From lab to patient: Development of API and formulation manufacturing processes for Cancidas®

The design and development of API and formulation manufacturing processes for caspofungin acetate (CANCIDAS®) represented unique challenges for process chemistry and pharmaceutical sciences. From the synthetic aspect, the starting material is derived from a complex fermentation process, which is difficult to control particularly with regard to the more than 20 closely related analogs that are typically part of the fermentation product. The chemical transformations in the process require exceptional selectivity for success, as one is working on a complex, chemically sensitive natural product that is loaded with reactive functional groups. The isolation, purification and crystallization of the final product are not straightforward, as the combination of a hydrophilic core plus a hydrophobic side chain makes for unusual solubility behavior and soapy qualities which render conventional work up procedures impossible. Caspofungin and its intermediates are unstable, degrading via hydrolysis, dimerization, and oxidative pathways, which limit the reactions and isolation procedures available. Soapy compounds like caspofungin are notoriously difficult to crystallize, but a crystalline diacetate salt was ultimately discovered that provided an increase in stability that was crucial for the commercialization of this product.

The inherent instability of the API made the development of a stable IV formulation a particular challenge. A solution formulation was ruled out early due to instability across all viable pH ranges, even at refrigerated temperatures. Other options pursued included sterile crystalline API, frozen solution, and lyophilized API. Ultimately a uniquely stable lyophilized product was developed consisting of acetate buffer, sucrose, and mannitol.