Shah R D, Kabadi M, Pope D G, Augsburger L L
Department of Pharmaceutical Sciences, University of Maryland, Baltimore 21201, USA.
Pharm Res. 1995 Apr;12(4):496-507. doi: 10.1023/a:1016237509740.
Spheres are widely used as the basis for the design of multiparticulate drug delivery systems. Although the extrusion and spheronization processes are frequently used to produce such spheres, there is a lack of basic understanding of these processes and of the requisite properties of excipients and formulations. It is hypothesized that the rheological or mechanical properties of the wet mass may address the requirements of both extrusion and spheronization. The fact that certain formulations can be extruded, yet not be successfully spheronized, suggests that the two processes depend on different formulation attributes, and that there are different rheological criteria that must be met for each process to be successful. As a preliminary test of these hypotheses, methods were developed to measure the rheological behavior and mechanical properties (plastic yield value, tensile strength, yield loci) of the wet mass and/or extrudate for a model formulation system (microcrystalline cellulose, lactose, hydroxypropylmethylcellulose). The finished spheres were characterized in terms of particle size, bulk density, individual bead crushing strength, and sphericity. A Box-Behnken experimental design was employed by which the independent formulation variables could be related to the dependent rheological/mechanical properties and finished pellet characteristics. It was observed that there was a critical range of rheological/mechanical variables within which pellets having desirable criteria such as yield of 18/25 mesh cut > 60%, a shape factor > 0.85, etc., can be prepared. Screen pressure was shown to be the most critical variable affecting the yield of 18/25 mesh cut, while the yield value and tensile strength markedly influenced the shape factor. Thus, for the formulations studied, it was possible to define a "window" of rheological/mechanical properties within which both extrusion and spheronization can be successfully carried out.
球体被广泛用作多颗粒药物递送系统设计的基础。尽管挤压和滚圆工艺经常用于生产此类球体，但对这些工艺以及辅料和制剂的必要特性缺乏基本了解。据推测，湿物料的流变学或机械性能可能满足挤压和滚圆的要求。某些制剂能够被挤压但不能成功滚圆这一事实表明，这两个工艺依赖于不同的制剂属性，并且每个工艺要成功都必须满足不同的流变学标准。作为对这些假设的初步测试，开发了一些方法来测量模型制剂系统（微晶纤维素、乳糖、羟丙基甲基纤维素）的湿物料和/或挤出物的流变行为和机械性能（塑性屈服值、拉伸强度、屈服轨迹）。对制成的球体在粒径、堆密度、单个微丸抗压强度和球形度方面进行了表征。采用了Box-Behnken实验设计，通过该设计可以将独立的制剂变量与相关的流变学/机械性能以及成品微丸特性联系起来。观察到存在一个流变学/机械变量的关键范围，在该范围内可以制备出具有诸如18/25目筛网截留率>60%、形状因子>0.85等理想标准的微丸。结果表明，筛网压力是影响18/25目筛网截留率的最关键变量，而屈服值和拉伸强度对形状因子有显著影响。因此，对于所研究的制剂，有可能定义一个流变学/机械性能的“窗口”，在该“窗口”内挤压和滚圆都可以成功进行。
