Laboratory of Pharmaceutical Process Analytical Technology, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
Laboratory of Pharmaceutical Process Analytical Technology, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
Int J Pharm. 2018 Apr 25;541(1-2):108-116. doi: 10.1016/j.ijpharm.2018.01.053. Epub 2018 Feb 1.
It was the aim of this study to elucidate the impact of the injection mold temperature upon the polymer crystallinity, its microstructure and the resulting drug release from immediate and sustained release tablets containing semi-crystalline polymers. The immediate release formulation contained 20% (w/w) ketoprofen (KETO) in poly (ethylene oxide) (PEO) and the sustained release formulation contained 20-40% (w/w) metoprolol tartrate (MPT) in polycaprolactone (PCL). Physical mixtures of drug-polymer were characterized via isothermal crystallization experiments using DSC and rheological measurements to elucidate the impact of the drug solid-state upon the crystallization kinetics. Tablets were prepared using various thermal histories (extrusion barrel temperature and injection mold temperatures). Polymer crystallinity and microstructure in the tablets was characterized via DSC and polarized optical microscopy. The polymer microstructure was altered by the various applied thermal histories. The differences in PEO crystallinity induced by the various mold temperatures did not affect the KETO dissolution from the tablets. On the other hand, MPT (20-40% w/w) dissolution from the PCL matrix when extruded at 80 °C and injection molded at 25 and 35 °C was significantly different due to the changes in the polymer microstructure. More perfect polymer crystals are obtained with higher mold temperatures, decreasing the drug diffusion rate through the PCL matrix. The results presented in this study imply that the injection mold temperature should be carefully controlled for sustained release formulations containing hydrophobic semi-crystalline polymers.
本研究旨在阐明注塑模温度对聚合物结晶度、微观结构以及含半结晶聚合物的即释和缓释片剂中药物释放的影响。即释制剂含有 20%（w/w）的酮洛芬（KETO）和聚环氧乙烷（PEO），缓释制剂含有 20-40%（w/w）的酒石酸美托洛尔（MPT）和聚己内酯（PCL）。通过 DSC 和流变测量进行等温结晶实验对药物-聚合物物理混合物进行了表征，以阐明药物固态对结晶动力学的影响。使用各种热历史（挤出机筒温度和注塑模温度）制备了片剂。通过 DSC 和偏光显微镜对片剂中的聚合物结晶度和微观结构进行了表征。各种应用的热历史改变了聚合物的微观结构。不同模具温度引起的 PEO 结晶度差异对片剂中 KETO 的溶解没有影响。另一方面，由于聚合物微观结构的变化，当在 80°C 下挤出并在 25 和 35°C 下注塑模制时，PCL 基质中 20-40%（w/w）的 MPT 的溶解明显不同。较高的模具温度会得到更完美的聚合物晶体，从而降低药物通过 PCL 基质的扩散速率。本研究的结果表明，对于含有疏水性半结晶聚合物的缓释制剂，应仔细控制注塑模温度。
