Pharmaceutical Engineering and 3D Printing (PharmE3D) Lab, Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA.
Pharmaceutical Engineering and 3D Printing (PharmE3D) Lab, Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA.
Eur J Pharm Biopharm. 2021 Jun;163:141-156. doi: 10.1016/j.ejpb.2021.03.016. Epub 2021 Apr 8.
This study demonstrated the first case of combining a novel continuous granulation technique with powder-bed fusion-based selective laser sintering (SLS) process to enhance the dissolution rate and physical properties of a poorly water-soluble drug. Selective laser sintering and binder jetting 3D printing processes have gained much attention in pharmaceutical dosage form manufacturing in recent times. These powder bed-based 3D printing platforms have been known to face printing and uniformity problems due to the inherent poor flow properties of the pharmaceutical physical mixtures. To address this issue a hot-melt extrusion-based versatile granulation process equipped with a process analytical technology (PAT) tool for the in-line monitoring of critical quality attributes (i.e., solid-state) of indomethacin was developed. The collected granules with enhanced flow properties were mixed with Kollidon® VA64 and a conductive excipient for efficient sintering. These mixtures were further characterized for their bulk properties observing an excellent flow and later subjected to an SLS-3D printing process. The physical mixtures, processed granules, and printed tablets were characterized using conventional as well as advanced solid-state characterizations. These characterizations revealed the amorphous nature of the drug in the processed granules and printed tablets. Further, the in vitro release testing of the tablets with produced granules as a reference standard depicted a notable dissolution advantage (100% drug released in 5 min at >pH 6.8) over the pure drug and the physical mixture. Our developed system known as DosePlus combines innovative continuous granulation and SLS-3D printing process which can potentially improve the physical properties of the bulk drug and formulations in comparison to when used in isolation. This process can further find application in continuous manufacturing of granules and additive manufacturing of pharmaceuticals to produce dosage forms with excellent uniformity and solubility advantage.
本研究首次展示了将新型连续造粒技术与基于粉末床熔融的选择性激光烧结（SLS）工艺相结合，以提高难溶性药物的溶出速率和物理性质。近年来，选择性激光烧结和粘结剂喷射 3D 打印工艺在药物剂型制造中受到了广泛关注。众所周知，由于药物物理混合物固有的较差流变性，这些基于粉末床的 3D 打印平台存在打印和均匀性问题。为了解决这个问题，开发了一种基于热熔挤出的多功能造粒工艺，该工艺配备了过程分析技术（PAT）工具，可在线监测吲哚美辛的关键质量属性（即固态）。收集到的具有增强流动性的颗粒与 Kollidon®VA64 和一种导电赋形剂混合，以实现高效烧结。进一步对这些混合物的体积性质进行了表征，观察到了优异的流动性，然后进行了 SLS-3D 打印工艺。对物理混合物、加工颗粒和打印片剂进行了常规和先进的固态特性分析。这些特性表明，药物在加工颗粒和打印片剂中呈无定形状态。此外，以生产的颗粒为参比标准的片剂体外释放测试显示出显著的溶解优势（在 >pH 6.8 下 5 分钟内 100%释放药物），优于纯药物和物理混合物。我们开发的系统称为 DosePlus，它结合了创新的连续造粒和 SLS-3D 打印工艺，与单独使用相比，可以潜在地改善原料药和制剂的物理性质。该工艺还可以进一步应用于连续制粒和药物添加剂制造，以生产具有优异均匀性和溶解优势的剂型。
