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Elucidating an amorphous form stabilization mechanism for tenapanor hydrochloride: crystal structure analysis using X-ray diffraction, NMR crystallography, and molecular modeling

DOI: 10.1021/acs.molpharmaceut.7b01047 DOI Help

Authors: Sten O. Nilsson Lill (AstraZeneca Gothenburg) , Cory M. Widdifield (Institut des Sciences Analytiques, Université de Lyon) , Anna Pettersen (AstraZeneca Gothenburg) , Anna Svensk Ankarberg (AstraZeneca Gothenburg) , Maria Lindkvist (AstraZeneca Gothenburg) , Peter Aldred (AstraZeneca Gothenburg) , Sandra Gracin (AstraZeneca Gothenburg) , Norman Shankland (CrystallografX Ltd) , Kenneth Shankland (University of Reading) , Staffan Schantz (AstraZeneca Gothenburg) , Lyndon Emsley (Institut des Sciences Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL))
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Molecular Pharmaceutics

State: Published (Approved)
Published: February 2018
Diamond Proposal Number(s): 5018

Abstract: By the combined use of powder and single crystal X-ray diffraction, solid-state NMR, and molecular modelling, 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 the structural informatics analysis of ANHY and 2HCl, conformational ring differences in one part of the molecule were observed which influences the relative orientation of a methyl group on a ring nitrogen and thereby impacts 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 protonat-ed 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 originates from the minor (i.e., energetically less stable) ring conformations, one needs to involve nitrogen deprotonation to allow exchange between minor and major conformations of ANHY in solution. Thus, by controlling the solution pH value to well below the pKa of ANHY, the equilibrium between ANHY and 2HCl can be con-trolled and by this mechanism the crystallization of 2HCl can be avoided and the amorphous form of the dichloride salt can therefore be stabilized.

Journal Keywords: Amorphous; Crystal structure; Density functional theory; Solid-state NMR,;Stabilization; X-ray diffraction

Subject Areas: Chemistry, Medicine


Instruments: I11-High Resolution Powder Diffraction

Added On: 02/03/2018 09:26

Discipline Tags:

Health & Wellbeing Chemistry Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction X-ray Powder Diffraction