title: Solid phase transition of CS-891 enantiotropes during grinding.
abstract: The physical properties of N-[1-(4-methoxyphenyl)-1-methylethyl]-3-oxo-4-aza-5a-androst-1-ene-17beta-carboxamide (CS-891), a novel and orally effective testosterone 5-reductase inhibitor, were investigated by differential scanning calorimetry, powder X-ray diffraction at elevated temperature and single crystal X-ray crystallography. CS-891 was revealed to exist as two enantiotropic forms, a low-temperature stable form (Form A) and a high-temperature stable form (Form B) which reversibly transforms to Form A at around 58 degrees C. The effect of grinding temperature on the transition of CS-891 between the amorphous and the crystalline state during grinding of the eantiotropes was examined. Form A transformed into an amorphous form during the grinding process while the product temperature was kept below the transition temperature. On the other hand, when the product temperature during grinding reached above the transition temperature, Form A transformed into an amorphous form and some of the amorphous form converted back to Form B. Form B crystallized from the amorphous form was physically stable even at below the transition temperature. The amorphous form in equilibrium with Form B exhibited remarkable physical stability in comparison with the amorphous form obtained by continued grinding below the transition temperature.
authors.affiliation: Product Development Laboratories, Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. syyada@shina.sanyko.co.jp
authors.forename: Shuichi
authors.initials: S
authors.lastname: Yada
authors.forename: Masaoki
authors.initials: M
authors.lastname: Ohya
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ohuchi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hamaura
authors.forename: Naoki
authors.initials: N
authors.lastname: Wakiyama
authors.forename: Fusao
authors.initials: F
authors.lastname: Usui
authors.forename: Akira
authors.initials: A
authors.lastname: Kusai
authors.forename: Keiji
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D058891:5-alpha Reductase Inhibitors; D000736:Androstenes / Q000737:chemistry*; D001378:Azasteroids / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D003460:Crystallization; D004355:Drug Stability; D008968:Molecular Conformation; D012995:Solubility; D013237:Stereoisomerism; D013678:Technology, Pharmaceutical / Q000379:methods; D013696:Temperature; D014961:X-Ray Diffraction
chemical_list: D058891:5-alpha Reductase Inhibitors; D000736:Androstenes; D001378:Azasteroids; C477151:N-(1-(4-methoxyphenyl)-1-methylethyl)-3-oxo-4-azaandrost-1-ene-17-carboxamide