依达拉奉的多晶型研究

Research on Polymorphs of Edaravone

目的研究依达拉奉多晶型现象,寻找对临床有效的优势药用晶型。方法通过多种物理或化学方法制备获得依达拉奉的4种晶型样品,采用单晶X射线衍射技术(SXRD)、粉末X射线衍射技术(PXRD)、差示扫描量热技术(DSC)、红外光谱分析技术(IR)与熔点技术(MP)对上述4种晶型样品进行表征;通过多种影响因素实验对晶型样品的稳定性进行评价;SD大鼠灌胃给予不同晶型依达拉奉,采用高效液相色谱法检测不同时间大鼠血药浓度变化,比较不同晶型的药动学特点。结果通过晶型筛查发现依达拉奉存在4种晶型(晶A型、晶B型、晶C型、晶D型),并获得了4种晶型纯品最佳制备方法;证明PXRD法、DSC法、IR法均可实现对4种晶型物质状态的表征和鉴别;发现不同晶型会对依达拉奉的稳定性及药动学产生影响。结论通过对依达拉奉多晶型现象进行系统研究,阐明了其多种晶型样品的物质组成、制备方法、晶型稳定性及药动学特点,确定了依达拉奉晶A型为优势药用晶型;该研究结果为优势药用晶型的选择和药品质量标准的提高提拱了数据支持和技术支撑。

Objective To study^polymorphism of the free radical scavenger edaravone and to find the one which has good advantages to the clinical medication.Methods Preparation of four forms of edaravone through kinds of physical or chemical methods.These polymorphs"were characterized by single crystal X-ra y diffraction method(S X R D),po^wder X-ra y diffraction method(PX R D),differential scanning calorimetry method(D S C),infrared spectrum method(I R)and melting point method(MP);a variety of influence factors experiment were used to research the stability of polymorphs.Solid edaravone in different for^ns were orally administered to SD rats respectively,the plasma concentration of the drug was determined by HPLC,and the pharmacokinetic characteristic of different forms"was compared according to the HPLC results.Results Four fomis(form A,form B,foiim C,foiim D)and the preparation of pure crystal forms were obtained by crystal screening technology.These polymorphs were identified by PXRD,DSC and IR.The edaravone polymorphs have an influence on the stability and pharmacokinetic.Conclusion Edaravone research provideds a variety of crystal material composition,preparation methods,stability,solubility and pharmacokinetic characteristic,and form A has been proved of good advantage one.This research provides data and technology support for choice of preponderant pharmaceutical polymorphs and drug quality standard improvement.