Development of Composite, Reinforced, Highly Drug-Loaded Pharmaceutical Printlets Manufactured by Selective Laser Sintering-In Search of Relevant Excipients for Pharmaceutical 3D Printing

Abstract

3D printing by selective laser sintering (SLS) of high-dose drug delivery systems using pure brittle crystalline active pharmaceutical ingredients (API) is possible but impractical. Currently used pharmaceutical grade excipients, including polymers, are primarily designed for powder compression, ensuring good mechanical properties. Using these excipients for SLS usually leads to poor mechanical properties of printed tablets (printlets). Composite printlets consisting of sintered carbon-stained polyamide (PA12) and metronidazole (Met) were manufactured by SLS to overcome the issue. The printlets were characterized using DSC and IR spectroscopy together with an assessment of mechanical properties. Functional properties of the printlets, i.e., drug release in USP3 and USP4 apparatus together with flotation assessment, were evaluated. The printlets contained 80 to 90% of Met (therapeutic dose ca. 600 mg), had hardness above 40 N (comparable with compressed tablets) and were of good quality with internal porous structure, which assured flotation. The thermal stability of the composite material and the identity of its constituents were confirmed. Elastic PA12 mesh maintained the shape and structure of the printlets during drug dissolution and flotation. Laser speed and the addition of an osmotic agent in low content influenced drug release virtually not changing composition of the printlet; time to release 80% of Met varied from 0.5 to 5 h. Composite printlets consisting of elastic insoluble PA12 mesh filled with high content of crystalline Met were manufactured by 3D SLS printing. Dissolution modification by the addition of an osmotic agent was demonstrated. The study shows the need to define the requirements for excipients dedicated to 3D printing and to search for appropriate materials for this purpose.

Keywords: 3D printing; composite materials; drug delivery; floating dosage forms; gastroretentive drug delivery systems; metronidazole; nylon; pharmaceutical additive manufacturing; polyamide 12; powder bed fusion.

Figure 1

The example of printlet: (a) technical drawing (dimensions in mm), (b) printed Formulation A (80/20/0/100).

Figure 2

SEM images of (a) Formulation A (80/20/0/100) at 40× magnification; (b) Formulation D (90/10/0/75) at 50× magnification; (c) Formulation A (80/20/0/100) at 100× magnification; (d) Formulation D (90/10/0/75) at 100× magnification. The markings are commented on in the text.

Figure 3

DSC curves of pure Met, PA12 and physical mixtures Met/PA12 (90/10 and 80/20).

Figure 4

DSC curves of printlets from Formulation A (80/20/0/100) and Formulation D (90/10/0/75).

Figure 5

DSC curves from the thermal loop of Met (blue), PA12 (green), mixture (black) and Formulation A printlet (red); the 3rd segment-cooling from 200 °C to −60 °C.

Figure 6

IR-ATR spectra of the pure components and physical mixtures of powders (a) in the range of 3700–2400 cm⁻¹; (b) in the range of 1850–650 cm⁻¹.

Figure 7

IR-ATR spectra of the printlets and corresponding physical mixtures (a) in the range of 3040–2800 cm⁻¹; (b) in the range of 1710–1400 cm⁻¹.

Figure 8

The mean release profiles (n = 3) of Met from printlets in the USP4 apparatus.

Figure 9

Flotation of Formulation C (80/20/0/150) in USP4 apparatus after 10 h of the experiment.

Figure 10

The mean release profiles (n = 3) of Met from 3D printlets in the USP3 apparatus.