尿素/PVPk30联合增加氟苯尼考溶解度的研究

Increasing florfenicol solubility by combined urea and PVPk30

【目的】制备氟苯尼考(FF)联合载体固体分散体(FF/SDs),并对其特性进行表征。【方法】采用溶剂蒸发法制备FF/SDs,通过单因素试验考察载体种类(泊洛沙姆188(F68)、尿素、PEG4000、PEG6000、聚维酮k30(PVPk30))、溶剂种类(甲醇、乙醇、丙酮)、旋转蒸发温度(50,60,70,80和90℃)和超声时间(5,10,15和20min)及转速(70,90,110,130,150r/min)等对FF饱和溶解度的影响。在单因素试验的基础上,选取联合载体材料种类、联合载体质量比、溶剂、旋转蒸发温度等4个因素,设计L9(34)正交试验,确定制备FF/SDs的最佳条件。采用差示扫描量热法和X射线粉末衍射法对最佳条件下制备的FF/SDs进行验证,并测定其累计溶出度。【结果】以尿素、PVPk30为联合载体,FF、PVPk30、尿素质量比为1∶4∶5,甲醇为溶剂,旋转蒸发温度为80℃,最佳转速为150r/min,360 W超声波处理10min,可得到最优FF/SDs。FF、FF/SDs和二者物理混合物(PM)的差示扫描量热(DSC)图谱、X射线衍射图谱和溶出度存在明显差异,FF原粉是晶体态的片层结构,FF/SDs则为无定形态。最佳条件下制备的FF/SDs饱和溶解度为3.11mg/mL,是FF原药和PM的2.43和2.07倍。6min时FF/SDs累计溶出度达94.35%,是同一时间FF原药的3.72倍。【结论】得到了制备FF/SDs的最佳条件,且联合载体尿素/PVPk30(m(尿素)∶m(PVPk30)=5∶4)较单一载体能更好地提高氟苯尼考的水溶性,并加快其溶出。

【Objective】The solid dispersions containing florfenicol and combined carriers were prepared by solvent evaporation method and characterized.【Method】The influencing factors including carrier type（F68,urea,PEG4000,PEG6000 and PVPk30）,solvent（methanol,ethanol and acetone）,rotary evaporation temperature（50,60,70,80 and 90 ℃）,ultrasonic time（5,10,15 and 20min）and rotational speed（70,90,110,130,150r/min）were investigated using saturated solubility of florfenicol as indicator.On the basis of single factor experiments,the factors were selected and L9（34）orthogonal test was designed to determine the best conditions for FF/SDs preparation.Then X-ray powder diffraction and differential scanning calorimetry methods were used to validate FF/SDs,and measure its cumulative dissolution.【Result】It showed that the combined use of urea and povidone,the mass ratio of florfenicol,PVPk30 and urea was 1∶4∶5,methanol as solvent,rotary evaporation temperature is 80 ℃,rotational speed is 150r/min and 360 W ul-trasonic processing 10 min had the optimal formula.There were significant differences in X-ray,DSC diagrams and dissolution rate of FF,FF/SDs and PM.The structure of FF was crystal lamellar,while that of SDs was amorphous.The saturated solubility of FF/SDs was 3.11mg/mL at 37 ℃,which was 2.43-folds of florfenicol and 2.07-folds of physical mixtures.The cumulative solubility was 94.35%,which was 3.72 folds of florfenical.【Conclusion】The solubility of florfenicol solid dispersion with combined carrier urea/PVPk30（m（urea）∶m（PVPk30）=5∶4）was much better than single carrier,and the dissolution was increased significantly.