title: Stability and stabilization studies of TAK-599 (Ceftaroline Fosamil), a novel N-phosphono type prodrug of anti-methicillin resistant Staphylococcus aureus cephalosporin T-91825.
abstract: TAK-599 (known as ceftaroline fosamil) is a novel N-phosphono type prodrug of a cephalosporin compound, T-91825, that exhibits strong activity against methicillin resistant Staphylococcus aureus (MRSA). The stability and stabilization of TAK-599 were investigated by kinetic analysis focused on crystallinity and moisture content. Initially it was planned to develop TAK-599 as an injectable formulation using the amorphous solid powder prepared by lyophilization. However, amorphous of TAK-599 free form was found to be chemically unstable even when stored at 8 degrees C, and thus development was focused on the crystalline material. After exhaustive screening of crystallization condition, the monoacetic acid solvate was found to yield TAK-599 in a crystalline form. Physicochemical properties were studied to identify the key factors affecting the stabilization of TAK-599 in order to improve long-term stability, and the results indicated that the crystallinity of TAK-599 correlated with stability. Furthermore, moisture content was also identified in our studies as an important factor in stabilizing TAK-599. TAK-599 containing about 3% moisture was found to be the most stable form. It was concluded that both sufficient crystallinity and strict moisture control of TAK-599 were essential to maintain long-term stability at 25 degrees C.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., Osaka, Japan. Ikeda_Yukihiro@takeda.co.jp
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Junko
authors.initials: J
authors.lastname: Ban
authors.forename: Tomoyasu
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Shohei
authors.initials: S
authors.lastname: Hashiguchi
authors.forename: Shinichi
authors.initials: S
authors.lastname: Urayama
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Horibe
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D002511:Cephalosporins / Q000737:chemistry* / Q000494:pharmacology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D005612:Freeze Drying; D016106:Methicillin Resistance / Q000187:drug effects*; D011355:Prodrugs / Q000737:chemistry* / Q000494:pharmacology*; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D013211:Staphylococcus aureus / Q000187:drug effects*; D014867:Water / Q000032:analysis; D014961:X-Ray Diffraction; D000097583:Ceftaroline
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D011355:Prodrugs; D014867:Water; D000097583:Ceftaroline