硫酸氢氯吡格雷片处方和制备工艺研究

Investigation of Formulation and in-Process Parameters of Clopidogrel Bisulfate Tablets

目的制备稳定的硫酸氢氯吡格雷片(CPG,Ⅰ型),并考察影响颗粒特性的关键处方和工艺参数,以解决压片时的黏片现象,并确保稳定性。方法研究原料辅料的相容性并筛选处方,考察直接压片、滚压法和熔融法对杂质、压片特性和溶出度的影响。结果影响CPG稳定性最显著的因素是水分,其次为光照和温度;与滚压法、直接压片相比,熔融制粒的工艺更优;硬脂富马酸钠可防止压片时的黏片现象;溶出度与进口"波立维"相似因子f2>50;3个月加速实验结果表明,稳定性良好。结论制备工艺重现性良好,片剂质量稳定。

OBJECTIVE To investigate the formulation and process for preparing stable clopidogrel bisulfate tablets（Form I） by elucidating the critical formulation and in-process parameters affecting critical granule properties,in order to solve sticking problems in tablet processing as well as improving stability under storage.METHODS Drug-excipient interactions were evaluated,and different dry granulations such as direct compression,melt granulation and roller compaction were compared,in terms of impurity levels,tablet properties and in vitro dissolution.RESULTS The stability of free clopidogrel bisulfate was liable to the high moisture,strong light and elevated temperature.Compared with direct compression and roller compaction,melt granulation was more suitable to prepare clopidogrel bisulfate tablet.Sodium stearyl fumarate avoided sticking problem in tablet processing with PEG 6000.Comparable dissolution profiles were obtained and similar to that of Pavix of Sinofi,with the similar factors above 50.Furthermore,the accelerated stability test suggested that tablets prepared by melt granulation under storage at 40 C and 75% RH for 3 months were stable and showed good physicochemical properties.CONCLUSION The CPG tablets were stable and the established processes were simple and reproducible.