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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5427_Библиотеки_им_академика_М_И_Перельмана
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148 T. Karanwad et al.
Salmoria et al. (2017) prepared an implantable tablet containing PCL/fluorouracil
(FU) using the SLS 3D printing technology. As a result of variation in laser power,
mechanical strength and drug release pattern were varied. This study found that
when the laser power (3 W to 7 W) was increased, all sintered formulations
showed better coalescence with a higher degree of sintering, owing to greater
neck formation. In addition, they observed that the initial burst release of the
drug (FU) may be due to its aqueous solubility, followed by controlled release.
This phenomenon is beneficial for treating cancer owing to bursts, followed by the
accumulation of FU drug molecules at the tumor site (Salmoria et al.
2017a).
In the upcoming year, Fina et al. (2018) fabricated cylindrical and gyroid lattices
and structured printlets using SLS 3D printing technology with four different
pharmaceutical grade thermoplastic polymers: Eudragit L100–55, polyethylene
glycol, Eudragit RL, and ethyl cellulose N
(Fig. 4.6). This study aimed to check
7
the applicability of SLS 3D printing technology for the prototyping of different
structures and to check the release of the drug from different polymers owing to
the change in the design, while keeping the composition fixed. This study also
altered the laser scanning speed, which is an important process parameter in SLS 3D
printing. Based on the variation in the process parameters, they observed variation in
the porosity of the printlets, which directly affected the drug release pattern of the
structured printlets. This phenomenon occurred because of the varied interaction
time between the powder particles and the laser. The in vitro dissolution resulted in
Fig. 4.6 Images represented that (a) cylindrical printlets with different polymers such as polyethy-
lene oxide (PEO), Eudragit L100 (EUD L), ethyl cellulose (EC), and Eudragit RL (EUD RL), and
(b) cylindrical printlets with different polymers such as polyethylene oxide (PEO), Eudragit L100
(EUD L), ethyl cellulose (EC), and Eudragit RL (EUD RL), Adapted with permission from (Fina
et al.
2018b)
4 Selective Laser Sintering (SLS) in Pharmaceuticals 149
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the release of the drug from the fabricated gyroid lattice-structured printlets using
the four different polymers, which was faster than the cylindrical printlets owing
to the increase in the surface area of the gyroid lattice in the dissolution media.
Another vital observation of this study was the successful fabrication of the designed
structures owing to the precision and accuracy of the laser (Fina et al.
2018b). The
same author’s team (2018) investigated the applicability of an SLS 3D printer for
prototyping ODTs. In this study, thermoplastic pharmaceutical excipients, such as
Kollidon VA 64 and HPMC Vivapharm E
were used with paracetamol as a model
5
drug. Using observations from a previous study, the authors varied the laser scanning
speed for sintering ODTs. The results showed that when the laser scanning speed
was increased, the open and closed porosities increased, resulting the increased
release of the drug from the printlets for all six formulations. They observed that
the disintegration time of sintered printlets using Kollidon VA 64 with the highest
laser scanning speed (300 mm/s) was 4 s. Hence, the SLS 3D printer is feasible for
fabricating ODTs by varying the process parameters (Fina et al.
2018c).
To explore the feasibility of SLS 3D printing in pharmaceutical fabrication,
Trenfield et al. (2018) prepared different printlets with different shapes and a
high drug loading of up to 40% w/w (Fig.
4.7). These printlets were assessed
using non-destructive analytical tools such as process analytical techniques, Raman
confocal microscopy, and portable NIR spectroscopy. In this study, up to 40%
w/w paracetamol was loaded into the printlets, and the pharmaceutical grade
thermoplastic polymer Eudragit L100-55 was used as the polymer matrix. The
Fig. 4.7 Represents the different shape of dosage forms with the maximum 40% drug loading.
Adapted with permission from (Trenfield et al.
2018)
150 T. Karanwad et al.
results were corroborated using sophisticated destructive analytical tools, such as
PXRD and HPLC analyses. Hence, this study concluded that a non-destructive
analytical tool could be used to expedite the characterization of 3D printed SODFs
(Trenfield et al.
2018). To continue this study, the same research group (2020)
prepared polyprintlets containing two different drugs, amlodipine and lisinopril, at
various therapeutic concentrations. Subsequently, the drug content was evaluated
using a non-destructive portable NIR spectrometer. The first calibration curve was
plotted using pure 1–5% w/w amlodipine and pure 2–10% w/w lisinopril; the
regression values were found to be (R
2
= 0.997, 0.991), after which the accuracy
and specificity were calculated to be within the acceptable range. Finally, the results
obtained for drug content via HPLC and NIR spectroscopy were compared, and no
significant difference was observed in the drug content. The study concluded that the
non-destructive tool could analyze the contents of two drugs in 3D printed SODFs
(Trenfield et al.
2020).
SLS 3D printing technology was extensively explored in 2019 and 2020,
with additional advantages. Awad et al. (2019) prepared miniprintlets and dual
miniprintlets with diameters of 1 and 2 mm, respectively, with a modified release. In
this study, they used two pharmaceutical grade polymers: (1) Kollicoat IR was used
as an immediate-release polymer and (2) Ethyl cellulose was used as a sustainedrelease polymer. These miniprintlets and the dual miniprintlets exhibited controlled
drug release. The SEM images of the miniprintlets and dual miniprintlets show the
sintering morphology with a single polymer and dual polymers (Fig.
al.
2019). Process variables are the vital components of each technology. This affects
4.8) (Awad et
printlet quality and its different characteristics. Ali et al. (2019) studied the effects
of the process parameters on the quality of prototypes (printlets). The authors used
the Box-Behnken response surface methodology to assess the effect of the process
parameters on printlet quality. Laser scanning speed, printing chamber/print bed
temperature, and lactose monohydrate concentration were selected as the process
variables. The hardness, dissolution, disintegration, and weight variation were used
to assess the quality of the printlets. Based on this study, they found that the variation
in process parameters was affected on the characteristics of the printlets (Ali et al.
2019).
Mohamed et al. (2020) conducted a similar study using a Box-Behnken design.
The authors found that the process variable affected the quality of the printlets
(Mohamed et al.
2020). In the upcoming year, Allaham et al. (2020) prepared an
SLS-mediated 3D printed ODTs containing an ondansetron-cyclodextrin complex.
The complex was first prepared, and mannitol was added as a diluent. The fabricated
ondansetron ODTs was compared with the same ondansetron-containing marketed
ODTs formulation. Both formulations disintegrated within approximately 15 s, and
90% drug release was observed after 300 s. This might be owing to the maximum
open and closed pore formation in both formulations, which was assessed by using
the micro-CT (Fig.
4.9). Based on these results, the authors concluded that SLS-
mediated 3D printing technology was feasible for fabricating ODTs formulations,
which were similar to the marketed ODTs formulation. An additional role of SLS
3D printing is to customize the dose according to patient needs (Allahham et al.
2020).
4 Selective Laser Sintering (SLS) in Pharmaceuticals 151
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Fig. 4.8 SEM images of the (a) miniprintlets and (b) dual miniprintlets, blue region indicates the
Kollicoat IR region, and yellow region indicates the ethyl cellulose region (Awad et al.
2019)
152 T. Karanwad et al.
Fig. 4.9 X-ray micro-CT images of the formulation I and formulation II (Allahham et al. 2020)
For the first time in pharmaceuticals, ODTs formulations with Braille and Moon
patterns were sintered using SLS-mediated 3D printing technology (Fig.
4.10)fora
patient with visual impairment by Awad et al. (2020) The purpose of the formulation
was for the braille and moon patterns on the surface of ODTs to be readable to
blind patients. The sintered ODTs formulations disintegrated within 5 s. Despite this
immediate release, ODTs exhibit optimal mechanical strength (Awad et al.
2020b).
Since 2021, the SLS AM technology has been widely explored in the pharmaceutical field. In the same year, Dravis et al. (2021) prepared ASDs printlets using SLS
3D printing technology which is a single-step process. In this study, ritonavir was
used as the model drug, and copovidone was used as the ideal polymer. The author
attempted to develop a formulation with different ratios of ritonavir and copovidone
and varied process parameters. The main aim of this study was to evaluate the impact
of the process parameters with an optimum range for the successful preparation of
ASD formulations. Based on this study, they concluded that the selected parameters
played a vital role in the preparation of ASDs in ritonavir-containing SODFs.
Deviations from the optimized parameters led to batch failure. In addition, they
reported that ASDs augmented the 21-fold increase in solubility. Finally, SLS 3D
printing technology was feasible for formulating ASDs of ritonavir-copovidone,
with a drastic increase in drug release (Davis Jr et al.
2021).
Hamed et al. (2021) formulated an ASDs for lopinavir using an SLS-mediated
AM technology. The purpose of this investigation was to compute the crystalline
fraction of lopinavir using the XRPD-chemometric model and to prepare an
efficacious ASDs. In this study, 25–50% lopinavir concentration was used with
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Fig. 4.10 SLS-mediated 3D printlets with different shapes having the moon and braille pattern on
the surface (Awad et al.
2020b)
154 T. Karanwad et al.
a variation in the laser scanning speed of 75–100 mm/s. A chemometric model
was developed using principal component analysis (PCA) and partial least squares
(PLS). These results indicated that the drug percentage was not affected by the
crystallinity of lopinavir, but the laser scanning speed affected the crystallinity
of the drug. The authors also mentioned that SLS 3D printing technology has
an advantage over HME for the preparation of ASDs, owing to the single-step
process (Hamed et al.
2021). Pharmaceutical grade excipients and drugs have
not been extensively explored for the preparation of SODFs using SLS-mediated
rapid prototyping technology. Based on this, Yang et al. (2021) selected different
frequently used pharmaceutical grade excipients and drugs and assessed their
printability. In addition, the authors investigated the release behavior of selected
immediate and sustained-release polymers. The study showed that yellow-colored
drugs could be printed because the drugs were able to absorb the 450 nm wavelength
of the laser. However, the white-colored drugs were unable to absorb the 450 nm
wavelength of the laser. Additional colored dyes were tested for the printing of
white-colored drugs via mixing with each other; however, tartrazine dye could
absorb the laser at the optimum concentration. Finally, all drugs showed printability
with the different pharmaceutical grade polymers with varied ratios. In addition,
the effects of the polymer, drug, and process parameters were assessed, resulting
in a collective effect on printability and release patterns (Yang et al.
2021). Gueche
et al. (2021) sintered the SODFs of paracetamol and Kollidon VA 64 using a CO
laser. The CO2 laser has a 10.6 μm wavelength, which is the highest power laser
among all the SLS-mediated printers used for the sintering of SODFs. The authors
assessed the feasibility of using a CO
laser for sintering the SODFs. Two grades
2
of polymer (Kollidon VA 64 and Kollidon VA 64 fine), and two grades of drug
(paracetamol and paracetamol fine) were used to sinter SODFs. The sintered SODFs
were compared with Duraform PA12, a polymer frequently used for sintering
various prototypes. In the pharmaceutical field, the authors successfully fabricated
SODFs with pharmaceutical grade polymers, without adding a laser-absorbing
material. In addition, the results indicated that the drug was not degraded despite
the higher laser power, as confirmed by the UHPLC analysis. Hence, CO
2
laserembedded printer is also feasible for sinter SODFs using the process parameters,
which provide customization of the dosage forms according to patient needs. In
addition, thermosensitive drugs may be degraded owing to high laser power, which
needs to be confirmed using analytical tools (Gueche et al.
2021d). To continue
the above study, the same team (2021) evaluated the effects of process parameters
using the QbD approach. In this study, four vital process parameters were selected
such as the scan speed, heating temperature, layer thickness, and laser power. The
obtained results indicated that the optimum heating temperature is important for
the sinterability of solid oral forms, owing to the curling effect of the sintered
layers, which arises due to an undesired heating temperature range. In addition,
the authors found that the remaining three parameters were critical and ultimately
affected the sinterability of the formulation and the curling of the sintered layer
(Gueche et al.
2021a). The foremost concern in the pharmaceutical field is that more
than 40% of the drugs face solubility related issues. Thakkar et al. (2021) prepared
2
4 Selective Laser Sintering (SLS) in Pharmaceuticals 155
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Fig. 4.11 HME based granules embedded, sintered 3D printlets. Adopted with permission from
(Thakkar et al.
2021c)
granules using HME to enhance the solubility of indomethacin, a poorly soluble
drug. The prepared granules were analyzed using a UV-visible reflectance probe
for continuous assessment of the amorphous form of the drug. Then the granules
were mixed with the pharmaceutical grade thermoplastic polymer Kollidon VA
64. The blend was subjected to fabrication of the printlets via SLS-mediated 3D
printing technology, which resulted in successful sintering of the 3D printlets (Fig.
4.11). The three prepared components (granules, blends, and sintered printlets) were
characterized using conventional evaluation techniques and advanced solid-state
characterization tools. The results indicated that the flow properties of the blend
increased owing to the preparation of the granules, which improved the sinterability
of the printlets. In addition, the drug was converted into an amorphous form owing to
granulation; hence, the solubility of the drug was enhanced (Thakkar et al.
2021c).
The process parameters significantly affect the sintering and quality of the
printlets. Thakkar et al. (2021) assessed the effects of the drug particle size and
laser speed on the sintering of ASDs printlets using SLS 3D printing. They used
an indomethacin crystalline drug with a particle size of more than 50 μm and
HME-extruded granules of indomethacin with a particle size of less than 5 μm.
The prepared physical mixture of the drug and the polymer matrix was sintered
at various scan speeds (50, 75, and 100 mm/s). Characterization was performed
using an analytical tools, and amorphization of the drug was assessed at various
process parameter variations. The authors found that indomethacin particle size
and scan speed had a significant effect on the sintering of ASDs (Thakkar et
al.
2021a). The laser of a particular wavelength and temperature used in the
SLS process might result in the degradation of photosensitive drugs. Thakkar
et al. (2021) studied the impact of the process parameters and composition of
the formulation on the quality of sintered 3D printlets and assessed solid-state
changes and degradation of the drug. Nifedipine was selected as the model drug,
and Kollidon VA 64 was selected as the thermoplastic polymer with Candurin
®
156 T. Karanwad et al.
Fig. 4.12 Ferromagnetic nanoparticle embedded, SLS-mediated 3D printlets with the variation of
the Laser scanning speed and hatch spacing (Zhang et al.
2023)
Gold Sheen, a laser-absorbing material. A preliminary study suggested that the
laser speed, laser-absorbing material concentration, and surface temperature were
independent variables. The Box-Behnken design has resulted in the assessment
impact of the surface temperature on degradation, crystallinity, and solid-state
transformation (Thakkar et al.
(ferromagnetic nanoparticles)-embedded SLS-mediated 3D printlets (Fig.
this novel experiment, isoniazid was used as a model drug, Kollidon VA 64 as
the polymer, Candurin
®
2021b). Zhang et al. (2021) fabricated carbonyl iron
4.12). In
gold sheen as the photoabsorbing material, and carbonyl
iron was mixed to accelerate the consolidation of the printlets and release of the
drug. Ferromagnetic nanoparticle may play three important roles. This will help
in sintering owing to its laser absorption ability, accelerate drug release in the
presence of a magnetic field from the printlet, and fulfill the daily requirements of
iron. Subsequently, the process parameters were varied to optimize the process. In
conclusion, the incorporation of ferromagnetic nanoparticles improved the sintering
and release rates of the drug (Zhang et al.
2021).
Kulinowski et al. (2021) sintered high-dose-loaded printlets using an SLS 3D
printing platform. Paracetamol (95%) was used as the model drug, and charcoal
(5%) was used as the laser-absorbing material. The results showed that a large
4 Selective Laser Sintering (SLS) in Pharmaceuticals 157
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number of drug-containing printlets could be fabricated with a modified release
profile via process parameter variations (Kulinowski et al.
2021). The combination
of material properties and process parameters played a crucial role in the sintering
of the SODFs and drug release pattern. Gueche et al. (2021) sintered a solid dosage
form using dicarboxylic acids and copovidone. Dicarboxylic acid was used as
the plasticizer to minimize the printing temperature. Ibuprofen acid and ibuprofen
sodium salt were used to assess the plasticizing effects of different drugs. The
plasticizing effect was analyzed using DSC, which is a promising thermal analysis
tool. The authors found that dicarboxylic acid improved the plasticizing effect,
which reduced the heating temperature required for the fabrication of solid oral
forms of Kollidon VA 64 and model drugs (Gueche et al.
2021c). Madžarevi’c
et al. (2021) applied the decision tree model as a data-mining tool to assess the
effect of energy density and various formulation factors on the SLS-mediated
printability of irbesartan tablets. Authors obtained 80% accuracy from a decision
tree model to determine the correlation between formulation factors, energy density,
and SLS printability. It was found that the amount of crospovidone and energy
density applied during printing mostly affected the SLS printability. Energy density
had a positive effect on the weight and disintegration time of the printed tablets.
DSC confirmed that the amorphization of irbesartan was achieved during printing.
The authors reported that laser scanning speed and energy density mostly affected
the physical characterization of tablets and had negligible effect on drug release
(Madžarevi´cetal.
2021).
Later, Trenfield et al. (2022) successfully explored SLS as a single-step process
for producing ASDs using the BCS class II drug itraconazole (20% w/w) along
with various grades of HPC, such as HPC-SSL, HPC-SL, and HPC-L. In this
study, researchers initially analyzed the conversion of the drug into an amorphous
form using the XRPD technique, followed by non-destructive evaluation of the
amorphous solid content in the itraconazole-loaded formulation both qualitatively
and quantitatively using process analytical technology (PAT), including Raman and
NIR spectroscopy. A comparison of sinterability between the grades of the HPC
polymer used was performed based on bulk characterization (Trenfield et al.
2022b).
Khuroo et al. (2022) studied the significance of formulation and SLS-related process
parameters on rapidly dissolving isoniazid printlets through detailed analysis of their
physicochemical properties, stability, and pharmacokinetics of fabricated printlets.
As a result of this investigation, laser scanning speed was found to be the process
parameter that mostly affected the weight, breaking force, and disintegration time of
printlets. The oral bioavailability of these SLS-mediated 3D printlets was identical
to that of compressed tablets (Fig.
4.13) (Khuroo et al. 2022). Kulinowski et al.
(2022) observed that pharmaceutical grade polymers explored as matrix former for
SLS 3D printed SODFs encountered practical issues like poor mechanical strength.
They used carbon-stained PA12 to fabricate composite printlets with a high dose
of metronidazole of up to 80–90% (therapeutic dose of 600 mg). These printlets
had hardness values above 40 N, which is comparable to those of conventionally
compressed tablets. In addition, the effects of laser scanning speed and osmotic
agent on drug release were reported, and dissolution was found to be improved
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