title: Physicochemical and crystal structure analyses of the antidiabetic agent troglitazone.
abstract: The antidiabetic agent troglitazone has two asymmetric carbons located at the chroman ring and the thiazolidine ring and is produced as a mixture of equal amounts of four optical isomers, 2R-5S, 2S-5R, 2R-5R, and 2S-5S. The crystalline powdered drug substance consists of two diastereomer pairs, 2R-5R/2S-5S and 2R-5S/2S-5R. There are many types of crystals obtained from various crystallization conditions. The X-ray structure analysis and the physicochemical analyses of troglitazone were performed. The solvated crystals of the 2R-5R/2S-5S pair were crystallized from several solutions: methanol, ethanol, acetonitrile, and dichloromethane. The ratio of solvent and troglitazone was 1 : 2 (L1/2-form). The monohydrate crystals were obtained from aqueous acetone solution (L1-form). On the other hand, only an anhydrate crystal of the 2R-5S/2S-5R pair was crystallized from various solutions (H0-form). The dihydrous mixed crystal (MA2-form) was obtained from a mixture of the two diastereomer pairs of 2R-5R/2S-5S and 2R-5S/2S-5R in equal amounts by the slow evaporation of aqueous acetone solution. The crystal structure of the MA2-form is similar to the H0-form. When the MA2 crystal was kept under low humidity, it was converted into the dehydrated form (MA0-form) with retention of the single crystal form. The structure of the MA0-form is isomorphous to the H0-form. The MA2-form was converted into the MA0-form and vice versa with retention of the single crystal under low and high humidity, respectively. The crystallization and storage conditions of the drug substances were successfully analyzed.
authors.affiliation: Process Development Laboratories, Sankyo Co., Ltd, Hiratsuks, Kanagawa, Japan.
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fukuhara
authors.forename: Tadashi
authors.initials: T
authors.lastname: Hata
authors.forename: Akiko
authors.initials: A
authors.lastname: Sekine
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Uekusa
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ohashi
mesh_terms: D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002839:Chromans / Q000032:analysis / Q000737:chemistry*; D003460:Crystallization; D007004:Hypoglycemic Agents / Q000032:analysis / Q000737:chemistry*; D015394:Molecular Structure; D045162:Thiazolidinediones / Q000032:analysis / Q000737:chemistry*; D000077288:Troglitazone
chemical_list: D002839:Chromans; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000077288:Troglitazone