Dong Runqiao, DiNunzio James C, Regler Brian P, Wasylaschuk Walter, Socia Adam, Zeitler J Axel
Department of Chemical Engineering and Biotechnology, University of Cambridge, Philippa Fawcett Drive, Cambridge CB3 0AS, UK.
Pharmaceutical Sciences, Merck, Rahway, NJ 07065, USA.
Pharmaceutics. 2021 Jun 23;13(7):933. doi: 10.3390/pharmaceutics13070933.
The kinetics of water transport into tablets, and how it can be controlled by the formulation as well as the tablet microstructure, are of central importance in order to design and control the dissolution and drug release process, especially for immediate release tablets. This research employed terahertz pulsed imaging to measure the process of water penetrating through tablets using a flow cell. Tablets were prepared over a range of porosity between 10% to 20%. The formulations consist of two drugs (MK-8408: ruzasvir as a spray dried intermediate, and MK-3682: uprifosbuvir as a crystalline drug substance) and NaCl (0% to 20%) at varying levels of concentrations as well as other excipients. A power-law model is found to fit the liquid penetration exceptionally well (average R2>0.995). For each formulation, the rate of water penetration, extent of swelling and the USP dissolution rate were compared. A factorial analysis then revealed that the tablet porosity was the dominating factor for both liquid penetration and dissolution. NaCl more significantly influenced liquid penetration due to osmotic driving force as well as gelling suppression, but there appears to be little difference when NaCl loading in the formulation increases from 5% to 10%. The level of spray dried intermediate was observed to further limit the release of API in dissolution.
水进入片剂的动力学过程，以及如何通过制剂配方和片剂微观结构对其进行控制，对于设计和控制溶出及药物释放过程至关重要，尤其是对于速释片剂而言。本研究采用太赫兹脉冲成像技术，利用流通池来测量水穿透片剂的过程。制备了孔隙率在10%至20%范围内的片剂。制剂配方包含两种药物（MK - 8408：作为喷雾干燥中间体的鲁扎斯韦，以及MK - 3682：作为结晶药物的乌普瑞司他韦）和不同浓度水平的氯化钠（0%至20%）以及其他辅料。发现幂律模型能很好地拟合液体渗透过程（平均R2>0.995）。对每种制剂配方，比较了水的渗透速率、溶胀程度和美国药典规定的溶出速率。然后通过析因分析表明，片剂孔隙率是液体渗透和溶出的主导因素。由于渗透驱动力以及凝胶抑制作用，氯化钠对液体渗透的影响更为显著，但当制剂中氯化钠含量从5%增加到10%时，似乎差异不大。观察到喷雾干燥中间体的含量会进一步限制药物在溶出过程中的释放。
