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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5947_Библиотеки_им_академика_М_И_Перельмана
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138 T. Karanwad et al.
Software References
Build volume
(L × W × H)
10.6 14 100 × 100 × 100 Slic3r Sharebot (2022)
10.6 25–100 N/A SLS system 3D Systems (2022)
2
2
SLS 3D Printers Laser type Laser wavelength (μm) Laser power (W)
Sintratec Kit Diode (blue) 0.445 2.3 110 × 110 × 110 Sintratec central Sintratec (2022)
3500, Jinke Trading Diode (blue) 0.450 0.05–3.5 N/A N/A Yang et al. (2021)
Sharebot SnowWhite CO
Tab le 4 .3 List of SLS 3D printers explored for pharmaceutical applications
Sinterstation 2500 CO
10.6 40 250 × 250 × 300 Web based (local) Natubots (2022)
2
Sinterit Lisa Diode (red) 0.808 5 150 × 200 × 160 Sinterit studio Sinterit (2022)
Formlabs Fuse 1 Fiber 1.066 10 165 × 165 × 300 PreForm Formlabs (2022)
Natural Robotics VIT SLS CO
Red Rock 3D Diode (blue) 0.450 5 180 × 180 × 180 N/A Redrocksls (2022)
4 Selective Laser Sintering (SLS) in Pharmaceuticals 139
r
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Fig. 4.1 Images of commercially available SLS printers (Sintratec 2022; Sharebot 2022;3D
Systems
2022; Sinterit 2022; Formlabs 2022; Natubots 2022; Redrocksls 2022)
Blue diode lase
Red diode laser
CO2 laser
18.2%
3%
78.8%
Fig. 4.2 Demonstrates the percentage exploration of SLS 3D printers based on laser source used
(Up to 2022)
Post-printing processing, such as polishing, coating, or surface finishing, generally
enhances the mechanical strength and aesthetic value of a printed object (Charoo et
al.
2020).
4.5 Advantages of SLS over other AM and Conventional
Manufacturing (CM) Technologies
SLS could be superior to other 3D printing technologies, owing to its advantages
over other 3D printing and CM technologies. It eliminates any pre-treatment stage
140 T. Karanwad et al.
Fig. 4.3 Principle of SLS
of raw materials (e.g., preparation of filaments in FDM or granulation in the
case of tablet compression) and provides printlets in one step. SLS is a solventfree technique that is mainly applicable to drugs that are at risk of degradation
due to hydrolysis and is safer because it reduces the risk of solvent toxicity;
therefore, it could be a green technology. SLS can be used to sinter objects with
a higher resolution owing to the precision of the laser. SLS offers a wide range of
transformable materials such as plastics, polymers, ceramics, alloys, and metals,
which are stable at high temperatures and laser exposure. The feedstock in the
SLS batch could be processed and recycled to reduce waste generation. Additional
excipients are not required in SLS (compared to the conventional method), which
reduces toxicity and production costs. SLS helps to fabricate objects with the
desired porosity and internal architecture; therefore, control over drug release can be
achieved as per the required application. SLS fabricated an object by partial melting
or sintering of the powder material, without using a solvent as a binding agent.
SLS technology is more suitable for scale-up and mass production in industry than
other 3D printing technologies. These are the reasons why SLS can be considered
the most advanced, one of the latest, effective, and green technologies proposed for
the fabrication of pharmaceutical SODFs (Allahham et al.
Awad et al.
2019; Riza et al. 2020).
2020;Finaetal. 2018b;
4.6 Selection of Process Parameters for SLS
The process parameters involved in SLS must be identified to fabricate an SLSprinted dosage form with desired qualities. The energy density (ED) (J/mm
amount of energy transmission per unit volume in the SLS, which determines the
3
)isthe
4 Selective Laser Sintering (SLS) in Pharmaceuticals 141
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Fig. 4.4 Process parameters related to the SLS 3D printing technology
degree of sintering of an object. Four parameters influence this critical parameter:
laser power (LP), scanning speed (SS), layer thickness (LT) (Brown et al.
and hatch spacing (HS) (Dadbakhsh et al.
2016). The correlation between these
parameters can be explained using the following equation (Gueche et al.
2018),
2021a):
ED =
LP
SS × HS × LT
These printing variables can strongly influence the properties of a sintered
component, such as the porosity, mechanical strength, density, hardness, and surface
roughness. Controlling porosity provides control over the release pattern. Thus,
researchers are utilizing these process parameters, which are tunable in various SLS
3D printers, to obtain the desired characteristics of sintered 3D objects (Okafor-Muo
et al.
2020).
The following process parameters strongly affect the features of the object as
mentioned above (Fig.
4.4).
4.6.1 Preheating and Printing Temperature
The preheating temperature plays a vital role in the sinterability of the material
as well as the consolidation and accuracy of the printed object. The preheating
effect modulates the preheating temperature in terms of the nature of the polymer.
In case of amorphous polymers, the preheating temperature should be near the glass
transition temperature, but less than the glass transition temperature. In case of a
crystalline polymer, the preheating temperature should be near the onset melting
temperature of the polymer but less than the melting temperature. If the preheating
temperature exceeds the glass transition temperature and melting temperature, the
flow of powder from the feed bed to the print bed could be improper owing to the
loss in the mobility of particles, finally generating a caking and bonding effect of
the powder in the feed bed (Shi et al.
The printing temperature indicates two different temperatures: a) the feed bed
temperature and b) the print bed temperature. The feed bed temperature was
defined as the temperature of the powder-holding tank. This temperature aids in
2021).
142 T. Karanwad et al.
the preheating of the powder, which ultimately reduces the amount of laser energy
required for sintering, the thermal gradient between the sintered and unsintered
materials, and the thermal expansion of the feedstock caused by the laser to improve
the sintering process (Goodridge et al.
2012).
The print bed temperature refers to the surface temperature, which is the
superficial temperature of the powder present on the build platform/print bed (Awad
et al.
2020a). Both feed bed and print bed temperatures are crucial for proper
sintering (Funkhouser et al.
2020). The previously sintered layer can experience
curling if a more significant temperature difference is present between the scanned
and newly spread layers (Goodridge et al.
2012).
Thermoplastic powder polymers, which are either crystalline or amorphous, are
used as raw materials. Optimum and different printing temperatures are required for
sintering both types of polymers. For amorphous polymers, the required temperature
is slightly above the glass transition temperature (T
required temperature is slightly lower than the melting temperature (T
◦
C) (Goodridge et al. 2012). For mixtures and semi-crystalline materials, the
4
required temperature is close to the glass transition temperature (T
using the simple fox equation (Fina et al.
2018a).
). For crystalline polymers, the
g
) (e.g., 3–
m
) calculated
g
1
=
T
g
W1 and W2 are the weight fractions of the respective polymers, and T
W
T
g1
W
2
1
+
T
g2
and T
g1
g2
are the glass transition temperatures of the individual polymers.
4.6.2 Laser Power
The SLS instrument comprised of different parts, of which, the laser is the most
crucial part of the printer. Diverse SLS printer models have various types of lasers,
such as Nd: YAG, CO
have different wavelengths and powers. An optimum laser wavelength is required
for sintering diverse materials owing to their optical characteristics. For example,
thermoplastic materials are sintered superiorly in the presence of high wavelength
(Awad et al.
2020a;Awadetal.2021). According to the applications and materials,
an optimized laser power and scanning speed are essential (Leong et al.
However, numerous materials cannot absorb laser energy because of their laserabsorbing capacity of a particular material at a particular wavelength. In this case,
an external laser-absorbing agent is required (Awad et al.
as discussed in detail in Sect.
The effect of laser power on the strength of the object was not as significant as
that of the hatch spacing and scan speed. However, it affects the porosity of an object
(Brown et al.
2018). In addition, the dimensional accuracy of sintered parts depends
on the optimal laser power (Hou et al.
SLS-mediated fabrication increases, the porosity of the printed object decreases.
, CO, fiber, and diodes. These various types of lasers
2
2006).
2020a;Awadetal. 2021),
8.2.
2021). As the laser power employed for the
4 Selective Laser Sintering (SLS) in Pharmaceuticals 143
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This phenomenon can also be confirmed by X-ray micro-computed topography
(micro-CT) analysis (Fina et al.
2018a), as well as by observing the increased fusion
of particles in scanning electron microscopy (SEM) analysis of objects printed at
various laser powers (Cheah et al.
2002; Leong et al. 2006). An increase in laser
power improves printing efficiency, but decreases printing accuracy (Yang et al.
2021). The porosity of sintered objects is strongly correlated with drug release.
Thus, Yang et al. (2021) employed a lower laser power (1.0 W) for the SLSmediated fabrication of immediate release formulations and higher laser power
(1.75 W and 3.15 W) for sustained-release formulations (Yang et al.
2021).
4.6.3 Laser Scanning Speed
The scanning speed of the laser indicates the rate at which the laser beam
bombarded the powder surface directly. The laser power is not tunable in some
SLS printer models; hence, adjustment of the laser scanning speed is the best
choice for optimization of the laser energy employed for sintering. The laserscanning speed is directly correlated with the porosity and printing time of the
printed object. When the laser scanning speed is lowered, the interaction of the
laser with the powder material present on the build plate/print bed increases, thereby
reducing the porosity of the sintered object owing to the increased SLS-mediated
consolidation/densification and longer printing time, and vice versa (Cheah et al.
2002; Leong et al. 2006; Thakkar et al. 2021a).
Fina et al. (2018) observed that printlets sintered at higher scan speeds received
less energy input than those sintered at lower scan speeds. Thus, they were less
heavy and less dense because of the smaller number of necks formed. In addition,
it was observed that they had less mechanical strength in terms of the breaking
force and higher % open porosity. The drug release rate increases as the scanning
speed increases (Fina et al.
at various laser scanning speeds in terms of printing time, amorphization achieved,
voids, and dissolution rate. Printlets fabricated at higher scan speeds required less
printing time and showed less amorphization, more voids, and an increased drug
dissolution rate than printlets fabricated at a lower scanning speed (Hamed et al.
2021). The optimal scanning speed helps maintain the dimensional accuracy and
processing efficiency for the completion of object fabrication (Hou et al.
2018c). Hamed et al. (2021) compared SODFs printed
2021).
4.6.4 Hatch Spacing
The hatch spacing, also known as the line offset, is the distance between two
consecutive scanning vectors. Therefore, a short hatch spacing resulted in better
energy transfer (Gueche et al. 2021b). This improved energy transfer increases the
sintering and printing quality; however, it also increases printing time. The distance
between two vectors is lengthier, which lowers the quality of printing, affects the
features of the printed object, and reduces printing time. The hatch spacing is too
144 T. Karanwad et al.
large, which means that an object cannot sinter and has low mechanical strength.
Therefore, an optimum hatch spacing is required to sinter the desired object (Awad
et al.
2020a). Davis et al. (2021) studied the effect of hatch spacing on the fabrication
of an ASDs. Based on experimental trials, it was concluded that if the hatch spacing
is too large, the object cannot be printed, and the ASDs cannot be fabricated (Davis
Jr et al.
parameters such as the porosity and surface roughness. An imperfect bond forms
between the individual paths when the hatch distance is greater than the path width.
When the hatch distance equals the path width, an imperfect melt pool is created in
a similar manner (Halama et al.
2021).
There is a great deal of importance in the hatch distance, which is related to
2022).
4.6.5 Layer Thickness
The layer thickness is essential for sintering of 3D printed objects via SLS. The
layer thickness refers to the thickness of the fresh powder layer spread on the print
bed from the feed chamber/feed bed using a recoater. The Z-axis of the printer was
lowered according to the layer thickness, and the recoater rolled out the powder from
the feed bed chamber to the print bed. The layer thickness also affects the printlet
resolution. The layer is thinner, which means that the resolution of the printed object
is high; however, this also increases fabrication time. A thicker layer results in lower
resolution of the printed object, which decreases the printing time. An optimum
layer thickness is required for sintering a desired object (Awad et al.
This geometric deviation is known as the “staircase effect” and is associated with
the thickness of the powder layer and appears on the side walls of the built parts.
During the building process, the thickness of the layers determines the resolution
of the sidewall surface. Thinner layers result in a higher level of surface quality but
also prolong the manufacturing process (Kozak and Zakrzewski
2020a).
2018).
4.7 Powder Properties Crucial for Printability in SLS
4.7.1 Particle Size and Shape
The particle shape and size plays vital role in the sintering of printed objects.
An optimum particle morphology is required to achieve sintering of the desired
object. Smaller particles hamper flow owing to electrostatic forces and form clusters.
Larger particles entail additional energy to sinter and have low mechanical strength
owing to their larger vacant spaces (Awad et al.
conducted by Dadbakhsh et al. (2016) on the effect of particle size and shape
on the processability of SLS and the mechanical properties of TPO elastomers.
Based on the experimental results, it was concluded that smaller particles require
a higher temperature for consolidation than coarser particles, resulting in a denser
2020a). There has been research
4 Selective Laser Sintering (SLS) in Pharmaceuticals 145
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object. However, the DSC profiles were the same for both coarse and fine particles
(Dadbakhsh et al.
The irregular particle shapes hinder the flowability, which means unequal distribution of the laser energy, and hence, uneven sintering of the desired object. The
particles should have a spherical shape and an acceptable particle size distribution
(58–180 μm) for a homogenous energy distribution and sintering (Awad et al.
2020a).
2016).
4.7.2 Flow Properties
Hausner’s ratio is the ratio of the tap and bulk densities of the powders and
determines the flowability of the powder material. Determination of the flowability
of the powder used as SLS feedstock material is essential to avoid spreadability
issues of feedstock during layer formation with the help of a moving recoater.
Powders with a Hausner’s ratio should typically be less than 1.25 to provide the
high flowability required for SLS (Schmid et al.
2013).
4.8 Material Selection for the SLS
4.8.1 Thermoplastic Polymers
In general, thermoplastic polymers are used to consolidate 3D-printed objects
using SLS in the pharmaceutical field. Researchers initially explored amorphous
polymers, such as polycarbonates, for SLS-mediated part building, which resulted
in a high resolution and dimensional accuracy of the printlet with respect to the
provided computer-aided design (CAD). However, the drawbacks of polycarbonate
printlets are their low mechanical strength and robustness of the builded part (Awad
et al.
2020a). Semi-crystalline engineering polymers, such as PA, are considered the
best-suited polymers for SLS-mediated manufacturing in the engineering industry
because of their unique properties, such as optimum processability, good mechanical
strength, and thermal stability. In addition, PA can consolidate high-density objects
(Salmoria et al.
companies provide this polymer with a 3D printer. For various pharmaceutical
applications, researchers have explored numerous thermoplastic polymers such
as PCL (Leong et al.
polyethylene (HDPE), polylactic acid (PLA), polymethylmethacrylate (PMMA),
polyurethane, poly(ether ether ketone) (PEEK), and polyvinyl alcohol (PVA) (Awad
et al.
2020a).
Currently, researchers are exploring different pharmaceutical grade polymers for
their application as matrix formers in the SODFs as listed in Table
2011); owing to these properties, different SLS manufacturing
2006; Salmoria et al. 2016, 2017a), PLLA, high-density
4.1.
146 T. Karanwad et al.
4.8.2 Laser Absorbing Agent
The source of the thermal energy utilized for sintering is the laser, the feedstock
used for sintering must have a laser light-absorbing capacity. PA resin generally
shows high laser absorption ability; thus, there is no need for any specific laserabsorbing agent when PA is used as feedstock for SLS-mediated sintering. In case
of pharmaceutical grade thermoplastic polymers, a laser-absorbing agent is required
to absorb the laser and radiate the heat generated in the feedstock material (Charoo
et al.
2020). For SLS 3D printers containing a blue diode laser source (445 nm
wavelength), Candurin
to enhance laser absorption. Candurin
two forms: Candurin
Fina et al.
and Candurin
al.
2019) used for SLS-mediated 3D printing using various pharmaceutical grade
2017; Allahham et al. 2020; Thakkar et al. 2021a; Trenfield et al. 2020)
®
thermoplastic polymers.
In addition to Candurin ® many other laser-absorbing agents have been used as
aids in SLS-mediated sintering. A 1.16% w/w Food Blue No.1 aluminum lake and
0.16% w/w iron oxide were successfully used as laser-absorbing agents for a 3D
printer comprising a blue diode laser (Mohamed et al.
studied the effects of various photoabsorbers on the SLS printability. Different
pigments (brilliant blue, cocaine, and tartrazine) and lakes (cocaine and tartrazine)
were mixed at a constant concentration (0.2% w/w) with RL powder, and the
SLS printability was compared in terms of surface smoothness and mechanical
strength. Tartrazine lake was found to be the optimal photoabsorber for RL powder.
In continuation of this study, researchers have also analyzed the effect of various
concentrations of tartrazine lakes on RL powder. They considered H and H
as indicators of printing accuracy and energy conversion efficiency, respectively.
As the tartrazine lake concentration increased from 0.2% to 0.4%, the printing
efficiency increased, but a simultaneous decrease in printing accuracy was observed
owing to over sintering. This study was performed using an SLS 3D printer with
a blue diode laser (Yang et al.
dose paracetamol tablets using powdered charcoal (5%w/w) as a laser-absorbing
agent, and the SLS 3D printer used had a blue diode laser (Kulinowski et al.
Subsequently, Lekurwale et al. (2022) sintered 3D printlets using an SLS 3D printer
equipped with an IR/red diode laser. A novel IR-absorbing agent was combined
with Kollicoat IR, which is a thermoplastic polymer, at various concentrations. The
material was sintered at a dye concentration of 1.25%w/w after attempts to sinter
the feedstock into suitable printlets at lower dye concentrations (0%, 0.04%, and
0.6%) (Lekurwale et al.
®
has been successfully employed by various researchers
®
Gold Sheen (3%) (Trenfield et al. 2018;Awadetal. 2020a;
®
is a metallic colorant and is available in
NXT Ruby Red (Hamed et al. 2021; Khuroo et al. 2022;Aliet
2020). Yang et al. (2021)
2021). Kulinowski et al. (2021) fabricated high-
2021).
2022).
o
4 Selective Laser Sintering (SLS) in Pharmaceuticals 147
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4.9 Pharmaceutical Applications of SLS
Salmoria et al. (2012) determined the effect of the concentration gradient used
during the manufacturing of the diffusion-based drug delivery profile of an SLSmediated drug delivery device (DDD). Two reservoir-type DDD have been developed using PCL. Two types of controlled drug-release devices were designed:
the first with a reservoir wall made up of only PCL polymer, and the other
with polycaprolactone and 15% progesterone. The drug release kinetics for both
reservoirs were zero-order, showing linear release over time. This study confirmed
that it is possible to construct a reservoir-type DDD based on the principle of
functional gradient for controlled drug release (Salmoria et al. 2012).
In 2017, for the first time in the pharmaceutical field, Fina et al. (2017) fabricated
the
oral drug-loaded product using two thermoplastic pharmaceutical grade excipients: Kollicoat IR and Eudragit L100–55. At three different concentrations (5%,
20%, and 35%), paracetamol as a model drug was incorporated into the six different
printed formulations (Fig.
formulation
and verified the adaptability of the SLS 3D printer in the pharmaceutical
field. Kollicoat IR showed a pH-independent release pattern, whereas Eudragit
L100–55 showed a pH-dependent release pattern. Additionally, the study concluded
that SLS-based AM technology could be useful in the pharmaceutical field (Fina et
al.
2017
).
4.5). Authors have analyzed the drug release pattern of the
Fig. 4.5 Printlets shown the percentage of paracetamol combination with the respective polymers
at upper row, starting from left to right 1) Paracetamol (5%) with Kollicoat IR, 2) Paracetamol
(20%) with Kollicoat IR, 3) Paracetamol (35%) with Kollicoat IR, at lower row, starting from
left to right (1) Paracetamol (5%) with Eudragit L100-55, (2) Paracetamol (20%) with Eudragit
L100-55, (3) Paracetamol (35%) with Eudragit L100-55. Adapted with permission from (Fina et
al. 2017)
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