De Novo Determination of the Crystal Structure of a Large Drug Molecule by Crystal Structure Prediction-Based Powder NMR Crystallography

• Published in: Journal of the American Chemical Society Vol. 135; no. 46; pp. 17501 - 17507
• Main Authors: Baias, Maria, Dumez, Jean-Nicolas, Svensson, Per H, Schantz, Staffan, Day, Graeme M, Emsley, Lyndon
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 20.11.2013
• Subjects: Analytical chemistry; Benzoates - chemistry; Chemical Sciences; Crystal structure determination; Crystal structure prediction; H NMR spectroscopy; Isotopic abundances; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular compounds; Molecular Structure; NMR crystallography; or physical chemistry; Pharmaceutical Preparations - chemistry; Powder crystallography; Prediction-based; Pyrazoles - chemistry; Theoretical and; 5TH BLIND TEST; SOLID-STATE NMR; 11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-1; SPECTROSCOPY; QUANTUM-CHEMICAL-CALCULATIONS; HIGH-RESOLUTION H-1; SHIFT CALCULATIONS; CARBON-CARBON CONNECTIVITIES; 1ST PRINCIPLES; POLYMORPHS
• ISSN: 0002-7863; 1520-5126; 1520-5126
• DOI: 10.1021/ja4088874

The crystal structure of form 4 of the drug 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid is determined using a protocol for NMR powder crystallography at natural isotopic abundance combining solid-state 1H NMR spectroscopy, crystal structure prediction, and density functional theory chemical shift calculations. This is the first example of NMR crystal structure determination for a molecular compound of previously unknown structure, and at 422 g/mol this is the largest compound to which this method has been applied so far.