(T1030-07-42) Fabrication of Controlled Release Dosages via Selective Laser Sintering Three-Dimensional (3D) Printing Technology

Purpose: Over the years, the rapid growth of three-dimensional printed (3DP) dosages forms has attracted the interest of pharmaceutical researchers due to the unique and tremendous potential to transform the way medicine is developed and dispensed (Wang et al., 2021). Typically, the 3DP tablets fabricated via powder-based printing techniques like selective laser sintering (SLS) tend to disintegrate and release the drug within a few minutes because of their inherent porous nature and loose structure (Davis et al., 2021. Moreover, earlier literatures show that the crystallinity of the active pharmaceutical ingredients (APIs) is either reduced or converted to its amorphous form when subjected to the laser which leads to enhanced solubility and faster drug release profile (Thakkar et al., 2021). Due to these reasons, achieving a controlled release profile from the SLS 3DP dosages is challenging. The goal of this study was to demonstrate the suitability of SLS 3D printing technology for manufacturing-controlled release 3DP dosage utilizing Kollidon®SR, a matrix forming excipient composed of polyvinyl acetate and polyvinylpyrrolidone (8:2).

Methods: A feedstock comprising a 10:85:5 weight ratio of acetaminophen (ACH), a model drug, Kollidone®SR, and potassium aluminum silicate-based pearlescent pigment (Candurin), an electromagnetic energy-absorbing excipient, was sieved and fed into the feed region of a benchtop SLS 3D printer equipped with a 2.3 W 455 nm blue visible laser. After the preliminary screening and optimization of process parameters, the printing parameters were set at a laser speed of 25 mm/s, hatching offset 120 µm, hatching spacing 25 µm, print surface temperature and chamber temperature at 48 °>C and 65 °C, respectively. The solid state of the API, carriers and printed tablets was assessed using polarized light microscopy (PLM), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and wide-angle X-ray diffraction (WAXD). Moreover, scanning electron microscopy (SEM) and digital microscopy (Dino light) were used to visualize the surface texture and dimensions of the 3DP tablets. Furthermore, a non-pH shift dissolution studies was performed to compare the drug release profiles from the SLS 3DP tablets, pure drug and physical mixture (n = 3).

Results: ACH-loaded robust tablets with 13 mm diameter and 8 mm height were successfully 3DP via SLS (Fig. 1). Interestingly, unlike previous literatures, the printing must be carried at a lower temperature than the drug’s melting point and at a lower laser speed and hatch spacing. Increase in the printing and chamber temperature results in the formation of a cake like structure as the Tg of the polymer is low (~46 °C), while decrease in temperature below Tg of the polymer leads to failure in printing. Advanced solid-state characterizations with PLM, DSC, PXRD, and WAXD confirmed that ACH remained in its native crystalline state (Fig. 2). However, it was found that the intensities of the ACH peaks reduced in the 3DP tablets which could be attributed to the lower drug loading (10% w/w) and/or physical dispersion of the API in the polymer matrix. The SEM images revealed some cracks and presence of rough and loose powder on the tablet's outer surfaces which could all have contributed to the faster drug release initially. When these 3D tablets are immersed in dissolving media, the water-soluble polyvinylpyrrolidone (povidone) is initially dissolved and leached out, forming pores in the tablet through which the media penetrates and slowly releases the medicine via diffusion. As a result, the Kollidone^®SR matrix 3D tablets showed an extended drug release profile, releasing more than 90% of the ACH over 12 hours as opposed to a burst release from the pure drug and physical mixture (Fig. 3).

Conclusion: In conclusion, our work demonstrated for the first time that Kollidone®SR can be used as a polymer matrix to manufacture controlled release 3DP medications utilizing the digitally controllable SLS 3D printing technology with high flexibility, simplicity of printing dosages directly from the powder feedstock, and control over the release properties. As a result, the benefit of this technology and the use of novel carriers is highlighted, making it favourable to alternative commercial systems for pharmaceutical manufacturing.

References: Davis, D. A., Thakkar, R., Su, Y., Williams, R. O., & Maniruzzaman, M. (2021). Selective Laser Sintering 3-Dimensional Printing as a Single Step Process to Prepare Amorphous Solid Dispersion Dosage Forms for Improved Solubility and Dissolution Rate. Journal of Pharmaceutical Sciences, 110(4), 1432–1443. https://doi.org/10.1016/j.xphs.2020.11.012
Thakkar, R., Davis, D. A., Williams, R. O., & Maniruzzaman, M. (2021). Selective Laser Sintering of a Photosensitive Drug: Impact of Processing and Formulation Parameters on Degradation, Solid-State, and Quality of 3D Printed Dosage Forms. BioRxiv, 2021.04.09.439089. https://doi.org/10.1101/2021.04.09.439089
Wang, J., Zhang, Y., Aghda, N. H., Pillai, A. R., Thakkar, R., Nokhodchi, A., & Maniruzzaman, M. (2021). Emerging 3D printing technologies for drug delivery devices: Current status and future perspective. In Advanced Drug Delivery Reviews (Vol. 174, pp. 294–316). Elsevier. https://doi.org/10.1016/j.addr.2021.04.019

Acknowledgments: None

Figure-1: The images of SLS 3D-printed tablets captured using cell phone, digital microscopy (Dino light) and scanning electron microscopy (SEM).



Figure-2: Solid-state characterization of the drug (ACH), carriers and ACH-loaded 3D-printed tablet using polarized light microscopy (PLM), powder X-ray diffraction (PXRD), and wide-angle X-ray diffraction (WAXD).



Figure-3: In vitro, non-pH shift dissolution testing of pure drug (ACH), physical mixture (PM) and the ACH-loaded SLS 3DP tablet.