Conformational Isomerism in Solid State of AMG 853-Structure Studies Using Solid-State Nuclear Magnetic Resonance and X-ray Diffraction

Investigation of an additional resonance peak in the 19F solid-state nuclear magnetic resonance (NMR) spectrum of AMG 853, a dual antagonist of DP and CRTH2 previously in clinical development for asthma, has led to the identification of two conformational isomers coexisting in the crystal lattice in a continuous composition range between 89.7%:10.3% and 96.5%:3.5%. These two isomers differ in the chloro-flurorophenyl moiety orientation-the aromatic ring is flipped by 180° in these two isomers. The level of the minor isomer is directly measured through integration of the two peaks in the 19F solid-state NMR spectrum. The values obtained from the NMR data are in excellent agreement with the degree of disorder of the fluorine atom in the crystal structure, refined using both single-crystal and high-resolution powder X-ray diffraction data.