(W1130-03-20) Additive Manufacturing via Laser Sintering: Assessing the Influence of Parameter Selection on Printing Performance

Purpose: Pharmaceutical research has undergone fundamental changes in recent decades [1]. Both medicine and drug development are currently experiencing a paradigm shift known as "personalized medicine" [2]. The advantage of personalized medicine is the ability to identify which treatment options are best suited to the patient to avoid side effects that could lead to reduced life expectancy. Up to 75% to 85% of side effects result from inappropriate dosages or combinations of doses [3]. Therefore, methods for adapting dosage forms to the individual needs of the patient are in high demand [4]. With today's conventional pharmaceutical manufacturing processes, dosages cannot be easily adjusted [5]. This is where additive manufacturing (3D printing) can play a key role in enabling personalized medicine, thanks to its advantages such as the ability to produce complex specimens tailored to the customization and personalization of medications with individually tailored drugs [6]. Furthermore, it is important to have a deep understanding of 3D printing technologies and materials to enable successful application in the pharmaceutical industry. Statistical experimental design is an important approach in the development and optimization of 3D printing technologies to produce pharmaceutical specimens. This analytical tool has received considerable attention in pharmaceutical development since the introduction of the concept of "Quality by Design" (QbD) by the FDA [7]. Design of experiment (DoE) allows the systematic investigation and optimization of the effects of various process parameters on the quality and properties of specimens [8]. Aim is to understand the influencing parameters of the selective laser sintering (SLS) printing technology and to find the optimal parameter to produce tailored specimens.

Methods: To produce the specimens, the 3D-SLS printer from Sharebot SnowWhite2 (Sharebot, Nibionno, Italy) equipped with a CO₂ laser (14 Watt) was used. A particle optimized polyvinyl alcohol (Parteck® MXP 4-88, Merck KGaA, Darmstadt, Germany) was used for the trials. A full-factorial DoE was performed. Selected factors and ranges are displayed in Table 1. The dependent variable responses were absolute mass, relative standard deviation of mass and height according to the methods described in the Ph.Eur. The software that was used to create the experimental design with the respective influencing parameters was MOODE^® Pro 13 (Sartorius Stedim Data Analytics AB, Umeå, Sweden). A cylindrical shape with a diameter of 10 mm and a height of 4 mm was used for the dimensions of the test specimens. The test specimens were initially designed using Autodesk Fusion 360 software (Version 2.0.16007) and loaded into the slicing software Cura (Version 4.10.0) as STL files. For the experiments of the DoE, 30 tablets were printed for each experiment. The determination of mass and height was performed using an Erweka Multicheck 5.1 (ERWEKA GmbH, Heusenstamm, Germany).

Results: From the results, it can be inferred that the influential factors have a significant impact on the processability of Parteck MXP 4-88. The laser speed and laser power had a significant influence on the absolute mass and relative standard deviation of the mass. The model for the relative standard deviation of the mass showed a good model fit in terms of the R2 and Q2 values (values > 0.9). For the absolute mass, there was also a high R2 value ( > 0.8), but a lower Q2 value ( < 0.5). In experiments with higher mass deviation, the energy input was high due to the low speed. At the same time, in these experiments with increased energy input, there was a higher height than expected, which resulted in larger fluctuations in the absolute mass, leading to the poor predictability of the absolute mass.

Conclusion: In summary, this study provides a deeper insight into the SLS 3D printing technology in terms of understanding the critical influential parameters and their effects on the desired target variables. Optimal parameter ranges for printing polyvinyl alcohol based material (Parteck MXP 4-88) were successfully determined. With the proper selection of parameters, this process is suitable for producing uniform specimens. The described approach can be translated to other polymers and offers a fast optimization of process parameters.

References: 1] Stock, G. and S. Sydow (2013). "[Personalized medicine. Paradigm shift within drug research and therapy]." Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz 56(11): 1495-1501.
[2] Ruppert T, Sydow S and Stock G, 2016, Personalized medicine: consequences for drug research and therapy. Advances in Precision Medicine, vol.1(2): 1–9
[3] Cohen, J. S. (1999). "Ways to minimize adverse drug reactions." Postgraduate Medicine 106(3): 163-172.
[4] Alhnan, M. A., T. C. Okwuosa, M. Sadia, K.-W. Wan, W. Ahmed and B. Arafat (2016). "Emergence of 3D Printed Dosage Forms: Opportunities and Challenges." Pharmaceutical Research 33(8): 1817-1832.
[5] Vaz, V. M. and L. Kumar (2021). "3D Printing as a Promising Tool in Personalized Medicine." AAPS PharmSciTech 22(1): 49.
[6] Park, B. J., H. J. Choi, S. J. Moon, S. J. Kim, R. Bajracharya, J. Y. Min and H.-K. Han (2019). "Pharmaceutical applications of 3D printing technology: current understanding and future perspectives." Journal of Pharmaceutical Investigation 49(6): 575-585.
[7] N. Politis, Stavros, et al. "Design of experiments (DoE) in pharmaceutical development." Drug development and industrial pharmacy 43.6 (2017): 889-901.
[8] Gueche, Y.A.; Sanchez-Ballester, N.M.; Bataille, B.; Aubert, A.; Rossi, J.-C.; Soulairol, I. A QbD Approach for Evaluating the Effect of Selective Laser Sintering Parameters on Printability and Properties of Solid Oral Forms. Pharmaceutics 2021, 13, 1701.

Table 1: Selection of parameters and ranges for DoE

Figure 1: Contour plot of the standard deviation of mass with 120°C as a constant powder bed temperature

Figure 2: Contour plot of the absolute mass with 120°C as a constant powder bed temperature