Study On Key Impurities In Quality Control Of Caspofungin Acetate

Caspofungin acetate is the first echinocandin semisynthetic antifungal drug,which is produced by the fermentative product of fungus Glarea ozoyensis.It is the first echinocandin class semisynthetic antifungal drug by synthesising and modifying some groups.Due to its complex structure and poor stability,it is easy to generate impurities and degrade in the process of production,storage and transportation,and result in the increase of impurity of products.Therefore,it is of great significance to study the impurities of caspofungin acetate for quality control,production,storage and transportation.In this paper,the chromatographic column,gradient elution procedure and diluent for determining caspofungin acetate by HPLC were studied.Three batches of process validation samples,commercial preparations and stability test samples were detected and analyzed by this method.The results showed that the number of impurities in the three batches of process validation samples was consistent with that of commercial preparations,and the impurity content was significantly lower than that of commercial preparations.However,during the accelerated or long-term stability test,the impurity C increased significantly,and the content of impurity C exceeded the level of commercially available preparations close to the limit of quality standard.Therefore,it was confirmed that the impurity C was the key impurity affecting the quality of caspofungin acetate.Then impurity C was separated and purified by nano PSA50um resin and C18packing.The purity of impurity C was 96%and the recovery rate was 81%.The structure of impurity C was confirmed by IR,HRMS,¹³C-NMR,¹H-NMR,¹³C-¹H cosy,¹H-¹H cosy,HSQC and HMBC spectra.It was the product of 5-membered ring structure after the ring opening of caspofungin 1-ornithine and 6-proline.The molecular formula was C₅₀H₈₂N₈O₁₆ and[M+H]⁺was 1051.5849.