注射用替莫唑胺的制备及质量研究

Study of preparation and quality of Temozolomide for injection

目的探讨生产高质量及稳定的注射用替莫唑胺处方及制备工艺。方法通过枸橼酸用量确定注射用替莫唑胺处方,通过配液温度、活性炭用量和冻干工艺的考察,确定注射用替莫唑胺的制备工艺。结果最佳处方为替莫唑胺(100 mg),甘露醇(600 mg),枸橼酸(100 mg),聚山梨酯-80(120 mg),枸橼酸钠(235 mg),盐酸(160 mg)。配制温度控制在25℃以下,药液采用盐酸调节pH值至3.0~4.5,同时存放于15℃以下;最佳冻干工艺为制品在-40℃,预冻3 h;导热油升温至0℃,保温64~80 h;导热油升温至15℃,保温18~24 h;最终制品在35℃,保温6~12 h。高效液相色谱法检测141101、141102、141103样品的含量分别为101.1%、100.8%、100.6%。141101和141103样品在12个月长期试验、加速试验考察期间,本品在市售包装下,有关物质略有增加,水分结果略有增大,但均在限度范围内,其他各考察指标均没有明显变化;141102样品在12个月长期试验、加速试验考察期间,市售包装下,水分有所增加,但均在限度范围内,其他各考察指标均没有明显变化。结论以本品处方及工艺制备的替莫唑胺制剂,质量稳定,重复性好,可行性佳,适于工业化生产。

Objective To explore the formulation and preparation process of Temozolomide for injection with high quality and stability.Methods The formulation of Temozolomide for injection was determined by the amount of citric acid.The preparation process of temozolomide for injection was determined by investigating the temperature of liquid mixing,the amount of activated carbon removal and the freeze-drying process.Results The best prescriptions were Temozolomide(100 mg),Mannitol(600 mg),citric acid(100 mg),polysorbide-80(120 mg),sodium citrate(235 mg),hydrochloric acid(160 mg).The preparation temperature was controlled below 25℃,and the pH value of the liquid was adjusted to 3.0-4.5 by hydrochloric acid,and stored below 15℃at the same time.The optimum freeze-drying process was that the product was pre-frozen for 3 hours at-40℃.The heat conducting oil was heated to 0℃for 64-80 hours.The heat conducting oil was heated to 15℃for 18-24 hours.The final product was kept at 35℃for 6-12 hours.The contents of 141101,141102 and 141103 samples were 101.1%,100.8%and 100.6%respectively by high performance liquid chromatography.During the 12 months long-term test and accelerated test of 141101 and 141103 samples,the related substances increased slightly and the moisture content increased slightly under the market packaging,but all of them were within the limits,and the other indexes did not change significantly.During the 12 months long-term test and accelerated test,the moisture content of 141102 samples increased under the commercial packaging,but all of them were within the limit,and other inspection indexes did not change significantly.Conclusion The Temozolomide preparation prepared by the prescription and technology of this product has stable quality,good repeatability and good feasibility,which is suitable for industrial production.