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3 Stereolithography (SLA) in Pharmaceuticals 117
Fig. 3.11 Schematic showing the three orthogonal light beam projections (left, right, bottom)
for achieving volumetric 3D printing of the torus-shaped pill without support structures in 17 s.
Reproduced from (Rodríguez-Pombo et al.
2022)
17 s from the several minutes to hours frequently consumed to 3D print tablets still
represents a significant improvement in the throughput.
Another area of pharmaceutical research being affected by SLA 3D printing is
microneedles (MN) for transdermal delivery because of the technology’s ability to
print tiny features (1 × 1 mm cross section) with excellent resolution and accuracy.
Economidou et al. successfully printed insulin-sugar coated arrays of spear and
pyramid-shaped MNs which facilitated rapid low glucose level in mice, and 3D
printed MNs were easy to operate than standard metal MNs (Pere et al.
Economidou et al.
2019). While keeping in mind the biocompatibility of their
2018;
resin, Lim et al. used a 7:3 ratio of vinyl pyrrolidone and PEGDA with AHP
loading to formulate a resin and 3D print a personalized MN patch to demonstrate
potential for transdermal delivery for wrinkle management (Lim et al.
2021). In
vitro tests on human cadaver skin demonstrated the 3D printed resin’s ability to
penetrate successfully while at the same time minimize cytotoxicity to human
fibroblasts. Researchers have shown that MNs fabricated through SLA 3D printing
are equivalent or sufficient in strength compared to metal MNs to puncture human
skin for delivering dye and insulin-sugar (Xenikakis et al.
2019).
118 P. Ravi and P. Patel
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3.6 Challenges and Future Potential
Although SLA 3D printing is a promising technology with demonstrated initial
potential in the pharmaceutical domain, several challenges remain. Some of these
challenges include the presence of unreacted monomers in the 3D printed pills,
the occurrence of unexpected drug-photopolymer reactions in the pills, unintended
temperature increase of the photopolymer in the curing region due to the exothermic
nature of the process, the need for manual/semi-automatic optimization of the
printing parameters for every formulation, and regulatory hurdles relating to the
quality and safety of the 3D printed pharmaceuticals (Xu et al.
Regulatory challenges remain for 3D printing despite the US FDA issuing a
technical guidance for manufacturing medical devices through additive manufacturing (Di Prima et al.
2016). The conventional manufacturing of drugs benefits from
mass production, validation, and verification in batches, quality assurance methods,
and already established procedures for submitting FDA new drug applications. It
is unlikely that the same process and product validation protocols can be followed
for the custom-made drugs using SLA technology which are tailored to a patient.
The process variability in SLA 3D printing is one of the important variables that
affect the repeatability of the printed tablets and other excipients. At present there
are no guidelines available for 3D printed products for drug delivery which is
an area of research currently benefitting from the advantages offered by SLA 3D
printing. Despite existence of the Prescription Drug User Fee Act (PDUFA) in the
US which allows biopharma companies to fast-track drug approval through a user
fee (CDER
2018), the competitive environment for making drugs within the US
and the broader North American continent does not push industry manufacturers to
invest in new technology such as SLA 3D printing and come up with verification,
validation, and quality assurance techniques which can then be adapted by the US
FDA for testing and clearance of 3D printed drugs. Generating materials that are
biocompatible, SLA-3D-printable, ready for production, compatible with multiple
drugs, and applicable across age groups highlights one of the primary challenges
facing SLA 3D printed medicines. It is highly unlikely that a single developed resin
can serve as a universal filler material for SLA printed medicines, just like there
are a plethora of material options available for biocompatible dental applications,
anatomic surgical guides, anatomic models, and implants. However, the future
potential of custom-made drugs can transform medicine, especially when creating
drugs with controlled substances such as anti-depressants, or for medication to treat
attention-deficit hyperactivity disorder (ADHD) for which the mass-manufactured
drug options are not a great solution for different individuals across age groups.
A key aspect to consider here is the ability to monitor the quality of SLA 3D
printed drugs in real-time and achieve high quality analogous to the tight and wellestablished quality control processes in conventional pharmaceutical manufacturing.
Furthermore, the 3D printed parts require meticulous support structure removal and
other post-processing, the material can potentially lead to toxicity, and the mechanical properties tend to reduce with time (Awad et al.
2018). Additionally, SLA 3D
2021a).
3 Stereolithography (SLA) in Pharmaceuticals 119
printing cannot yet match industrial pharmaceutical manufacturing techniques in
terms of the quality, repeatability, and throughput. As these challenges are gradually
addressed, it is anticipated that SLA 3D printing could potentially begin to impact
clinical practice, although its widespread adoption will require a huge attitudinal
and vocational shift from pharmaceutical professionals. SLA has proven its initial
utility in pharmaceutical research with many peer-reviewed reports demonstrating
promising results. With further improvements in the technology and the materials
the ability to fabricate yet more complicated drug-loaded constructs for additional
diseases is to be expected.
3.7 Summary
SLA 3D printing of pharmaceuticals is a relatively new and burgeoning niche within
the broader space of 3D printed pharmaceuticals and medical devices. Although the
niche is in its nascent stage, there is an increasing number of papers appearing in the
peer-reviewed literature. A simple PubMed search revealed 170 papers in the niche
since 2010, with nearly 85% of these papers being published just in the last 5 years,
showing the exponential growth of research activity in the area. However, the first
focused original research paper was published only in 2016 (Wang et al. 2016).
SLA
3D
printing has been used to 3D print tablets containing a plethora of different
drugs as well as to 3D print soft drug releasing devices. The high surface quality
and accuracy of the technology offer key benefits for 3D printing pharmaceutical
pills, although certain drawbacks such as lack of an extensive material library
and tight quality control processes are hindering rapid progress. The recent advent
of volumetric 3D printing promises the rapid fabrication of tablets, although key
issues such as dimensional stability, material compatibility, and optimization of
post-processing steps remain to be addressed.
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in Pharmaceuticals
Tukaram Karanwad, Srushti Lekurwale, and Subham Banerjee
Abstract
Rapidly developing and evolving rapid prototyping technologies and the emergence of 3D printable materials integrated with drug moieties have enormous
potential in the customization of dosage forms required for patients. Feature-rich
functionalities of solid dosage forms such as desired control over porous internal
architecture, complex geometry, and wide varieties of possible shapes and size,
which are very difficult to achieve with mass manufacturing, are now possible
with Selective Laser Sintering (SLS) mediated rapid prototyping. SLS-mediated
3D printing technology is the powder bed fusion technology that provides control
over the release pattern of the drug incorporated in the dosage form in terms of
immediate or controlled as well as the sustained release of the drug. This can be
easily achieved using appropriate matrix-forming agents from a wide range of
processable polymers and fine-tuning of various process parameters. An added
benefit of this powder bed fusion technology is that, it allows the fabrication
of any solid oral dosage form in just a single step without use of any solvent,
which turns this technique of rapid prototyping into green technology. Thus,
the purpose of this chapter is to discuss basic fundaments of SLS, its potential
pharmaceutical applications along with diverse processable materials, essential
process parameters and their effect on SLS-mediated fabrication, setbacks for
scale-up, regulatory consideration, and future aspects of SLS-mediated 3D
printing in pharmaceuticals.
4
T. Karanwad · S. Lekurwale · S. Banerjee ()
Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research
(NIPER)-Guwahati, Changsari, Assam, India
e-mail:
subham.banerjee@niperguwahati.ac.in
© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023
S. Banerjee (ed.), Additive Manufacturing in Pharmaceuticals,
https://doi.org/10.1007/978-981-99-2404- 2_4
125
126 T. Karanwad et al.
Keywords
Selective laser sintering (SLS) · Additive manufacturing (AM) · Solid oral
dosage forms (SODFs) · Pharmaceuticals
4.1 Introduction
Additive manufacturing (AM)/ 3D printing techniques have revolutionized various
industries since their emergence in the 1980s. This rapid manufacturing technology
was initially used globally with a wide range of applications in construction,
automotive, and aerospace engineering (Alhnan et al.
2020). Later, researchers contributing to the biomedical and pharmaceutical fields
were highly fascinated by the specific attributes of AM technology, which is the
ability of personalization and customization, which has the ability to turn the
biomedical and pharmaceutical industries toward personalized and highly precise
healthcare products (Ventola
2014).
Conventional pharmaceutical manufacturing of solid oral dosage forms (SODFs)
has limitations in terms of time, cost, labor consumption, rigidity, and tediousness.
However, the newly emerging field of AM has the potential to overcome these
limitations, as it offers more flexibility in terms of the dose and geometry of the
dosage form with desired drug release kinetics, which can fulfill the needs of
patients on demand. These benefits parallel the provision of enhancing the safety
and efficacy of the drug incorporated into the formulation (Warsi et al.
et al.
2019).
Currently, researcher are using 3D printing technology to fabricate pharmaceutical oral dosage forms and drug delivery devices for personalized medicine with
different shapes, sizes, compositions, and release kinetics (Trenfield et al. 2018).
Applications of 3D printing in pharmaceuticals globally attracted attention when
the first pharmaceutical 3D printed product Spritam (levetiracetam) tablet based on
ZipDose Technology was manufactured using binder jet platform technology by the
USA based pharmaceutical company Aprecia Pharmaceuticals, which was approved
by the Food and Drug Administration (FDA) in 2015 (Seoane-Viaño et al.
Binder jetting is a powder-based technology in which a binder solution is deposited
on a powder bed (Melnyk and Oyewumi
2021).
However, other AM techniques have also been well explored in the pharmaceutical field, such as fused deposition modeling (FDM), where filaments are used as
potential feedstock materials and work on the principle of extrusion (Mathew et al.
2020). Stereolithography (SLA), in which polymerization/solidification of photo-
sensitive materials occurs selectively, is based on vat polymerization (Kafle et al.
2021). Selective laser sintering (SLS) is based on the principle of fusion of powder
particles using laser-derived heat (Charoo et al.
technology has unique features and requires diverse feedstock materials, making it
exceptional for numerous applications (Awad et al.
actively contributing to drug delivery applications and manufacturing of biomedical
2016; Shahrubudin et al.
2018;Park
2021).
2020;Awadetal. 2020a). Each
2021). These technologies are
4 Selective Laser Sintering (SLS) in Pharmaceuticals 127
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products, such as organs, tissues, artificial skin, and bone cartilage (Shahrubudin et
al.
2020).
SLS is more comparable to conventional tablet manufacturing by the powder
press/compression phenomenon, as it also utilizes loose powder as a feedstock,
and these powder particles are joined selectively at the end of the process, utilizing
laser-derived heat to produce the desired 3D printed object (Lepowsky and Tasoglu
2018; Gioumouxouzis et al. 2019). The thermoplastic materials are required to
sintered the 3D printed object. For consolidation or sintering of these thermoplastic
polymers into a unique 3D printed object, SLS has different laser sources, such as
carbon dioxide (CO
), fiber, diode, etc. (Kamsani et al. 2022). In SLS 3D printing
2
technology, powder particles are fused together into a solid mass just before melting
using a laser source, which is called sintering (Zhang et al.
2018).
In the pharmaceutical field, researchers are exploring SLS technology of 3D
printing for the fabrication of SODFs and other drug delivery devices through
the sintering of drug-incorporated polymers. SLS 3D printing technology can
fabricate complex structures without external support because in this powderbased technology, the unsintered powder acts as a support for the sintering of
the object (Awad et al.
affect the fabrication and features of 3D-printed objects (Awad et al.
2021). Furthermore, the process parameters significantly
2020a). These
attributes provide opportunities for the use of SLS-based AM technology in the
pharmaceutical field.
This chapter focuses on the journey of SLS 3D printing technology in the
pharmaceutical field, different SLS 3D printers explored for pharmaceutical dosage
form fabrication, the principle of sintering, various challenges associated with the
selection of materials and process parameters, setbacks of SLS in pharmaceuticals,
and applications of SLS-mediated 3D printing technology in the pharmaceutical
field with necessary and expected regulatory considerations.
4.2 History of SLS
In 1986, the first SLS 3D printer was invented by Dr. Carl Deckard and Dr.
Joe Beaman at the University of Texas, Austin, USA (Juster
decided to collaborate with Nova Automation (Fina et al.
Automation became a DTM corporation in 1987 and manufactured SLS model
125. Subsequently, a production version of SLS technology, Sinterstation 2000, was
introduced into the market in 1993 (Juster
1994).
In 2001, Nanyang Technological University in Singapore developed a pharmaceutical application for SLS. During the same year, Leong et al. (2001) explored
the possibility of fabrication of a porous polymeric matrix using SLS 3D printing
technology at the first time, which could be used for drug delivery applications. The
aim of this study was to fabricate porous matrices by controlling the porosity. In
addition, laser power and scan speed were investigated to determine the resultant
variations in drug penetration and pore morphology. Fine nylon powder was used as
the matrix former, along with methylene blue as a model drug for the planned part
1994). The group
2018a); as a result, Nova
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