Study On Process Crystallization Of Artesunate

As a pharmaceutical intermediate of artemisinin,artesunate has the advantages of relatively high solubility,low toxicity,and rapid action,and plays an important role in the treatment of malaria.With the deepening of research,artemisinin and its derivatives have been found not only to have antimalarial activity,but also to show pharmacological effects for treating schistosomiasis,tumor,bacterial and viral infection,inflammatory,fibrosis.The solubility and crystalline form of artesunate can directly affect the drug effect and biological activity,but there are no reports on the solid-liquid phase equilibrium data and crystallization process of artesunate.Therefore,a more comprehensive study on the solid-liquid phase equilibrium data and optimal crystallization process conditions of artesunate has been conducted in this paper.In order to obtain thermodynamic data of artesunate drug,the solubility of artesunate in 15 pure solvents was determined by laser dynamic method in the temperature range of 283-323 K.It was found that the solubility of artesunate increased with increasing temperature.At 298 K,the solubility of artesunate was ranked as follows:methyl propionate>ethyl acetate>pentanol>propyl acetate>ethanol>butyl acetate>isopropyl acetate>propanol>butanol>amyl acetate>isopropyl alcohol>isoamyl alcohol>isobutanol≈n-heptanol>n-octanol.Thereafter,the experimental data were correlated using Apelblat,van’t Hoff,lambda h,Wilson model and NRTL model,and all models were found to fit well,with the Wilson model fitting best.The solvent effect was analyzed using the KAT-LSER equation and it was found that the dipolarity/polarizability（π^*）was most relevant to the solubility of artesunate in the proton solvent,and for the ester solvents other than propyl acetate,the Hildebrand solubility parameter（δ_H）and dipolarity/polarizability（π^*）of the solvent were found to have a greater effect on solubility.The mixed thermodynamic properties of the systems(Δ_mixG,Δ_mixH,Δ_mixS,lnγ₁^∞和H₁^E,∞)were estimated according to the Lewis-Randall rule and the dissolution process of artesunate was found to behave spontaneously.Next,the crystal morphology of artesunate was predicted and simulated using Materials studio software.The MS software was used to simulate the artesunate solution system,obtain the parameters of the system and analyze the compatibility of the solute-solvent system;the X-ray data was used to obtain the artesunate crystalline cell parameters,which were used as the initial values to predict the crystal structure and crystal habit of artesunate.The predicted crystalline habit was similar to the actual crystalline habit and the prediction results were good.Finally,the crystallization process of artesunate was improved.The effects of different crystallization conditions on the crystallization process（yield and crystal morphology）of artesunate were investigated.Finally,solventing out crystallization was selected as the crystallization method,the optimum conditions for the crystallization of artesunate were determined as follows:the dropwise addition of solvents to solvents was 2:5,the initial concentration of the solution was 0.23 g/mL,the dropwise acceleration of solvents was 1 mL/min,the stirring speed was 150 rpm,the ageing time was60 min,the addition of crystalline seeds was 0.5%and the crystallization temperature was 15°C.Crystals of artesunate with good crystalline morphology and high yield of 95.67%were obtained according to the above optimal process conditions.