阿立哌唑长效微晶注射剂的制备及质量研究

Preparation and Quality Study of Aripiprazole Long Acting Microcrystalline Injection

目的:考察不同来源阿立哌唑一水合物(ALM)的质量差异,并采用湿法介质研磨技术制备阿立哌唑长效微晶注射剂,考察其体外释放特性和稳定性。方法:通过检索原研药物相关信息,选择ALM为原料药、羧甲基纤维素钠(CMC-Na)为助悬剂、D-甘露醇(D-mannitol)为冻干保护剂进行处方研究,并考察湿法介质研磨过程中的关键工艺参数,确定制备工艺。结果:经过优化,确定以供应商3生产的ALM为原料药、型号A的CMC-Na为助悬剂、delta晶型的D-mannitol为冻干保护剂;研磨工艺为采用0.8 mm氧化锆珠,70%填充量,2000 r/min转速条件下湿法研磨20 min,通过冷冻干燥后可得到粒径(D50)2.5μm,span为1.9~2.1的样品。结论:不同来源的ALM质量存在略微差异;制备的阿立哌唑长效微晶注射剂在0.25%十二烷基硫酸钠溶液中480 min累积释放度可达到90%,与参比制剂具有相似的体外释放行为,并能在45℃、75%湿度(RH)条件下稳定放置6个月。

Objective:The quality attributes of aripiprazole monohydrate(ALM)from different sources are compared,and the long-acting microcrystalline injection of aripiprazole is prepared using wet grinding technology to investigate its in-vitro release characteristics and stability.Methods:By searching for formulation information of the reference listed drug(RLD),ALM is selected as the active pharmaceutical ingredient(API),carboxymethyl cellulose sodium(CMC-Na)as the stabilizer,and D-mannitol as the freeze-dried protective agent,and the process parameters of medium grinding is optimized.Results:After optimization,it is determined that Supplier 3 is selected as the API vendor,CMC-Na of Model A as the suspension agent and D-mannitol of delta crystal form as the freeze-dried protective agent.In formulation process,a suspension with an average particle size of 2.5µm and a span of 1.9 to 2.1 can be obtained after wet ground at 2000 r/min for 20 minutes using 0.3 mm zirconia beads with 70%filled.Conclusion:There are slight differences in the quality of ALM from different sources;the long-acting microcrystalline injection of aripiprazole can release up to 90%in 0.25%sodium lauryl sulfate solution within 480 minutes,exhibiting a similar in vitro release behavior with the reference formulation,and showing good stability after stored at 45℃RH and 75%RH for 6 months.