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36 3D Printing of Pharmaceutical and Drug Delivery Devices: Progress from Bench to Bedside
500 µm
81 82
123
83
Low speed
High speed
High temperatureMedium temperatureLow temperature
(a)
(b)
(c)
Medium speed
– 1
000 mm/min
Medium speed
– 1
500 mm/min
Figure 2.6 (a) Sample cross-section microscopy images of the 3D-printed filaments under different
printing speeds and temperatures [24]. (b) Different graded meshes were 3D printed by designing
a variable extrusion width [26]. (c) Multi-phase 3D printing: the core is located in a median level
between the bottom shell (75%) and the top shell (25%); the shell is printed first followed by
complete filling of the shell bottom; the printing is completed by printing the shell top [27]. (Source:
(a) [24] / with permission from Elsevier; (b) [26] / with permission from Elsevier; (c) [27] / with
permission from Elsevier.)
2.4 3D Designs Influence Drug Release
2.4.1 Controlling Drug Release
Controlled drug release mechanisms from pills, implants, or devices often improve the
therapeutic effects. Several modes of release are possible depending on the geometry,
materials chemistry, and degradation/erosion of the drug-loaded device. The classical drug
release mechanisms in standard drug releases of the drug-loaded devices are the first-order
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The Use of Microstructure Design and 3D Printing for Tailored Drug Release 37
and zero-order drug release mechanisms. The first-order drug release mechanism is drug
release rate decreasing with time, which can be beneficial to reach a suitable drug concen-
tration needed for rapid action followed by sustained levels of activity, while for the zero-
order drug release mechanism, there is a constant rate of drug release for drugs with a
narrow therapeutic window. Zhang et al. [9] developed a case study to demonstrate that the
effect of pore alignment can be used to tailor the drug release rate when porosity and pore
volume is kept constant, as shown in Figure 2.7. They demonstrated that it is possible to
control the drug release rate whilst keeping other parameters constant, such as pore size or
porosity, and crucially with no change to the feedstock materials or 3D-printing equipment.
This demonstrates the ability to customise or personalise drug release rates purely through
geometric design, offering enormous potential for distributed manufacture, on-demand
with a single machine and single standard feedstock [5].
Figure 2.7 (a) The appearances of the 3D-printed constructs with constant porosity and print
settings, but minor adjustments to the print path to combine aligned pores and staggered pores
led to tailored drug release rate. (b) The drug release profiles and (c) the mean dissolution time
(MDT) values of the constructs with aligned, staggered, and a combination (n=3) [5]. (Source:
[5] / with permission from Elsevier.)
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38 3D Printing of Pharmaceutical and Drug Delivery Devices: Progress from Bench to Bedside
3D printing has been used to deposit drug-loaded material with spatial control to fabricate
drug products with tailored release profiles. The geometry, and more specifically the surface
area-to-volume ratio and infill percentage, govern drug release in 3D-printed tablets and
implants [18, 31]. One advantage of 3D printing is the ability to tailor drug product proper-
ties to enable release beyond classic release profiles. 3D printing enables more sophisticated
control over the drug distribution within the product and the shape/geometry of the product
through freeform designs. In addition, 3D-printing processes can improve the complexity
and resolution of the drug-loaded device. 3D printing makes it possible to design and print
a drug product of any geometry, architecture, and/or internal structure. Based on these con-
cepts, 3D-printing processes have been leveraged to expand the possibilities of tailored
release and produce drug-loaded devices with unconventional release profiles that are dif-
ficult (or impossible) to achieve using traditional manufacturing processes. For example,
drug products with high infill density dissolved more slowly than similar constructs with
low infill density due to the lower surface area in contact with the surrounding medium [12].
Goyanes et al. investigated the effect of geometry on drug release from 3D-printed tablets
[18]. They indicated that drug products with increased surface-area-to-volume ratios (e.g.,
torus or pyramid-shaped objects) exhibited faster release rates as compared with similar
devices that had smaller surface-area-to-volume ratios (e.g., cylindrical or spherical objects).
2.4.2 Modifying Drug Release
Apart from the first- and zero-order, there are some complex and modified drug release
mechanisms, such as the pulsatile release mechanism. Pulsatile release can be used to syn-
chronise drug release with biological cycles. Complex sequences of release patterns (e.g.,
burst, zero-order, burst) can be achieved by controlling the spatial distribution of one or
multiple APIs. Another strategy to control the release profile is by using 3D printing to print
tablets with a core-shell structure. As shown in Figure 2.8, Okwuosa et al. used the FDM
Figure 2.8 Various types of drug release mechanisms from 3D-printed tablets [21]. (Source:
[21] / with permission from Elsevier.)
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The Use of Microstructure Design and 3D Printing for Tailored Drug Release 39
3D-printing technique to fabricate tablets with an external layer that restricts dissolution and
drug release. In the device, the external layer prevented rapid release in the acidic environ-
ment of the stomach and was followed by a pronounced release in the intestine [32]. Xu
etal. designed a hollow and solid bladder drug-loaded device containing different amounts
of lidocaine hydrochloride using SLA. Hollow geometries released the API more quickly
than solid geometries, and the release rate increased with drug loading [33].
Rowe et al. designed a 3D-printed tablet with two compartments for dual-stage release. In
their device, each compartment contained the same API but was coated with a different poly-
mer. The first compartment was coated with Eudragit E 100 for burst release (50% of the dose
was released in 10 minutes), whilst the second compartment was coated with Eudragit RL PO
for prolonged release (the remaining 50% of the dose was released over 8 hours) [34]. Similar
concepts have been applied to programmed release rates using deposition-based printing of
drug products, with Pluronic F127 as the main excipient [35]. Several geometries were printed
to tailor drug release. A core-shell structure was used for delayed release (drug-loaded core sur-
rounded by polymer shell), a multilayer structure enabled pulsatile release (alternating of drug
and polymer layers), and a gradient distribution was prepared for constant release.
2.5 Challenges and Perspective
Spritam
®
is the first 3D-printing-based drug delivery system to be approved by the FDA,
which is for an anti-epileptic therapy [36]. The fabrication process uses binder jetting and
consists of depositing an incremental layer of levetiracetam-containing powder followed by
the deposition of binding fluid onto the incremental layer to bind particles in the powder. A
Spritam
®
conventional tablet is manufactured by compression. In comparison to the conven-
tional tablet, the main advantage of 3D-printed Spritam
®
is a more convenient dosage form
for patients, especially elderly and paediatric populations, than traditional tablets, as it is
easier to swallow [7, 37]. Although 3D-printed drugs have advantages compared to conven-
tional manufacturing methods, only a few pharmaceutical products have reached the market
so far. One of the reasons for this is the lack of materials for building up structures. There is
a crucial need for a broader range of approved materials that can be used for 3D printing to
develop new drug products. The selection and variety of materials available are dictated by
the 3D-printing technology itself. For example, there is a relatively low number of approved
thermoplastics available for FDM 3D printing [38, 39] and there is no approved and com-
mercialised material for selective laser sintering. There is also a lack of specifications for
starting materials suitable for 3D printing with drugs, which remains a key limitation.
One of the other challenges is that some 3D-printing technologies require a post process-
ing drying step [38], extending manufacturing time, and potential degradation of the drug.
Hot-melt extrusion involving high temperatures may have detrimental impacts on the API.
Increasing temperature may create API amorphous phases that will have to be evaluated for
physical stability and polymorphism, which is time- and resource-intensive [40]. Additionally,
in the case of deposition-based methods like FDM, filaments containing the drug are fabri-
cated by hot-melt extrusion. Such filaments need to be monitored carefully during storage, as
their physico-chemical properties may degrade with ageing, with a detrimental impact on the
properties of the printed dosage form. Additionally, printing by FDM might have subjected
the API to elevated temperatures twice because hot-melt extrusion is needed to fabricate the
feedstock filament and then again during the printing [12]. Thus, controlling parameters in
pharmaceutics is essential for drug release and developing safe products for the patient.
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40 3D Printing of Pharmaceutical and Drug Delivery Devices: Progress from Bench to Bedside
Another challenge is cleaning and sterilisation. 3D-printing facilitates the creation of
objects with complex geometries, such as engineered porosity, channels, and internal voids
or cavities that cannot be produced by traditional manufacturing methods [12, 17, 41].
These complex geometries can make it more difficult to remove material residues (clean-
ing) and sterilise the device due to increased surface area, generation of extensive tortuous
pathways, and the creation of internal voids with limited or no access. Material removal
is also a consideration in the case of 3D-printing technologies that use temporary support
structures. Achieving adequate cleaning, sterility, and biocompatibility of a 3D-printed
device is also an open challenge [17, 42]. Assessing and verifying sterility in porous or
internally complex 3D-printed devices or drug products can present additional difficulties.
Moreover, changing the paradigm of drug manufacturing is also a significant challenge
[43]. On-demand 3D printing, for example, by FDM, in hospital pharmacies would present
some advantages, but under current practices would require different quality controls. This
modification of the traditional value chain will require effective auditing procedures at the
organisational and regulatory levels [44].
Overall, 3D printing has the potential to revolutionise the production of pharmaceuti-
cal products, allowing for decentralised and customised manufacturing of therapeutics.
However, the 3D-printing ‘utopia’ in pharmaceutics is contingent upon whether the
challenges facing the market can be overcome so the technology may reach its full
potential.
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3D Printing of Pharmaceutical and Drug Delivery Devices: Progress from Bench to Bedside, First Edition.
Edited by Dimitrios A. Lamprou, Dennis Douroumis and Sheng Qi.
© 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.
3
3D Printing of Oral Solid Dosage
Forms Using Selective Laser Sintering
Atabak Tabriz Ghanizadeh
1,2
, Hannah Kuofie
1
, James Scoble
1
, Sam Boulton
1
and Dennis
Douroumis
1,2
1
Faculty of Engineering and Science, University of Greenwich, Medway Campus, Kent, UK
2
Delta Pharmaceutics Ltd., Kent, UK
3.1 Introduction
Three-dimensional printing (3DP) has gained increasing popularity over the last 10 years
in healthcare due to its enormous capability for resolving several of the limitations associ-
ated with conventional drug delivery and therapeutic technologies [1]. Binder jetting, fused
deposition modelling (FDM), powder bed fusion (PBF), and vat polymerisation are just a
few of the printing technologies that have been developed and employed in the pharmaceu-
tical and biomedical industries throughout the years. Around 1981, Hideo Kodama devel-
oped a method for creating 3D models using photo-hardening polymers and UV radiation
[2]. A few years later, Chuck W. Hull created the first 3D-printing technology, stereolithog-
raphy, which was marketed by 3D systems. Initially, these technologies were limited in
their application due to poor printing quality and excessive costs. Nevertheless, technologi-
cal breakthroughs have resulted in the development of cost-effective, high-print-speed, and
high-precision 3D printers that have already been employed in a multitude of sectors
including biomedical, space, education, automotive, and art over the last two decades.
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44 3D Printing of Pharmaceutical and Drug Delivery Devices: Progress from Bench to Bedside
In recent years, considerable technological advancements (Figure 3.1) resulted in the
development of Spritam
®
, an antiepileptic drug, the first commercially available 3D-printed
oral medication approved by the FDA (Food and Drug Administration) in 2015. Two years
later, FDA produced the ‘Technical Considerations for Additive Manufactured Medical
Devices,’ a guide for industry and FDA employees, while research into 3D-printed
medicines continues [3].
3D printing, or additive manufacturing, refers to the fabrication of a 3D object from a
computer-aided design (CAD), in a layer-by-layer manner. The CAD file is converted into a
stereolithography file (.stl file) that contains the necessary information for the spatial geom-
etry of the object to be produced using CAD programs. The .stl file is divided into multiple
segments after initiation, one of which is the slice file (SLI segment), which is subsequently
transferred to the 3D printer for printing. Most of the 3D-printing technologies have the
capacity to transform the pharmaceutical sector from one-size-fits-all tablet and capsule mass
manufacturing to customised dosage forms that fit the clinical needs of the patients [4].
Since the introduction of 3D printing with stereolithography, various other techniques
have been established (Figure 3.2), allowing for the processing of a broader range of mate-
rials, such as polymers, metals, and ceramics. Nanomaterials, medicines, and biological
materials like cells can all be included in 3D constructions, opening a whole new world of
possibilities for medical 3D printing.
Extrusion-based technologies, such as FDM, are by far the most extensively used
3D-printing technology. The technology was invented by Scott Crump, Stratasys’
co-founder,
and patented in 1989 [5]. An FDM printer system (Figure 3.2c) comprises of a feeder gear
system that enables material to be driven through the system, a heated liquefier that is located
in the print head and is a system for making the material extrudable, the print head and noz-
zle, the printer’s axels that allow the print head to move following cartesian patterns, and
finally the build platform. In this process, layers of molten or softened thermoplastic materi-
als in the form of filaments are deposited via the printer’s head at specified directions con-
trolled by the computer software for the fabrication of the designed structure. In comparison
to other 3D-printing technologies, FDM is comparatively inexpensive, and has been success-
fully implemented in a variety of industries [6–8].
Material jetting (MJ), also known as Poly-jetting and Drop on Demand (DoD), are two
other types of 3D-printing technologies that have been used for the manufacturing of
1981
Hideo
Kodama rst
at
tempts in rapid
prototyping
1988
Charles Deckard
led a patent for
SLS
2015
1st FDA
approved 3D
printed oral
drug Spritam*
2017
FDA published
“Technical
Consideration for
Additive Manufactured
Medical Devices
1989
Scott
Crump led
a patent
for FDM
1983
Charles Hull
patented
stereolithography
Figure 3.1 Historic timeline of 3D printing.
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3D Printing of Oral Solid Dosage Forms Using Selective Laser Sintering 45
Figure 3.2 Typical schematic diagrams of six major 3D-printing technologies:
(a)Stereolithography; (b) Selective laser sintering; (c) Fused deposition modelling; (d) Binder
jetting; (e) Drop on demand; and (f) Material jetting. (Source: Courtesy of Peyman Sohrabi.)
https://t.me/med1917
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