5-氟尿嘧啶与4,4′-联吡啶共晶的合成与表征的研究  

SYNTHESIS AND CHARACTERIZATION OF THE CO-CRYSTAL FORMED BY 5-FLUOROURACIL AND 4,4′-BIPYRIDINE

作　　者：肖忠伟 杨钊 徐红 李敏[1] 赵永凤 XIAO Zhongwei;YANG Zhao;XU Hong;LI Min;ZHAO Yongfeng(School of Pharmacy, Qingdao University, Qingdao 266021, China)

机构地区：[1]青岛大学药学院,山东青岛266021 [2]青岛大学附属医院药剂科 [3]青岛市食品药品检验研究院 [4]山东科技大学

出　　处：《精准医学杂志》2021年第5期433-436,441,共5页Journal of Precision Medicine

基　　金：国家科技重大专项-重大新药创制“药物一致性评价关键技术与标准研究”课题子课题6(2017ZX09101001006)。

摘　　要：目的以5-氟尿嘧啶(5-FU)为活性药物成分,4,4′-联吡啶(BPY)为共晶配体,运用共结晶技术制备一种新的5-FU-BPY共晶,并对该共晶进行结构表征及性质研究。方法采用结合超声技术的溶剂蒸发法制备共晶,使用X-射线单晶衍射(SCXRD)测定单晶结构,通过X-射线粉末衍射(PXRD)、差示扫描量热法(DSC)、傅里叶变换红外光谱法(FT-IR)、扫描电镜(SEM)对共晶进行表征分析。结果5-FU与BPY以4∶1的化学计量比形成共晶。SCXRD测定结果表明,该晶体属于单斜晶系,P21/c空间群。5-FU-BPY的PXRD图谱在衍射角2θ为12.94°、14.90°、16.78°及33.83°处有新的特征衍射峰。DSC结果显示,5-FU-BPY在256.66℃处具有新的熔点峰。FT-IR分析结果显示,5-FU在3068、1725/cm处对应的亚酰胺基伸缩振动峰以及BPY在1401/cm处对应的吡啶氮伸缩振动峰均发生位移。SEM下该共晶呈现出不同于5-FU和BPY的长条状形态。结论一种具有新熔点的5-FU-BPY新晶相形成。FT-IR结果表明5-FU的亚酰胺基和BPY的吡啶氮参与了5-FU-BPY结构中氢键的形成。SCXRD结构研究揭示,4个5-FU分子通过分子间氢键相连形成超分子环形单元,中间连接1个BPY分子,形成双孔状环形结构,这种罕见的超分子孔洞结构将对共晶的理化性质产生一定影响。Objective To prepare a novel 5-FU-BPY cocrystal by cocrystallization with 5-fluorouracil(5-FU)as the active pharmaceutical ingredient and 4,4′-bipyridine(BPY)as the cocrystal coformer.Methods The cocrystal was successfully obtained by the solvent evaporation method combined with ultrasonic technology.Single-crystal X-ray diffraction(SCXRD)was performed to determine single-crystal structure,and a characterization analysis of the cocrystal was performed by powder X-ray diffraction(PXRD),differential scanning calorimetry(DSC),Fourier transform infrared spectroscopy(FT-IR),and scanning electron microscopy(SEM).Results 5-FU and BPY formed the cocrystal at a stoichiometric ratio of 4∶1.SCXRD showed that the cocrystal crystallizes in the monoclinic system,space group P21/c.The PXRD spectrum of 5-FU-BPY showed new characteristic diffraction peaks at the diffraction angle 2θof 12.94°,14.90°,16.78°,and 33.83°.DSC results showed that 5-FU-BPY had a new melting peak at 256.66℃.FT-IR analysis showed displacement of the corresponding amide stretching vibration peaks of 5-FU at 3068/cm and 1725/cm and the corresponding pyridine nitrogen stretching vibration peaks of BPY at 1401/cm.SEM showed that the cocrystal had a long strip shape which was different from 5-FU and BPY.Conclusion A novel crystalline phase of 5-FU-BPY with a new melting point is formed.FT-IR results suggests that the amide group of 5-FU and pyridine nitrogen of BPY are involved in the formation of hydrogen bonds in the structure of 5-FU-BPY.SCXRD structural analysis shows that four 5-FU molecules form a supramolecular ring-shaped unit through hydrogen bonds between molecules,with a BPY molecule connected in the center to form a double-pore ring structure,and this rare supramolecular porous structure may have a certain effect on the physicochemical properties of the cocrystal.

关 键 词：化学 药物 氟尿嘧啶 4 4′-联吡啶 共晶 结晶 多晶型 分子结构 

分 类 号：R31[医药卫生—基础医学] R34