title: Enantiotropically-related polymorphs of {4-(4-chloro-3-fluorophenyl)-2-[4-(methyloxy)phenyl]-1,3-thiazol-5-yl} acetic acid: crystal structures and multinuclear solid-state NMR.
abstract: Single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), and solid-state NMR (SSNMR) techniques are used to analyze the structures of two nonsolvated polymorphs of {4-(4-chloro-3-fluorophenyl)-2-[4-(methyloxy)phenyl]-1,3-thiazol-5-yl} acetic acid. These polymorphs are enantiotropically-related with a thermodynamic transition temperature of 35 +/- 3 degrees C. The crystal structure of Form 1, which is thermodynamically more stable at lower temperatures, was determined by SCXRD. The crystal structure of Form 2 was determined using PXRD structure solution methods that were assisted using two types of SSNMR experiments, dipolar connectivity experiments and chemical shift measurements. These experiments determined certain aspects of local conformation and intermolecular packing in Form 2 in comparison to Form 1, and provided qualitative knowledge that assisted in obtaining the best possible powder structure solution from the X-ray data. NMR chemical shifts for 1H, 13C, 15N, and 19F nuclei in Forms 1 and 2 are sensitive to hydrogen-bonding behavior, molecular conformation, and aromatic pi-stacking interactions. Density functional theory (DFT) geometry optimizations were used in tandem with Rietveld refinement and NMR chemical shielding calculations to improve and verify the Form 2 structure. The energy balance of the system and other properties relevant to drug development are predicted and discussed.
authors.affiliation: Preclinical Development, GlaxoSmithKline plc., 709 Swedeland Road, King of Prussia, Pennsylvania 19406, USA. fred.g.vogt@gsk.com
authors.forename: Frederick G
authors.initials: FG
authors.lastname: Vogt
authors.forename: Lee M
authors.initials: LM
authors.lastname: Katrincic
authors.forename: Stacey T
authors.initials: ST
authors.lastname: Long
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Mueller
authors.forename: Robert A
authors.initials: RA
authors.lastname: Carlton
authors.forename: Yan T
authors.initials: YT
authors.lastname: Sun
authors.forename: Matthew N
authors.initials: MN
authors.lastname: Johnson
authors.forename: Royston C B
authors.initials: RC
authors.lastname: Copley
authors.forename: Mark E
authors.initials: ME
authors.lastname: Light
mesh_terms: D000085:Acetates / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D015394:Molecular Structure; D013237:Stereoisomerism; D013844:Thiazoles / Q000737:chemistry*
chemical_list: C534706:(4-(4-chloro-3-fluorophenyl)-2-(4-methoxyphenyl)-1,3-thiazol-5-yl)acetic acid; D000085:Acetates; D013844:Thiazoles