不同辅料对酸根类药物稳定性的影响及不稳定产物分析

Effects of Different Excipients on the Stability of Acid Radical Drugs and Analysis of Unstable Products

目的酸根类药物在成盐的过程中由于分子间排列堆积方式不同会呈现多种晶型,在制剂过程中碱性辅料往往会对酸根类药物稳定性产生影响,如:降解或晶型转化等。本文的目的是探讨不同条件下常规辅料对硫酸氢氯吡格雷和甲磺酸伊马替尼晶型稳定性的影响,为生产工艺及制剂稳定性提供依据。方法本文通过差式扫描量热法研究了四种碱性辅料(聚乙二醇6000,磷酸钙,硬脂酸镁,甘露醇)、三种纤维素类辅料(微晶纤维素,羟丙基纤维素,羟丙基甲基纤维素)及一种酸性辅料二氧化硅对于伊马替尼甲磺酸盐和氯吡格雷硫酸氢盐稳定性的影响,并通过液相色谱质谱联用分析了不相容产物。结果三种纤维素类辅料及一种酸性辅料与两种酸根类药物相容性均较好,不影响药物的稳定性。碱性辅料聚乙二醇6000对两种酸根类药物稳定性影响较小,但是磷酸钙容易导致氯吡格雷硫酸氢盐发生转晶,硬脂酸镁会导致伊马替尼甲磺酸盐脱掉酸根,甘露醇与两种酸根类药物均易形成低共熔物,影响药物的稳定性。结论本文通过研究不同辅料对酸根类药物的影响为后续酸根类药物相容性研究提供了研究方法及思路,为硫酸氢氯吡格雷和甲磺酸伊马替尼制剂研究提供依据。

OBJECTIVE In the process of salt formation,acid radical drugs will show a variety of crystal forms due to the different arrangement and accumulation of molecules.In the preparation process,the basic excipients often affect the stability of acid radical drugs,such as degradation or crystal form conversion.The purpose of this paper is to investigate the effect of conventional excipients on the crystal stability of clopidogrel bisulfate and imatinib mesylate under different conditions,so as to provide a basis for the production process and preparation stability.METHODS In this article,four alkaline excipients(plyethylene glycol 6000,calcium phosphate,magnesium stearate,mannitol),three cellulose excipients(microcrystalline cellulose,hydroxypropyl cellulose,hydroxypropyl methyl Cellulose)and an acidic excipient silicon dioxide were studied on the effects of imatinib mesylate and clopidogrel bisulfate.RESULTS The results showed that three cellulose excipients,one acidic excipient did not affect the stability of two acid radical drugs.The basic excipient polyethylene glycol 6000 hardly affected the stability of the drug,but calcium phosphate could easily cause clopidogrel bisulfate to crystallize.Magnesium stearate would cause imatinib mesylate to remove acid radicals.Mannitol could easily form a eutectic with two acid radical drugs,which affected the stability of the drug.CONCLUSION This article studies the effects of different excipients on acid radical drugs,which provides research methods for subsequent studies on the compatibility of acid radicals and preparation research.