Synthesis and Solid State Pharmaceutical Centre, Department of Chemical Sciences, and The Bernal Institute, University of Limerick, Limerick V94 T9PX, Ireland; SSPC the Science Foundation Ireland Research Centre for Pharmaceutics, University of Limerick, Limerick V94 T9PX, Ireland.
Synthesis and Solid State Pharmaceutical Centre, Department of Chemical Sciences, and The Bernal Institute, University of Limerick, Limerick V94 T9PX, Ireland.
Int J Pharm. 2021 Mar 15;597:120199. doi: 10.1016/j.ijpharm.2021.120199. Epub 2021 Jan 21.
This work investigated the technical feasibility of preparing, stabilizing and isolating poorly water-soluble drug nanoparticles via a small-scale antisolvent precipitation process operating in semi-continuous mode. Specifically, a novel semi-continuous process was demonstrated for the carrier particle mediated production, stabilization and isolation of valsartan nanoparticles into a solid form using montmorillonite clay particles as the carrier. The semi-continuous process operated robustly for the full duration of the experiment (~16 min) and steady-state conditions were reached after ~5 min. Nanoparticles of valsartan (51 ± 1 nm) were successfully prepared, stabilized and isolated with the help of montmorillonite (MMT) or protamine functionalized montmorillonite (PA-MMT) into the dried form by this semi-continuous route. The dissolution profile of the isolated valsartan nanocomposite solids was similar to that of valsartan nanocomposite solids produced via the corresponding laboratory scale batch mode process, indicating that the product quality (principally the nanoscale particle size and solid-state form) is retained during the semi-continuous processing of the nanoparticles. Furthermore, tablets produced via direct compression of the isolated valsartan nanocomposite solids displayed a dissolution profile comparable with that of the powdered nanocomposite material. PXRD, DSC, SSNMR and dissolution studies indicate that the valsartan nanoparticles produced via this semi-continuous process were amorphous and exhibited shelf-life stability equivalent to > 10 months.
本工作研究了通过小规模抗溶剂沉淀工艺在半连续模式下制备、稳定和分离疏水性药物纳米粒子的技术可行性。具体而言，采用新型半连续工艺，使用蒙脱石粘土颗粒作为载体，通过载体颗粒介导的方法生产、稳定和分离缬沙坦纳米粒子，使其形成固体形式。半连续工艺在整个实验过程中（约 16 分钟）运行稳健，在 5 分钟后达到稳定状态。在蒙脱石（MMT）或鱼精蛋白功能化蒙脱石（PA-MMT）的帮助下，成功制备、稳定和分离了缬沙坦纳米粒子（51±1nm），并通过这种半连续路线将其干燥形式隔离出来。所分离的缬沙坦纳米复合物固体的溶解曲线与通过相应的实验室规模间歇模式工艺生产的缬沙坦纳米复合物固体的溶解曲线相似，表明在纳米粒子的半连续处理过程中保留了产品质量（主要是纳米级粒径和固态形式）。此外，通过直接压缩分离的缬沙坦纳米复合物固体所制备的片剂的溶解曲线与粉末状纳米复合物材料的溶解曲线相当。PXRD、DSC、SSNMR 和溶解研究表明，通过这种半连续工艺制备的缬沙坦纳米粒子为无定形，且货架期稳定性等同于超过 10 个月。
