Research On New Preparation Process And Quality Control Of Amifostine

Amifostine (WR-2721, S-[2-(3-Aminopropyl) amino]ethyl]dihydrogenphosphorothioate) is the only one cytoprotectant agent approved by the FDA in1995and later approved by SFDA in2001, for the reducing of cytotoxicity of chemotherapy and radiotherapy. However, there exists severe adverse effects due to the relatively low quality standard of the domestic amifostine, which limites the application for clinical therapy. Therefore, it is of great significance to upgrade the quality standard by developing synthesis and purification process of amifostine to reduce impurity content so as to reduce toxic side effects, in the meanwhile, increase the yield so as to lower clinical cost.In this paper, research was conducted on the synthesis and purification process of amifostine. Different polar aprotic accelerators were investigated in terms of the effect on the yield of amifostine, which was prepared by the condensation reaction between N-(2-bromoethyl)-1,3-propanediamine dihydrobromide (bromine salt) and sodium thiophosphate dodechydrate (sodium salt). The optimized synthesis process parameters with DMSO as the accelerator, the molar ratio of the reactant1:1, and reaction temperature Y℃were obtained, resulting in the yield of89%, amifostine content of93%. Then, the purification process was optimized by applying the solubility of amifostine and one of the related substance sodium thiophosphate, which were determined via HPLC. The optimum recrystallization parameters with recrystallization temperature8℃, recrystallization solvent20%Methanol/H2O (W:W) as the preliminary recrystallization and20%Ethanol/H2O (W:W) as secondary recrystallization were choosen. The above optimized process, when applied to three small tests of laboratory and three lots scale-up pilot, could be easily repeated, and afford the amifostine with higher quality when compared with the previous process, resulting in the related substances sodium thiophosphate<0.1%, amifostine thiol<0.1%, any other individual impurity<0.1%, and the total impurities<0.3%. Eventually, three lots scale up of amifostine for injection were manufactured with the improved quality standard of bulk drug amifostine applied. Research was also conducted on the stability of the amifostine for injection for12monthes, offering theoretical basis for changing storage conditions.On the basis of the above process, a novel green process, featured with adding polar protic solvent methanol as the accelerator instead of the traditional DMSO, DMF was developed to prepare amifostine. The process parameters were optimized with D%methanol added [CH3OH/H2O (W:W)], molar ratio of the reactant1:1, reaction temperature Y℃, resulting in the yield of80%, purity of99%.Besides, the reference substance used for the HPLC analysis were systhesized, purified, structure confirmed and content calibrated, which including amifostine thiol, amifostine disulfide, sodium thiophosphate, and amifostine.