Bruce Caroline, Fegely Kurt A, Rajabi-Siahboomi Ali R, McGinity James W
College of Pharmacy, The University of Texas, Austin, TX 78712, United States.
Int J Pharm. 2007 Aug 16;341(1-2):162-72. doi: 10.1016/j.ijpharm.2007.04.008. Epub 2007 Apr 19.
The purpose of the study was to investigate the physical state of hot-melt extruded guaifenesin tablets containing either Acryl-EZE or Eudragit L100-55 and to study the physicochemical factors influencing crystal growth of guaifenesin on the surface of the extrudates. The powder mixtures containing Acryl-EZE were extruded on a single-screw Randcastle Microtruder at 20rpm and at temperatures of 90, 95, 110 degrees C (zones 1, 2, 3, respectively) and 115 degrees C (die), before being manually cut into tablets (250+/-5mg). Extrudates containing Eudragit L100-55, TEC and guaifenesin were extruded at temperatures ranging from 60 to 115 degrees C. Modulated differential calorimetry (DSC) was used to demonstrate the plasticizing effect of guaifenesin on Eudragit L100-55. Powder X-ray diffraction (PXRD) showed that while the drug powder is crystalline, extrudates containing up to 25% drug exhibited an amorphous diffraction profile. Extrudates containing higher drug concentrations showed an amorphous profile with some crystalline peaks corresponding to guaifenesin, indicating that the limit of solubility of drug in the matrix had been exceeded. Scanning electron microscopy was used to demonstrate that drug crystallization was a surface phenomenon and dependent on the drug concentration. In vitro dissolution testing showed no effect of surface crystallization of guaifenesin on drug release rates of extruded matrix tablets. The influence of hydrophilic polymeric additives including PVP K25, polycarbophil, PEG 3,350, poloxamer 188 or poly(ethylene oxide) as crystal growth inhibitors was investigated at a level of 10% based on the drug content. The extent of crystal growth was reduced for all additives. Complete drug release in pH 6.8 phosphate buffer was prolonged from 4h in extrudates containing Acryl-EZE and guaifenesin to 8h in extrudates containing Eudragit L100-55, TEC and guaifenesin. Drug release in extrudates containing Eudragit L100-55 and guaifenesin was not affected by the presence of hydrophilic additives present at 10% based on the drug content. In vitro drug release studies showed no significant change during storage for up to 6 months at 25 degrees C/60% relative humidity and 40 degrees C/75% relative humidity.
本研究的目的是调查含有丙烯酸乙酯（Acryl-EZE）或尤特奇L100-55（Eudragit L100-55）的热熔挤出愈创甘油醚片的物理状态，并研究影响愈创甘油醚在挤出物表面晶体生长的物理化学因素。将含有丙烯酸乙酯的粉末混合物在单螺杆Randcastle微型挤出机上以20转/分钟的速度、在90℃、95℃、110℃（分别为第1、2、3区）和115℃（模头）的温度下挤出，然后手动切成片剂（250±5毫克）。含有尤特奇L100-55、三醋精（TEC）和愈创甘油醚的挤出物在60至115℃的温度范围内挤出。调制差示量热法（DSC）用于证明愈创甘油醚对尤特奇L100-55的增塑作用。粉末X射线衍射（PXRD）表明，虽然药物粉末是结晶的，但含有高达25%药物的挤出物呈现出无定形衍射图谱。含有较高药物浓度的挤出物呈现出无定形图谱，带有一些对应于愈创甘油醚的结晶峰，表明药物在基质中的溶解度极限已被超过。扫描电子显微镜用于证明药物结晶是一种表面现象，且取决于药物浓度。体外溶出度测试表明，愈创甘油醚的表面结晶对挤出基质片剂的药物释放速率没有影响。研究了包括聚乙烯吡咯烷酮K25（PVP K25）、聚卡波非、聚乙二醇3350（PEG 3,350）、泊洛沙姆188或聚环氧乙烷作为晶体生长抑制剂的亲水性聚合物添加剂的影响，添加量基于药物含量为10%。所有添加剂都降低了晶体生长的程度。在pH 6.8磷酸盐缓冲液中的完全药物释放时间从含有丙烯酸乙酯和愈创甘油醚的挤出物中的4小时延长到含有尤特奇L100-55、三醋精和愈创甘油醚的挤出物中的8小时。含有尤特奇L100-55和愈创甘油醚的挤出物中的药物释放不受基于药物含量10%的亲水性添加剂存在的影响。体外药物释放研究表明，在25℃/60%相对湿度和40℃/75%相对湿度下储存长达6个月期间没有显著变化。
