基于QbD理念研究醋酸奥曲肽PLGA微球的冻干工艺

摘要

目的 研究醋酸奥曲肽乳酸-羟基乙酸共聚物(PLGA)微球的冻干工艺,建立合适的冻干工艺参数控制区间.方法 基于质量源于设计(QbD)理念,采用JMP10.0.0软件设计并执行试验,分析冻干工艺参数对样品质量属性的影响.结果 第一阶段干燥参数板温、冻干时间和真空度对样品的有关物质无影响,板温和冻干时间对样品的水分和二氯甲烷残留有显著影响.第二阶段干燥参数板温对样品的有关物质有显著影响;冻干时间对样品的水分有显著影响;板温和冻干时间对样品的二氯甲烷残留有显著影响.结论 采用冻干法干燥醋酸奥曲肽PLGA微球时,最终控制冻干全过程干燥参数设计区间为:预冻阶段控制板温≤-20℃,预冻时间≥3 h,真空度为常压;第一阶段干燥控制板温-5℃,冻干真空度≤5 Pa,冻干时间>2 h;第二阶段干燥控制板温45~50℃,冻干真空度≤5 Pa,冻干时间>14 h.%Objective To study the freeze-drying process of octreotide acetate PLGA microspheres and establish suitable parameter design space of freeze-drying process.Methods The experiments design was carried out on the basis of QbD concept, and the influence of freeze-drying process parameters on the sample quality properties were analyzed by the experiments designed with software JMP10.0.0.Results The first-stage drying parameters such as plate temperature, freeze-drying time and vacuum degree had no significant effects on the related substances; the plate temperature and freeze-drying time had significant effects on the moisture and methylene chloride residue. The plate temperature of the second-stage drying process had a significant effect on the related substances of the samples. The freeze-drying time had a significant effect on the moisture content. The plate temperature and freeze-drying time had significant effects on the methylene chloride content of the samples.Conclusion The freeze-drying process design space of the microspheres was summarized as follows: pre-freezing step, plate temperature no more than -20℃, pre-freezing time no less than 3 h and atmospheric pressure; first drying step, plate temperature of -5℃, vacuum degree no more than 5 Pa and freeze-drying time no less than 2 h; second drying step, plate temperature 45-50℃, vacuum degree no more than 5 Pa and freeze-drying time no less than 14 h.