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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5355_Библиотеки_им_академика_М_И_Перельмана
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Handbook of 3D Printing in Pharmaceutics
a concern. Fusion- based AM technologies use heat to melt the powder layers, which
causes residual tension in the nished product. Because the BJ method uses relatively
little heat, heat- induced stress and distortion are quite rare. Various densities with
controlled porosity are obtained on sintering temperature and time. It involves several
steps and requires post- processing. Due to the relatively low relative density of the
printed pieces, densication in this state typically causes severe geometric distortion.
Compared to powder bed fusion, there is a higher surface roughness and lesser resolution. For the bulk materials, post- processing strategy development is still necessary
(Danae Karali et al., 2012).
6.2 PHARMACEUTICAL APPLICATIONS OF BINDING JETTING
(PERSONALIZED MEDICINE AND DOSAGE FORMS)
6.2.1 custOmizeD Drug DOsing anD FOrmulatiOns
Two methods exist for incorporating pure medications into the mixture (Goole et al.,
2016). According to one method, the solvent and binder are the only ingredients in
the cartridge after the API and excipients are well combined into a printed powder.
As an alternative, API can be sprayed onto the powder bed in the form of a suspension or solution. According to Goole et al. (2016), the nal dispersible tablets
created using 3D printing had a uniform drug content, improved mechanical qualities,
and a highly porous structure that accelerated the rate of disintegration as shown in
Figure 6.1. A children’s formulation with an eye- catching appearance and instant
release properties was created using color inkjet three- dimensional printing (CJ- 3DP)
and a binder. The tablet strength and model volume showed a consistently linear relationship (>0.999).
6.2.2 Patient- sPeciFic imPlants anD meDical DeVices
Drug implants created through 3D printing may have unique morphologies and
intricate release schedules for every patient. Through the use of two potential
water- soluble adhesives, technology was able to replace bone with hydroxyl apatite
(HA) in the chemical composition phase and real bone in the inorganic phase.
An implant made of bone tissue was coated with HA powder in order to improve
the bond between the powdered HA and the HA in the implant. Micro- architecture,
manufacturing precision and appropriate mechanical properties of the phosphoric
acid implants was superior to those of the polyvinyl alcohol implants. The study also
showed how varied HA and tricalcium phosphate (TCP) composition ratios affected
FIGURE 6.1 Structure diagram for the 3D- printed formulation. (Hong X et al., 2021)
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Binder Jetting
TABLE 6.1
105
Examples of Rapid- Release Formulations used in BJ3DP
Dosage form API Powder Binder References
Dissolving
tablets
Dispersible
tablets
Fast dissolving
tablets
Oral
disintegrating
tablets
Dispersible
tablets
Oral
disintegrating
tablets
Levetiracetam Microcrystalline
cellulose, mannitol,
colloidal silicon
dioxide (CSD), PVP
Ketoprofen Spray dried lactose
monohydrate,
spray- dried lactose,
microcrystalline
cellulose, mannitol,
PVP grade K25, silica.
Indomethacin Lactose monohydrate
Kollidon VA64 (KL)
Warfarin
sodium
D- sucrose,
pregelatinizedstarch,
Povidone K30,
Microcrystalline
cellulose, silicon
dioxide
Clozapine Mannitol, lactose,
microcrystalline
cellulose, straw berry
avor, colloidal silicon
dioxide
Andrograp-
holide
Sucrose, mannitol, PVP
K30, microcrystalline
cellulose, aspartame
40% (v/ v)
isopropanol
aqueous solution
containing
0.05% (w/ w)
PVP and 4% (w/
w) glycerin
Ethanol solution
with 10%
polyethylene
glycol 1500
5% (W/ V) KL in
water
38% (v/ v) ethanol
solution
50% (v/ v) ethanol
solution
containing 0,
.3 (w/ w) PVP
and 4% (w/ w)
glycerin
30% (v/ v) ethanol
solution
Wang Z et
al., 2021
Kreft K et
al., 2024
Chang S- Y
et al.,
2020
Tian P et
al., 2018
Chen R et
al., 2021
Huang SY
et al.,
2020
mechanical properties (Pandey et al., 2020). Table 6.1 provides examples of rapid-
release formulations used in BJ3DP.
6.3 NOVEL DRUG DELIVERY SYSTEMS
6.3.1 sustaineD release FOrmulatiOns
To the rst controlled- release 3D- printed tablet was created using alizarin yellow and
methylene blue as model drugs. Second, acetaminophen served as the model drug
for pie- shaped controlled- release. Third, lactose, HPMC, and PVP were combined to
create an intermediate layer in an API gradient oral controlled- release drug- delivery
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Handbook of 3D Printing in Pharmaceutics
system; BJ3DP and dissolved diclofenac sodium in the binder were used to create the
top and bottom layers (Goole et al., 2016).
6.3.2 multi- Drug cOmBinatiOn PrODucts
PN- containing solutions and blank printing solutions were the two categories into
which the printing solutions were divided. Using BJ3DP technology, a PN printing
solution was sprayed into the tablet to prevent medication deterioration caused by
light and other factors. For this experiment, an LEV- PN compound with extraordinary
mechanical properties was developed. This work involved precisely controlling the
volume of a single- layer inkjet by varying the size and quantity of drug- containing
droplets. Lisinopril and spironolactone were dissolved in light- curing biological inks
before being injected into a two- chamber pharmaceutical carrier that was 3D printed
with a binder- jet printer and a piezoelectric nozzle. During production, the subsequent treatment stopped the right drug solution from being absorbed into the carrier
tablet, and each chamber held 250 L of drug solution (Goole et al., 2016 and Chen
et al., 2022).
6.4 PROCESS PARAMETERS AND OPTIMIZATION FOR
PHARMACEUTICAL APPLICATION
6.4.1 rheOlOgical PrOPerties anD FlOw BehaViOr OF Pharmaceutical
BinDers
In BJ, viscosity is a deciding factor. It is determined by surface tension: Weber number
(We) and Reynolds numbers (Re). These two factors decide the behavior of liquid
binding with respect to drop formation during ink jetting. They are dened as follows:
Re = ÞdV/ ƞ
We = ÞdV2/ γ
where Þ = density of liquid, V = ow speed, d = droplet diameter, ƞ = dynamic viscosity, γ = surface tension.
Normally binding jetting technology uses a drop- on demand inkjet deposition which acts by pushing liquid from a small nozzle with pressure as depicted
in Figure 6.2. Jettability of a uid can be determined by Ohnesorge number. It is a
dimensionless variable. Liquid binders with Oh numbers 0.1 to 1 are used.
6.4.2 BinDer PenetratiOn anD BOnDing strength OPtimizatiOn
FOr Drug DeliVery systems
Two types of print heads are as follows:
( Drop- on demand (DoD) printheads; (2) continuous jet print heads.
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FIGURE 6.2 (A) Continuous jet print head, (B) Drop on demand print head. (C) Various modes
of a droplet formation. (Soltman et al., 2008, Copyright 2008 American Chemical Society)
The DoD works by creating single drops on demand, DoD print heads are as
follows: piezoelectric and thermal ink jet heads. Ink droplets are squeezed out in a
specic shape using piezoelectric print heads. Liquid binder droplets are continuously
produced in continuous- jet print heads (Goole et al., 2016). Print head speed, binder
diffusion rate, drop- to- drop distance, and line spacing are some of the variables that
can affect pattern techniques and droplet deposition. Binder droplets migrate because
of gravity or capillary pressure until equilibrium is reached. The factors that inuence
penetration depth (D) and binder spread (W) are powder morphology, particle surface
chemistry, powder bed compactions, binder velocity and its chemistry, powder temperature, and binder bed compactions. Smaller line spacing increases the likelihood
of oversaturation and bleeding while also slowing down printing. Too much space
between the lines causes marginal stitching between them (Goole et al., 2016). The
shape, mean size, and dispersion of the powder can all affect its mobility. In an effort
to minimize powder segregation in ink jet 3D printing, hybrid binder is developed. In
recent times, scientists have been working with using a suspension of nanoparticles
to bind the metal powder bed particles. Submicron particles in the polymeric binder
help to increase the density of the green parts (Awad et al., 2019). The interaction
between binder and powder bed during the process regulates the geometry, precision,
strength of the green component, and nal surface texture as described in Figure 6.3.
The liquid binder wets the powder bed surface as soon as it enters into contact with
the top surface of the powdered material. Due to the kinetic energy of the binder
droplets, enabling the binder spread over the powder bed, a network of liquid bridges
connecting the nearby particles forms in microseconds (Vithani et al., 2018).
6.4.3 Print Parameters’ OPtimizatiOn
For printing purposes, it describes the height of the powder bed along the Z axis. The
range is from 15 to 300 m. The powder bed’s density decreases as layer thickness
increases. Print speed is primarily determined by the combination of the recoat,
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FIGURE 6.3 SLA technique showing a vat of liquid resin photopolymer from which the
3Dmodel is built layer by layer and cured by UV light. (Mostafaei et al., 2021)
Handbook of 3D Printing in Pharmaceutics
oscillator, and roller traverse speeds. It is based on the system’s ability to support
print head drops when necessary as shown in Figure 6.4. Inadequate binder saturation
can lead to a powder bed that does not maintain homogeneity as well as printed goods
that are not precise in terms of dimensions. Following is an estimation of binder saturation: S = 1000XV/ (1- (PR/ 100))XY Z.
Here, V- binder volume per drop, and PR packing pace. The layer thickness is Z,
and the binder droplet spacing is X and Y.
Drying time is inuenced by a number of variables, including the choice of
binder saturation level, binder composition, and chemistry, layer thickness, powder
wettability with binder, and packing density as mentioned in Figure 6.5. Thermal conductivity, surface area, permeability, and packing density are further considerations,
controlled by heater power. Therefore, the green components’ distortion, shrinkage,
dimensional accuracy, and surface polish are affected by the liquid binder’s drying
period (Vithani et al., 2018). The layer stacking orientation refers to the position of
the object being printed with respect to the Z axis, which is the stacking direction of
the roller. The build orientation describes how the printed parts are positioned in relation to the x, y, and z axes. The manufacturing parts’ quality is signicantly degraded
(van den Heuvel et al., 2021).
6.5 QUALITY CONTROL AND CHARACTERIZATION OF BINDER
JETTED PHARMACEUTICAL PRODUCTS
6.5.1 mechanical testing anD material characterizatiOn
The following are some of the crucial aspects of powder that BJ 3DP frequently
considers: the powder spreading process is important because it inuences the part’s
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FIGURE 6.4 (A) CAD model, STL le, and binder jetted parts (Ingaglio et al., 2019),
(B) Diagram illustrating various components of binder jet printers using two different powder
feeding methods: (left) powders are supplied via a hopper that oscillates, distributing the
powder on the powder bed and achieving powder compaction with a roller (the Innovent or
M- Flex ExOne printer, for example); (right) powder supply as a feeder that uses a roller to
swipe powder on the powder bed on the upper layer of the built area (the X1- Lab printer, for
example). (Mostafaei et al., 2021)
homogeneity and density. Other factors to consider are the powder’s owability,
packing density, and particle characteristics such as morphology, particle size, and
size distribution as shown in Figure 6.6. Studies using powder beds have been done
to investigate the results of powder distribution. Through experimental process optimization work in BJ with regard to the powder spreading parameters, such as layer
thickness and spreading speed, the characteristics of the green component have been
improved (Goole et al., 2016).
6.5.2 Drug– exciPient cOmPatiBility anD staBility stuDies
BJ is suitable with almost any powdered material because many powdered metals
and ceramics are presently sintered to their complete densities. New binders must,
however, satisfy a number of requirements in order to work with the process and
increase green strength. Some of these requirements for binders include viscosity,
surface tension, stability, reactivity with the components inside the inkjet print head,
and compatibility with the printed material (Goole et al., 2016).
The consistency and stability of the droplet formation process will be impacted
by the viscosity, density, and surface tension of the binder, ultimately inuencing the
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Handbook of 3D Printing in Pharmaceutics
FIGURE 6.5 Schematic representation of BJ3DP followed by post processing. (Do et al., 2017)
printing result. Finally, for components with pre- designed channels, a 10% binder
level was adequate to guarantee adequate handling stability, sintering, and particle
packing (Goole et al., 2016).
6.5.3 DissOlutiOn anD Drug- release testing
Modern inkjet printing has made it possible for medications that are not very water
soluble to dissolve more quickly. It is carried out using the USP (type I or type II)
dissolving test instrument. Samples were collected at various periods, and the HPLC
method was used to examine them (Gottschalk et al., 2023).
6.5.4 In Vitro anD In Vivo PerFOrmance assessment
The relationship between an in vivo absorption prole and an in vitro drug dissolution
curve is dened in large part by IVIVCs. The curves depend on the active pharmaceutical ingredient’s (API) qualities and nature, which affect its solubility and rate of
dissolution, the formulation’s release prole, and the pH of the apparatus, dissolving
medium, and procedure factors. The several elements inuencing the drug’s in vivo
release, include pH, surfactant, bile, ionic strength, and mobility (Goole et al., 2016).
6.6 CASE STUDIES AND EXAMPLES
6.6.1 case stuDy 1: BJ OF custOmizeD Oral DOsage FOrms
A thorough and systematic development process for drop- on powder 3D printing
also referred to as binder jetting of tablets containing substantial quantities of an
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FIGURE 6.6 (A) Micrographs of powder materials prepared using (Li et al., 2010) (A) gas
atomization, and (B) water atomization (Tan et al., 2017), and (C) Variations of size distribution
in powder materials.
amorphized, poorly soluble drug is documented in this article. Using copovidone as
the matrix polymer and ketoconazole as the model drug, the molecule was amorphized
by hot melt extrusion with drug loadings of 20% and 40% (Goole et al., 2016).
6.6.2 case stuDy 2: Patient- sPeciFic imPlants anD meDical DeVices
Phosphoric acid and polyvinyl alcohol (PVA) implants were created using the BJ3DP
method. According to studies, the mechanical characteristics of the implants were
barely affected by various HA and TCP composition ratios. A bone tissue implant
containing HA powder was printed in order to enhance the bonding between the
powdered HA and the HA within the implant. In terms of good printability, geometric precision, and compressive strength, the nal testing results indicated that a
combination of high molecular mass polyvinyl alcohol powder and HA performed
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Handbook of 3D Printing in Pharmaceutics
better than commercial calcium sulfate bone implants. For bone tissue engineering
applications, phosphoric acid implants with a HA/ - TCP weight ratio of 60:40 would
be the ideal choice due to their mechanical and biocompatible characteristics. Along
with the weight ratio of HA to TCP, the implants’ compressive strength increased.
Using 3DP technology, they produced porous TCP phosphate and silica implants.
Two substances that promote early bone development and mineralization upon
implantation are iron and silicon. New blood vessels began to form after 12 weeks,
which aided in the healing of the wound (Chen et al., 2022).
6.6.3 case stuDy 3: BJ FOr cOntrOlleD- release Drug DeliVery systems
In 1996, the rst controlled- release tablet developed utilizing binder- jet 3D printing
with methylene blue and alizarin yellow as model medications and a pie- shaped
controlled- release tablets were created by using acetaminophen as the model medication. A signicant amount of a drug- release blocking substance was also present
in high concentration in the annular region encircling the tablet. The drug- release
area of the inner hole rises synchronously while the drug- release area of the outside
cylindrical surface gradually declines. The height of the pill and the rate of medication release remained virtually unchanged throughout time. Another oral controlledrelease medication delivery method was also created employing binder- jet 3D printing
and diclofenac sodium that was dissolved in the binder. Lactose, HPMC, and PVP
were combined to create the powder that made up the core layer, while the top and
bottom layers were made to restrict release in an axial direction. Four lateral sections
were created by dividing the model from inside to outside. Reducing the amount of
binder spray at each location from inside to outside altered the drug gradient. The
radial two- dimensional controlled release from the three- dimensional natural release
was achieved by the drug- delivery method through the use of vertical up- and- down
release inhibition. In order to compensate for the smaller drug release zone, the controlled release function might be achieved by raising the radial drug concentration
(Goole et al., 2016). Examples of porous implants for bone tissue regeneration on
BJ3DP include various combinations of powders, binders, and layer thicknesses.
One such example uses α- tricalcium phosphate, hydroxyapatite (HA), and polyvinyl
alcohol with a 10% phosphoric acid solution as a binder, and a water- based binder,
with layer thicknesses of 50 µm and 100 µm. Another example utilizes a mixture of
calcium sulfate hemihydrate, HA, and tricalcium phosphate with a 2- pyrrolidinone
solution and phosphate buffer with Tween 80, both having a layer thickness of 89
µm. A third example features α- tricalcium phosphate, HA microsphere binder, and
a MgO/ ZnO- TCP mixture with a 2% dihydrogen sodium phosphate solution, with a
layer thickness of 90 µm.
6.7 REGULATORY CONSIDERATIONS AND CHALLENGES
Lack of a regulatory framework is another major barrier to producing pharmaceuticals
using this technology. Despite the fact that the FDA has only approved one 3Dprinted pharmaceutical product (Spritam), the agency did issue guidelines in 2017
outlining the legal prerequisites for producing medical devices. Regulating the use of
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3D printing to create dosage forms has, regrettably, not yet been done by any regulatory body (Chen et al., 2022). Furthermore, it is unclear at this time whether the
regulatory approval will apply to the entire product or just to a set of specications
covering every component of the product as well as all phases of development and
production (Goole et al., 2016).
Binder jetting needs to be reliable and consistent throughout the entire process
cycle in order to be used as a manufacturing method for large physical size and quantity end use parts. For all AM processes, achieving consistency in a process where
each part is unique presents a signicant challenge because geometry causes variation on a wide range of processes and part parameters. Parts that need to be sintered
to full density as a single alloy can be handled by binder jetting with ease, but
obtaining the desired nal geometry requires multiple exploratory sintering attempts
for parts that vary greatly in print. The main issues are erosion and slumping, even
in cases of inltration where shrinkage is only 1 to 2 percent (Chen et al., 2022).
However, depending on the nal density that is established by the green density,
holding temperature, and time, a binder jetted and sintered part may shrink by up to
25% after sintering. Swelling usually occurs more in the z- direction but more similarly in the x- and y- directions due to reduced packing density between layers and
gravity. Because of differences in the density of the powder bed within or between
layers, the green portion develops anisotropic properties that further distort the part
during the sintering process. A change in packing density, powder displacement,
or the z- dimension of the 3D- printed part may also result from the weight of the
accumulating powder layers compressing the lower layers as the z- height increases.
Therefore, further research into inltration and complex geometry sintering is
needed, if desired. While some research has been conducted on the creation of complex overhang structures, further investigation is needed to look at different feature
types and the effects of powder properties, print process parameters, and furnace
conditions on geometry distortion.
Differential shrinkage rates within the part as a result of thermal gradients are
a signicant cause of distortion during sintering. The nal part will have incorrect
geometry and undesirable properties if there is any unpredictable shrinkage rate or
distortion. It takes gradual temperature ramping to get past this problem. Furthermore,
the part may form in a semi- solid or even liquid phase at the sintering temperature
due to its composition and hot spots in the sintering sample. This makes shape retention and prediction for binder- jet 3D printed parts even more difcult. Applying nonreactive powder (such as alumina powder) to the affected areas is a workable way to
reduce the heat gradient. Additionally, the use of reactive binder is recommended,
which improves part strength and shape retention by forming interparticle bridges
between nano- crystalline structures during the initial stage of sintering. To simulate
shrinkage and sintering, part distortion can be predicted theoretically through modeling. Additionally, adding nanoparticles has been found to reduce slumping and
shrinkage.
A few studies looked at how printing parameters and powder affected the development of layering defects in binder- jetted parts. Because of the high- velocity binder and
the potential for improper binder spreading, ultra- ne powder may be ejected from
the powder bed’s upper surface due to binder effects like impact and powder– binder
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