Research On The Thermal Stability Of Artemisinin And Its Derivatives

Artemisinin and its derivatives are not only a very important kind of antimalarial drugs, but a unique class of cyclic organic peroxides. Although the unique endoperoxide is the critical and determining factor for the antimalarial activity, it is so weak that artemisinin and its derivatives possess poor thermal stability, and are very susceptible to heat to decompose. For promoting the pharmaceutical development and ensure the thermal stability of artemisinin and its derivatives in production, transposition, storage and use, the four representative materials, artemisinin (ARN), artesunate (ART), artemether (ARM) and dihydroartemisinin (DHA, including three samples) are selected as the object for research on the thermal stability.Firstly, the study on the thermal behavior of ARN, ART, ARM and DHA at linear temperature increase condition, isothermal condition and adiabatic condition, were carried out by using differential scanning calorimeter (DSC) and accelerating rate calorimeter (ARC), respectively. Next, the self-accelerating decomposition temperature (SADT) in50kg package was obtained based on the Semenov model and the Finite Element Analysis (FEA) model. Finally, according to the quantum chemistry theory, the stable configuration, bond order and bond dissociation energy of the endoperoxide (-O-O-) of four molecular were calculated.The DSC results showed that, under linear temperature increase condition, the melting and the thermal decomposition of both ARN and ART cannot be completely separated, which was a very dangerous situation, and the first exothermic peak of DHA decreased and eventually disappeared with the increase of storage time. The isothermal DSC measurements indicated that the thermal decomposition of the four tested materials had the property of autocatalytic, and ARN, ART and DHA decomposed in the solid state, while the thermal decomposition of ARM occued in liquid phase. Besides, the thermal decomposition of ARN, ART, ARM and DHA did not follow a single reaction mechanism. What is more, the ARC measurements displayed that the pressure of all the tested samples in thermal decomposition process increased over temperature linearly, and the initial stage of thermal decomposition reaction of DHA was accompanied by an endothermic process. The SADT calculated by the Semenov model and the FEA model were in good agreement. The SADT of DHA and the BDE of endoperoxide (-O-O-) in DHA was the minimum, which showed that the DHA was the most prone to thermal decomposition.