Does Z′ equal 1 or 2? Enhanced powder NMR crystallography verification of a disordered room temperature crystal structure of a p38 inhibitor for chronic obstructive pulmonary disease. Issue 25 (16th June 2017)

• Record Type: Journal Article
• Authors: Widdifield, Cory M.; Nilsson Lill, Sten O.; Broo, Anders; Lindkvist, Maria; Pettersen, Anna; Svensk Ankarberg, Anna; Aldred, Peter; Schantz, Staffan; Emsley, Lyndon
• Is Part Of: Physical chemistry chemical physics. Volume 19:Issue 25(2017)
• Page Start: 16650
• Page End: 16661
• Publication Date: 2017-06-16
• Subjects: Chemistry, Physical and theoretical -- Periodicals; 541.3
• DOI: 10.1039/c7cp02349a
• Languages: English
• ISSNs: 1463-9076

Abstract

Abstract : AZD7624-containing crystal structures are determined using multinuclear magnetic resonance, X-ray diffraction, and computational chemistry methods. Abstract : The crystal structure of the Form A polymorph of N -cyclopropyl-3-fluoro-4-methyl-5-[3-[[1-[2-[2-(methylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-pyrazin-1-yl]benzamide ( i.e., AZD7624), determined using single-crystal X-ray diffraction (scXRD) at 100 K, contains two molecules in the asymmetric unit ( Z ′ = 2) and has regions of local static disorder. This substance has been in phase IIa drug development trials for the treatment of chronic obstructive pulmonary disease, a disease which affects over 300 million people and contributes to nearly 3 million deaths annually. While attempting to verify the crystal structure using nuclear magnetic resonance crystallography (NMRX), we measured 13 C solid-state NMR (SSNMR) spectra at 295 K that appeared consistent with Z ′ = 1 rather than Z ′ = 2. To understand this surprising observation, we used multinuclear SSNMR ( 1 H, 13 C, 15 N), gauge-including projector augmented-wave density functional theory (GIPAW DFT) calculations, crystal structure prediction (CSP), and powder XRD (pXRD) to determine the room temperature crystal structure. Due to the large size of AZD7624 ( ca. 500 amu, 54 distinct 13 C environments for Z ′ = 2), static disorder at 100 K, and (as we show) dynamic disorder at ambient temperatures, NMR spectral assignment was a challenge. We introduce a method to enhance confidence in NMR assignments by comparing experimental 13 C isotropic chemical shifts against site-specific DFT-calculated shift distributions established using CSP-generated crystal structures. The assignment and room temperature NMRX structure determination process also included measurements of 13 C shift tensors and the observation of residual dipolar coupling between 13 C and 14 N. CSP generated ca. 90 reasonable candidate structures ( Z ′ = 1 and Z ′ = 2), which when coupled with GIPAW DFT results, room temperature pXRD, and the assigned SSNMR data, establish Z ′ = 2 at room temperature. We find that the polymorphic Form A of AZD7624 is maintained at room temperature, although dynamic disorder is present on the NMR timescale. Of the CSP-generated structures, 2 are found to be fully consistent with the SSNMR and pXRD data; within this pair, they are found to be structurally very similar (RMSD16 = 0.30 Å). We establish that the CSP structure in best agreement with the NMR data possesses the highest degree of structural similarity with the scXRD-determined structure (RMSD16 = 0.17 Å), and has the lowest DFT-calculated energy amongst all CSP-generated structures with Z ′ = 2.