抗甲氧西林金葡萄球菌头孢菌素91825新型膦酰基前药tak 599酯稳定性研究.pdfVIP

1406 Chem. Pharm. Bull. 56(10) 1406— 1411 (2008) Vol. 56, No. 10 Stability and Stabilization Studies of TAK-599 (Ceftaroline Fosamil), a Novel N-Phosphono Type Prodrug of thicillin Resistant Staphylococcus aureus Cephalosporin T-91825 Yukihiro IKEDA,*,a Junko BAN,a Tomoyasu ISHIKAWA,a Shohei HASHIGUCHI,a Shinichi URAYAMA,b and Hidetoshi HORIBEa a Pharmaceutical Research Division, Takeda Pharmaceutical , .; and b Pharmaceutical Production Division, Takeda Pharmaceutical , .; 2–17–85 Jusohonmachi, Yodogawa-ku, Osaka 532–8686, Japan. Received March 21, 2008; accepted July 13, 2008; published online July 16, 2008 TAK-599 (known as ceftaroline fosamil) is a novel N-phosphono type prodrug of a cephalospor ompound, T-91825, that exhibits strong activity methicillin resistant Staphylococcus aureus (MRSA). The stability and stabilization of TAK-599 were investigated by k ic ysis focused on crystallinity and moisture content. Initially it was nned to develop TAK-599 as an injectable formulation using the amorphous solid powder pre- pared by lyophilization. However, amorphous of TAK-599 form was found to be chemically unstable even when stored at 8 °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. Physico- chemical properties were studied to identify the key factors affecting the stabilization of TAK-599 in order to im- prove long-term stability, and the results indicated that the crystallinity of TAK-599 correlated with stability.