(T1330-12-72) Investigation of Polymers for SLS 3D-Printing of Solid Oral Dosage Forms

Purpose: Selective laser sintering (SLS) for oral dosage forms is a new field still in its infancy (Fina et al., 2017). This method does, however, show promise for the application of printing oral dosage forms, particularly for small-batch scenarios or for dosages in pediatric populations, where standard medications are often not suitable due to the different size and treatment requirements of children (Ivanovska et al., 2014). In addition, 3D printing technology provides a great opportunity to speed-up clinical trials and therefore shorten development timelines. SLS printing of oral dosage forms requires specific formulation design, which includes polymers often adapted for conventional pharmaceutical usage. Current commercially available polymers are often not specifically designed for SLS printing. Therefore, there is a high need to generate application data on how to optimally print these dosage forms as well as the need for dedicated polymers suitable for this application. The development of dedicated polymers with optimized properties includes the evaluation of amphiphilic PVA grades. A direct comparison of PVA 3-82, PVA 5-74 and PVA 4-88 with other commonly used polymers is presented here. This study aims to elaborate the print parameters for a host of common pharmaceutical polymers, as well as the new PVA polymers, with regards to print temperature and laser scan speed. Additionally, this study aims to follow as closely as possible to relevant Pharmacopeia standards for tablets to show the viability of SLS as a method and find print conditions for realistic oral dosage forms.

Methods: For this study PVA 3-82, PVA 5-74 and PVA 4-88 (Parteck® MXP), PVP-VA(1) (Kollidon® VA 64), PVP-VA(2) (Plasdone™) were examined. These polymers were used in formulations of 88.5% polymer, 10% API (indomethacin), 0.5% flow regulation agent (silicon dioxide colloidal), and 1% colorant (silica-based pigment, Candurin® NXT Ruby Red). A tablet design was created using Fusion 360 modelling software and translated to an STL file. A Sintratec Kit printer (2.3 W diode, λ=455 nm) was utilized to print 36 tablets per each batch, each with the same overall settings (i.e. layer height of 150 µm, 3 perimeters, hatch spacing of 50 µm). For each different polymer tested, three different temperatures and three different laser scan speeds were chosen to find optimal print conditions for each formulation; 75 ℃, 100 ℃, and 125 ℃ & 200 mm/s, 300 mm/s, and 400 mm/s, respectively. Some of the polymers, however, could not withstand the 125 ℃ print temperature, so a temperature of 112.5 ℃ was chosen instead as the upper temperature limit. After completion of printing of the tablets, characterization occurred via XRD, DSC, friability testing, mass and size analysis, HPLC, as well as dissolution.

Results: During printing of the tablets, it was found that the materials PVP-VA(1) and PVP-VA(2) showed signs of the material melting together in the powder bed at 125 ℃. Therefore, the temperature of upper limit for these formulations was 112.5 ℃. Upon evaluation, the most robust tablets per batch were generally printed at higher temperature (without exceeding the appropriate temperature window for each polymer) and lower laser scan speed. These tablets generally appeared better sintered together, had less signs of crystallinity with XRD and DSC analysis, and performed better in friability testing. The mass deviations for these samples also passed mass criteria of Pharmacopeia standards in several cases. Dissolution studies showed a strong solubility enhancement of PVA based formulation compared to the crystalline drug compound.

Conclusion: The print ranges for these polymers commonly used in the pharmaceutical industry, as well as the newly developed PVA grades PVA 3-82 and PVA 5-74, could be individually defined based on variations in temperature and laser scan speed. Generally, trends of higher temperatures within the print range and lower laser scan speeds showed the best results upon characterization and visual inspection. These tablets were less powdery on the surface, more fitting to the desired shape of the intended tablet (i.e. less shifting between layers), and darker in color (implying a more complete sintering). The application of SLS printing in the area of solubility enhancement is a great step into further advancing the technology and allowing the development of patient-centered medication.

References: Fina, Fabrizio, Alvaro Goyanes, Simon Gaisford, and Abdul W. Basit. “Selective Laser Sintering (SLS) 3D Printing of Medicines.” International Journal of Pharmaceutics 529, no. 1 (2017): 285–93. https://doi.org/10.1016/j.ijpharm.2017.06.082.
Ivanovska, Verica, Carin M.A. Rademaker, Liset van Dijk, and Aukje K. Mantel-Teeuwisse. “Pediatric Drug Formulations: A Review of Challenges and Progress.” Pediatrics 134, no. 2 (August 1, 2014): 361–72. https://doi.org/10.1542/peds.2013-3225.

Image 1: PVA-based successful 3D prints at different temperature and laser scan speed configurations.