3D printing: Principles and pharmaceutical applications of selective laser sintering.

TL;DR: The current state-of-the-art in SLS 3D printing is reviewed, including the main principles underpinning this technology and the diverse selection of materials and essential parameters that influence printing are highlighted.

Abstract: Pharmaceutical three-dimensional (3D) printing is a modern fabrication process with the potential to create bespoke drug products of virtually any shape and size from a computer-aided design model. Selective laser sintering (SLS) 3D printing combines the benefits of high printing precision and capability, enabling the manufacture of medicines with unique engineering and functional properties. This article reviews the current state-of-the-art in SLS 3D printing, including the main principles underpinning this technology, and highlights the diverse selection of materials and essential parameters that influence printing. The technical challenges and processing conditions are also considered in the context of their effects on the printed product. Finally, the pharmaceutical applications of SLS 3D printing are covered, providing an emphasis on the advantages the technology offers to drug product manufacturing and personalised medicine.

Summary

1. Introduction

• Currently, the majority of commercially available SLS printers employ carbon dioxide (CO2) lasers, which provide higher power at lower cost, permitting the use of a wide array of powdered thermoplastic materials.
• In the pharmaceutical sector, therapeutic products can be fabricated using SLS printing if the feedstock material is a powder blend of a drug and thermoplastic polymer.
• As such, it has been anticipated that SLS is more amenable for pharmaceutical use.
• Whilst other 3D printing technologies, such as binder jetting, are also based on powdered materials, being a solvent-free process makes SLS a faster process, wherein the need for additional drying steps to evaporate any residual binder is avoided.

2. Technological stratification

• Of these printing technologies, SLS is most well suited for use within pharmaceutical research, because it is able to sinter pharmaceutical-grade powders.
• Thus, it offers a novel and versatile approach for the rapid tailoring of medications.

3. Fundamentals

• The printing process entails raising the building platform to its uppermost position, whereupon a fresh layer of powder is spread and flattened by the roller (Gokuldoss et al., 2017) .
• This is followed by the activation of the laser beam, which scans across the powder and sinters it by following the pattern from the 3D file.
• The building platform is then lowered, creating enough space for a new powder layer.
• The process repeats until the printing job is finished (Sillani et al., 2019) .
• In some cases, the final object may require post-processing (e.g. coating, polishing or surface finishing) to improve its mechanical properties (e.g. tensile strength and hardness) or appearance (e.g. dimensions and surface precision).

4.3. Laser scanning speed

• Generally, lowering the laser scanning speed induces in a high laser energy density and increases the contact time between the powder bed and the laser beam (Fred et al., 2014) .
• This allows higher energy transmission to the powder bed, resulting in a higher degree of sintering and producing denser objects.
• A greater laser scanning speed results in a low energy density and less energy being transmitted to the powder and thus leads to less sintering and so more porous objects.

4.4. Scan spacing

• Scan spacing, which is also known as hatch distance or line offset, refers to the distance between two consecutive scanning vectors.
• The optimum scan spacing should be set with respect to the laser beam diameter and energy density.
• If the scan space is too large, the layers might undergo incomplete sintering, wherein the layers would not be connected, leaving unsintered parts in between and yielding objects with low mechanical strength.
• Like the slice thickness, the scan spacing is proportionate to the printing time.
• Decreasing the scan spacing lengthens the fabrication process, but it is best for creating thin and intricate structures.

4.5. Particle Size and Shape

• To achieve optimum sintering, a balance between optimum size and shape of the powder particles should be achieved.
• If the particles are too big, they would require more energy for proper sintering.
• More importantly, bigger particles will leave larger empty spaces between each other, resulting in poor mechanical properties, which cannot always be overcome with higher laser energy.
• On the other hand, the flow properties of very small particles are often hindered by high electrostatic forces, resulting in their agglomeration (Schulze, 2008) .
• More importantly, the particle size distribution should be narrow to ensure even absorption of energy.

4.6. Layer thickness

• Due to the complex nature of SLS 3D printing, there are other parameters that also contribute to the final outcome of the process.
• This includes the flow of inert gas (e.g. argon or nitrogen) inside the printing chamber, which prevents oxidation by removing condensates produced during printing.
• Another important factor is the dwell time, which refers to the cooldown time required at the start and end of each layer.
• The building orientation (e.g. horizontal, vertical or diagonal) controls the physical properties and mechanical performance of the final object (Kundera and Kozior, 2016, 2018) .
• Another dominating factor is post-treatment (e.g. coating, annealing or surface finishing), which could significantly affect the tensile strength, surface hardness, dimensional accuracy and precision (Dizon et al., 2018; Gibson and Shi, 1997; Nelson and Vail, 1991) .

6. Industrial applications

• Typically, the use of 3D printing within industrial production helps streamline a more sustainable and efficient manufacturing process.
• As an example, SLS has been widely applied for the manufacturing of electronics, substituting traditional micro-patterning methods (Theodorakos et al., 2015) .
• Within the automotive and aviation industries, SLS has been utilised to create lightweight parts whilst cutting down energy consumption during production (Hettesheimer et al., 2018) .
• The military has investigated the potential of utilising SLS to generate explosives in a harmless manner (Jiba et al., 2019) .
• In the medical field, SLS has been utilised to fabricate implants specifically tailored to the patient (Williams and Revington, 2010) and for surgical tooling (George et al., 2017) .

7. Pharmaceutical applications

• The United States (U.S.) Food and Drug Administration (FDA) approval of the first 3Dprinted tablet (Spritam ® ) marked an important milestone in the history of 3D printing, setting a benchmark for manufacture of pharmaceuticals (Aprecia Pharmaceuticals, 2018).
• Since then, 3D printing has continued to evolve rapidly, with cutting-edge research showing the many novel prospects the technology can offer.
• This has led researchers to investigate and explore more 3D printing technologies to evaluate their suitability for pharmaceutical applications.
• Compared with some of the other 3D printing technologies, SLS has had a slow-moving journey within pharmaceutical research.
• This is primarily due to initial fears of drug and excipients degradation caused by the laser beam (Alhnan et al., 2016) and absence of pharmaceutically approved materials that are commercialised for SLS use.

7.1. Adapting the technology

• Depending on the selected polymer and the laser type of the SLS printer, some powder blends may require the addition of an absorptance enhancer.
• The type of absorptance enhancer will depend on the wavelength of the laser.
• Pre-processing the polymer powder could improve the particle morphology.
• Grinding and milling could reduce the particle size, spray drying could improve particle morphology (Maa et al., 1997; Vehring, 2008) , whilst sieving could aid in controlling the size distribution (Awad et al., 2019) .
• Likewise, the inclusion of flow enhancers (e.g. magnesium stearate, talc and colloidal silica) could improve the flow characteristics of the powder (Vasilenko et al., 2011) .

7.2. Historical perspectives

• Two pharmaceutical grade polymers, Eudragit L100-55, having prolonged release properties, and Kollicoat IR, with immediate release characteristics, respectively, were successfully utilised to create paracetamol 3D printed tablets, termed Printlets TM .
• With drug degradation from the diode laser being a major concern, degradation studies showed that no drug degradation has occurred.
• It was evident, however, that no sintering can be achieved using the polymer and drug mixture on their own.
• This is because the diode laser absorbs in the visible light region and with most pharmaceutical powders being white, no absorption will occur.

7.3. New opportunities

• Previous studies have shown that SLS is more cost effective for the production of personalised parts when compared to other 3D printing technologies (e.g. FDM and SLA) and conventional production processes (e.g. injection moulding) (Awad et al., 2018; Hopkinson and Dicknes, 2003) .
• Moreover, printed objects can be stacked on top of one another, increasing the capacity of the build platform and enhancing productivity, making it highly amenable for scale up and mass production.
• Additionally, SLS offers the option of recycling and reprocessing feed material, reducing waste and supporting green pharmaceuticals.

7.4. Novel designs

• SLS is an adaptable technology suitable for printing a variety of dosage forms with unique properties.
• SLS offers a wide selection of materials with different inherent properties.
• By selecting a suitable polymer and fine-tuning the processing parameters, an array of drug release modes could be achieved.

7.4.1 Orally-disintegrating Printlets

• SLS is capable of forming 3D objects solely by loosely binding powder particles on the surface, resulting in very porous and fast-dissolving Printlets.
• As such, once dispersed in water, the water molecules quickly penetrate into the Printlets, leading to their rapid disintegration.
• This effect is intensified by increasing the laser scanning speed used for sintering.
• On this basis, Printlets incorporating Kollidon VA64, a vinylpyrrolidone-vinyl acetate copolymer, were fabricated .

Insert Figure 4

• In another study, 30% diclofenac sodium was incorporated into the formulation, reducing the disintegration rate and changing the mechanical properties of the Printlets (Barakh Ali et al., 2019) .
• This required the addition of lactose monohydrate to help modulate the mechanical characteristics and disintegration time of the Printlets.
• The partial least squares (PLS) concentration images of the Printlets displayed a uniformity in colour, indicating that the drug is uniformly distributed within Printlets .

7.4.4 Multi-reservoir systems

• Due to the high resolution of the laser beam, SLS can be utilised for the fabrication of complex and precise objects, such as multi-reservoir systems, enabling controlled drug delivery (Salmoria et al., 2013b) .
• The systems are designed to contain a PCL shell and a vacant core, and the device can be fabricated to contain the drug in both reservoirs or solely within the core.
• By varying the content of the reservoirs, different progesterone release patterns, extending up to 290 days, were achieved (Salmoria et al., 2012c) .

7.4.5 Implants for tissue and bone regeneration

• PCL implants incorporating ibuprofen have been exploited for tissue and bone regeneration (Salmoria et al., 2016) .
• It was shown that the addition of ibuprofen increased the intensity of sintering.
• Likewise, 5-fluorouracil implantable systems composed of either a PE (Salmoria et al., 2017b) or PCL (Salmoria et al., 2017c) matrix were fabricated for cancer therapy.
• Both systems showed an initial drug release burst followed by sustained delivery, wherein the PE implants had longer-lasting effect.
• By combining these concepts within a single device, dual drug therapy systems could be created.

7.5. Undesirable pitfalls

• As such, posing restrictions on the suitability of materials and drugs.
• Furthermore, in terms of technical aspects, to ensure consistent layer height and suitable flow of powders, the printing requires large quantities of powder, which might not be feasible in all cases (Telenko and Seepersad, 2010) .
• This is particularly important in the case of expensive drugs or those with limited quantities.
• In addition, whilst any unsintered powders can be recycled, they can only be reused for a limited number of prints due to concerns relating to chemical stability and physical changes (Dotchev and Yusoff, 2009) .
• Similarly, as the process sometimes might require post-treatment (e.g. the sieving and brushing of printed dosage forms), it may need an extra time-consuming step and impart additional costs (Thomas and Gilbert, 2014) .

7.6. Regulatory aspects

• Another technique could involve the use of NIR hyperspectral imaging for the quantification of drugs within the Printlets and assessing their spatial distribution (Vakili et al., 2015) .
• Collectively, these findings further facilitate and support the integration of SLS 3D printing within practice, providing suitable solutions to some of the existing QC challenges.

8.0. Conclusion

• Since its introduction, 3D printing has been forecast to pave the way for a new pharmaceutical revolution.
• Of all the 3D printing techniques, SLS is the most capable of being scaled up for mass production and with its starting materials holding the closest resemblance to current pharmaceutical production technologies, it is potentially highly amenable for adoption as a novel and versatile manufacturing tool for pharmaceutical fabrication.
• Due to the high resolution of its laser beam, SLS enables the engineering of intricate and delicate dosage forms that could be tailored to meet the needs of certain patient groups.
• Unlike other technologies, complex dosage forms can be attained without the need for additional support material or processes.
• Whilst technical and QC restraints have been the principal hinderance for the adoption of such innovative technologies, preliminary results appear promising.

Figures

Table 2. Summary of some of the benchtop SLS 3D printers, alongside their unique characteristics.

Table 1. Absorptance (𝑨) of thermoplastic polymers from two different laser beams: (a) neodymium-doped yttrium aluminum garnet (Nd:YAG) (λ = 1.06 µm), and (b) carbon dioxide (CO2) (λ = 10.6 µm). The data presented here are from those presented in the original sources (Kruth et al., 2003b; Tolochko et al., 2000).

Table 3. Summary of the cutting-edge pharmaceutical creations fabricated using SLS 3D printing.

Frequently asked questions

Q1. What are the contributions in this paper?

The selective laser sintering ( SLS ) is a subset of powder bed fusion 3D printing ; it uses a laser beam to create solid objects by heating powder particles, fusing them together at their surfaces this paper.