复方倍他米松注射液粒度及粒度分布测定方法研究

Determination Method of Particle Size and Particle Size Distribution of Compound Betamethasone Injection

目的建立激光粒度仪测定复方倍他米松注射液中微晶形态的二丙酸倍他米松粒度分布的方法,并评价微粉工艺及灭菌工艺对制剂中二丙酸倍他米松粒度的影响。方法采用Malvern Mastersizer 2000型激光粒度仪,表面活性剂为0.04%(W/W)吐温80,分散剂为水800 m L,遮光度界限为5%~10%,泵转速为2000 r/min,超声能量为12.5,超声时间为120 s,背景测量时间为10 s,背景测量快照为10000,样品测量时间为10 s,样品测量快照为10000。测定灭菌前的微粉化二丙酸倍他米松原料药及灭菌后的复方倍他米松注射液的粒度及其分布。结果微粉工艺中,通过调整气流粉碎工艺参数,可制备出不同粒径的微粉化二丙酸倍他米松,并用于热压灭菌工艺研究;灭菌工艺中,激光粒度仪器系统环形腔喷嘴压力为4~5 bar、文氏管压力为5~6 bar时,自制复方倍他米松注射液样品可获得与原研产品近似的粒度分布。不同粒度微粉化二丙酸倍他米松灭菌后,粒度均有增加。结论灭菌过程会引起二丙酸倍他米松的晶体微小增长,从而导致粒度增加。通过控制灭菌前的微粉化二丙酸倍他米松原料药的粒度,可有效控制灭菌后的二丙酸倍他米松制剂的粒度,从而与原研产品保持质量一致。

Objective To establish a method for determination of the particle size distribution of betamethasone dipropionate in Compound Betamethasone Injection by laser particle size analyzer,and to evaluate the effect of micronization process and sterilization process on the particle size of betamethasone dipropionate in the preparation.Methods The Malvern Mastersizer 2000 laser particle size analyzer was used.The surfactant was 0.04%(W/W)Tween 80,the dispersant was 800 m L water,the laser obscuration was 5%-10%,the speed of pump was 2000 r/min,the ultrasonic energy was 12.5,the ultrasonic time was 120 s,the background measurement time was10 s,the background measurement snapshot was 10000,the sample measurement time was 10 s,and the sample measurement snapshot was 10000.Under the above conditions,the particle size and particle size distribution of micronized active pharmaceutical ingredients(API)of betamethasone dipropionate before sterilization and Compound Betamethasone Injection after sterilization were determined.Results In the micronization process,betamethasone dipropionate with different particle sizes could be prepared by adjusting the parameters of the air jet pulverization process,and it could be used in the research of hot pressing sterilization process.In the sterilization process,with the pressure of the annular cavity nozzle of laser particle size instrument system of 4-5 bar and the pressure of venturi tube of 5-6 bar,the self-made Compound Betamethasone Injection could obtain the similar particle size distribution to the original product.The particle size of betamethasone dipropionate micronized with different particle sizes was increased after sterilization.Conclusion The sterilization process can cause the tiny crystal growth of betamethasone dipropionate,and thus increase the particle sizes.By controlling the particle size of the API of micronized betamethasone dipropionate before sterilization,the particle size of the sterilized betamethasone dipropionate preparation can be effectively controlled to keep its quality consistent with the original product.