Synergistic application of continuous 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 novel continuous granulation with powder-based pharmaceutical 3-dimensional (3D) printing processes to enhance the dissolution rate and physical properties of a poorly water-soluble drug. Powder bed fusion (PBF) and binder jetting 3D printing processes have gained much attention in pharmaceutical dosage form manufacturing in recent times. Although 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 (feedstock). Moreover, techniques such as binder jetting currently do not provide any solubility benefits to active pharmaceutical ingredients (APIs) with poor aqueous solubility (>40% of marketed drugs). For this study, a hot-melt extrusion-based versatile granulation process equipped with UV-Vis process analytical technology (PAT) tools 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 vinylpyrrolidone-vinyl acetate copolymer and a conductive excipient for efficient sintering. These mixtures were further characterized for their bulk properties observing an excellent flow and later subjected to a PBF-3D printing process. The physical mixtures, processed granules, and printed tablets were characterized using conventional as well as advanced solid-state characterization. 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 solubility advantage (100% drug released in 5 minutes at >pH 6.8) over the pure drug and the physical mixture. Our developed system known as DosePlus combines innovative continuous granulation and PBF-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.

Selective Laser Sintering of a Photosensitive Drug: Impact of Processing and Formulation Parameters on Degradation, Solid-State, and Quality of 3D Printed Dosage Forms

“…Thereby, a 3D printing process utilizing a laser source meant to sinter is known as selective laser sintering (SLS) 5 . An SLS process like other powder-bed-based processes utilizes a hopper or a reservoir containing the feedstock (build material), which is dispensed onto the build platform utilizing a roller or a blade in a controlled fashion to maintain the required layer thickness set 6,7 . The fresh feedstock is spread over the build surface and the high-power laser either sinters or systematically melts the material (x, y, z) described by the underlying g-code 8 .…”

“…Crucial processing parameters include laser speed, surface temperature, and chamber temperature, whereas print parameters include the layer height, number of perimeters, perimeter offset, hatching offset, and hatching spacing 13,14 . Moreover, material properties such as flowability impact the print quality and reproducibility for such powder-bed-based platforms, considering the precise layering and mass transfer required in the process 7,15,16 .…”

Selective Laser Sintering of a Photosensitive Drug: Impact of Processing and Formulation Parameters on Degradation, Solid State, and Quality of 3D-Printed Dosage Forms

“…From previous studies without modifying the print bed, typically 150−200 g of feedstock is required based on the dimensions of the printlet, although the unsintered powder can be recycled. 7,14 The powder volume can be estimated based on the layer height of the print and the number of layers required to print the part. The second limitation is the absence of mixing of the powder blend during the process.…”

“…13,14 Moreover, material properties such as flowability impact the print quality and reproducibility for such powder-bed-based platforms, considering the precise layering and mass transfer required in the process. 7,15,16 Owing to the versatility of additive manufacturing processes for rapid prototyping (RP)/rapid tooling (RT), dosage form designing, and the porosity induced by such powder-bed processes, SLS has found application in the manufacturing of pharmaceutical dosage forms. 3 Previous studies depicting the use of SLS in dosage form development have revolved around immediate release dosage forms, 17 orally disintegrating tablets, 18 modified released dosage forms, and multidrug releasing systems.…”

“…This fusion is attributed to the melting or sintering of the components present in the feedstock, where melting includes heating, liquid conversion, fusion, and solidification, and sintering includes heating and fusion without liquid conversion. − Thereby, a 3D printing process utilizing a laser source meant to sinter is known as selective laser sintering (SLS) . An SLS process like other powder-bed-based processes utilizes a hopper or a reservoir containing the feedstock (build material), which is dispensed onto the build platform utilizing a roller or a blade in a controlled fashion to maintain the required layer thickness set. , The fresh feedstock is spread over the build surface, and the high-power laser either sinters or systematically melts the material ( x , y , z ) described by the underlying g-code . Traditional PBF processes are carried out for thermoplastic polymers and metallic or ceramic composites to build machine parts and tools, where the processing temperature is maintained between the melting temperature ( T m ) and half of the melting temperature ( T m /2) in a sintering process, and at or above melting temperature in a melting process .…”