Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University , West Lafayette, Indiana 47907, United States.
Lilly Research Laboratories, Eli Lilly and Co. , Indianapolis, Indiana 46285, United States.
Mol Pharm. 2017 Nov 6;14(11):4052-4063. doi: 10.1021/acs.molpharmaceut.7b00740. Epub 2017 Oct 19.
One of the most commonly used formulation development tools is dissolution testing. However, for solubility enhancing formulations, a simple closed compartment conventional dissolution apparatus operating under sink conditions often fails to predict oral bioavailability and differentiate between formulations. Hence, increasing attention is being paid to combined dissolution-absorption testing. The currently available mass transport apparatuses, however, have certain limitations, the most important being the small membrane surface area, which results in slow mass transfer. In this study, a novel high surface area, flow-through absorptive dissolution testing apparatus was developed and tested on a weakly basic model drug, nevirapine. Following optimization of the experimental parameters, the mass transfer attained for a nevirapine solution was 30 times higher in 60 min as compared to a side-by-side diffusion cell. To further evaluate the system, nevirapine powder and commercial tablets were first dissolved at an acidic pH, followed by pH increase, creating a supersaturated solution. Detailed information related to the extent of supersaturation achieved in crystallizing and noncrystallizing systems could be obtained from the combined dissolution-mass transport measurements. Differences in donor cell compartment concentration-time profiles were noted for absorptive versus closed compartment conditions. It is anticipated that this approach could be a promising tool to identify solubility enabling formulations that perform optimally in vivo.
一种最常用的制剂开发工具是溶出度测试。然而，对于增溶制剂，简单的封闭式常规溶出装置在溶出条件下，往往无法预测口服生物利用度，也无法区分制剂。因此，人们越来越关注联合溶出-吸收测试。然而，目前可用的质量传递装置存在某些限制，最重要的是膜表面积小，导致传质缓慢。在这项研究中，开发了一种新型的高通量、流动式吸收溶出测试装置，并对弱碱性模型药物奈韦拉平进行了测试。在优化实验参数后，与平行扩散池相比，奈韦拉平溶液在 60 分钟内的传质提高了 30 倍。为了进一步评估该系统，首先将奈韦拉平粉末和市售片剂在酸性 pH 下溶解，然后提高 pH 值，形成过饱和溶液。通过联合溶出-质量传递测量，可以获得结晶和非结晶系统中达到的过饱和度的详细信息。在吸收和封闭式条件下，供体池浓度-时间曲线的差异得到了证实。预计这种方法可能成为一种很有前途的工具，可用于识别能够使药物在体内达到最佳效果的增溶制剂。
