Stability and Stabilization Studies of TAK-599 (Ceftaroline Fosamil), a Novel N-Phosphono Type Prodrug of Anti-methicillin Resistant Staphylococcus aureus Cephalosporin T-91825

• Published in: Chemical & Pharmaceutical Bulletin Vol. 56; no. 10; pp. 1406 - 1411
• Main Authors: Yukihiro IKEDAa, Junko BANa, Tomoyasu ISHIKAWAa, Shohei HASHIGUCHIa, Shinichi URAYAMAb, Hidetoshi HORIBEa
• Format: Journal Article
• Language: Japanese
• Published: Pharmaceutical Society of Japan 2008
• ISSN: 0009-2363; 1347-5223

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℃, 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℃.