Synergistic application of twin-screw granulation and selective laser sintering 3D printing for the development of pharmaceutical dosage forms with enhanced dissolution rates and physical properties

Abstract

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.

Keywords: 3D printing; Continuous manufacturing; DosePlus; Flow properties; Hot melt extrusion; Selective laser sintering; Solubility enhancement.