title: Crystal structure study and investigation of solid-state cyclization for AMG 222, a channel hydrate.
abstract: In this study, we investigate the solid-state structure and stability of AMG 222 (5-(2-[2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-propyl)-5-(1H-tetrazol-5-yl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2,8 dicarboxylic acid bisdimethylamide), a small molecule DPP-IV inhibitor. Crystal structure of AMG 222 has been solved from single crystal X-ray analysis. Crystallographic data are as follows: monoclinic, P2(1) (no. 4), a=9.0327(5)Å, b=18.6177(8)Å, c=21.4927(10)Å, β=90.126(3)°, V=3614.4(3)Å(3), Z=4. Based on single crystal structure, AMG 222 is a pentahydrate with the water molecules sitting in channels formed by the drug framework. There are three distinct crystal structures of AMG 222 between 0 and 95% relative humidity (RH), namely the anhydrate, hemihydrate, and pentahydrate forms. Solid-state stability of the GMP batch showed a high level of cyclized degradation product. It was postulated that the degradation was promoted by increased amorphous content generated as a result of excessive drying that was employed to remove residual crystallization solvent. Material produced using a modified procedure using a humidified nitrogen purge had lower amorphous content and lower levels of cyclic degradation when compared to the GMP batch.
authors.affiliation: Small Molecule Process and Product Development, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA. ykiang@amgen.com
authors.forename: Y-H
authors.initials: YH
authors.lastname: Kiang
authors.forename: Karthik
authors.initials: K
authors.lastname: Nagapudi
authors.forename: Jodi
authors.initials: J
authors.lastname: Liu
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Staples
authors.forename: Janan
authors.initials: J
authors.lastname: Jona
mesh_terms: D003460:Crystallization; D018360:Crystallography, X-Ray; D003986:Dibenzocycloheptenes / Q000737:chemistry*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry*; D004355:Drug Stability; D004356:Drug Storage; D006813:Humidity; D012997:Solvents / Q000737:chemistry; D013777:Tetrazoles / Q000737:chemistry*
chemical_list: C569813:5-(2-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethylamino)propyl)-5-(1H-tetrazol-5-yl)-10,11-dihydro-5H-dibenzo(a,d)cycloheptene-2,8-dicarboxylic acid bisdimethylamide; D003986:Dibenzocycloheptenes; D054873:Dipeptidyl-Peptidase IV Inhibitors; D012997:Solvents; D013777:Tetrazoles