Study On Crystallization Thermodynamics And Polymorphism Of β-Artemether

β-artemether is used to treat various malarias currently, and is recommended by WHO because of its high efficiency, low toxicity and no cross resistance with chloroquine. Different crystal shape and polymorphism will cause diversity in quality, stability and efficiency of products, thus the content of Polymorphism-A is required to exceed 90% forβ-artemether. In this paper, the thermodynamic properties, polymorphism and crystal habit ofβ-artemether were studied for providing fundamental for anti-solvent crystallization ofβ-artemether.The solubility data ofβ-artemether in ethanol+water, methanol+water, n-propanol, isopropanol, acetone, etc. were measured using the equilibrium method, and the experimental solubility data were correlated with empirical equation and idea solution model. The results show that the solubility ofβ-artemether in various solvents increase with the increase of temperature, but great difference is found for both solubility and its temperature sensitivities in different solvents, and the experimental data show good agreement with the calculated values. Considered comprehensively, ethanol was chosen as solvent and water was chosen as anti-solvent during anti-solvent crystallization ofβ-artemether.The metastable zone width (MSZW) was studied under different operating conditions by turbidimetric method, and the calibrated model for prediction of MSZW was developed. It is found that the experimental data of MSZW show good agreement with the calculated values, and the width of MSZW have different changes under different operating conditions.Finally, polymorphism experiments ofβ-artemether were conducted, and polymorphism was characterized by X-ray diffraction method and simulated by molecular dynamics simulation. Two polymorphisms are found forβ-artemether, one is monoclinic crystal with space-group of P21, and the other is triclinic crystal with space-group of P-1. The theoretical crystal habit ofβ-artemether, which was predicted based on AE model or BFDH model, show good agreement with the experimental ones.