ANHY, and a dihydrochloride salt form, 2HCl. Dynamic nuclear polarization (DNP) assisted solid-state NMR (SSNMR) crystallography investigations were found essential for the final assignment and were used to validate the crystal structure of ANHY. From a structural informatics analysis of ANHY and 2HCl, conformational ring differences in one part of the molecule were observed which influence the relative orientation of a methyl group on a ring nitrogen and thereby impact the crystallizability of the dihydrochloride salt. From quantum chemistry calculations, the dynamics between different ring conformations in tenapanor is predicted to be fast. Addition of HCl to tenapanor results in general in a mixture of protonated ring conformers and hence a statistical mix of diastereoisomers which builds up the amorphous form, a-2HCl. This was qualitatively verified by 13C CP/MAS NMR investigations of the amorphous form. Thus, to form any significant amount of the crystalline material 2HCl, which originate...Continue Reading

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Citations

Oct 22, 2019·Physical Chemistry Chemical Physics : PCCP·Edgar A EngelMichele Ceriotti
May 7, 2020·Pharmaceutics·Anna Helena MazurekDariusz Maciej Pisklak
Oct 31, 2018·Nature Communications·Federico M ParuzzoLyndon Emsley
Feb 14, 2020·Current Pharmaceutical Design·Beiqian TianHongxun Hao
Feb 13, 2020·Journal of Applied Crystallography·Clare F MacraePeter A Wood
Jun 26, 2021·Journal of the American Chemical Society·Pinelopi MoutzouriLyndon Emsley
Aug 10, 2021·Nature Reviews. Methods Primers·Bernd ReifMei Hong
May 24, 2019·Journal of the American Chemical Society·Albert HofstetterLyndon Emsley

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