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2 Fused Deposition Modeling (FDM) of Pharmaceuticals 47
Fig. 2.1 Different steps in the production of an FDM 3D-printed dosage form, starting from an
in-silico model. (Reprinted with permission under the open access CC BY 4.0 license from Jamróz
et al.
2018)
2.2 Process Technology and Principles of Printing
Fused deposition modeling (FDM) has a rather simple operating mechanism with
equipment generally being desktop-sized. The general operating mechanism is
similar to all FDM 3D-printers, illustrated in Fig.
however occur, for example, in terms of feeding behaviour.
Firstly, a digital model is constructed using computer-aided design (CAD)
software. This model is saved as a stereolithographic (.stl) file, where the surface
of the model is transformed into small triangles (Cailleaux et al.,
the in-silico model is imported in the printing or slicer software, where printing
parameters can be freely chosen based on the desired outcome. The desired object
will be saved, generating a set of instructions readable by the printer (g-code)
(Trenfield et al.,
2018). Thirdly, a feed and printable formulation in the form of
a filament is chosen, consisting of a drug dispersed into a thermoplastic material.
This feedstock filament is fed towards a heated nozzle, molten and deposited on
a platform. Nozzle and build platform can move along a different axis to create a
3D-object in a layer-by-layer fashion (Turner et al.,
2.1. Individual differences might
2021). Secondly,
2014).
2.2.1 Fused Deposition Modeling Equipment
FDM 3D-printing is a fairly new production technique, but it has known a swift rise
in the number of applications. The first industrial prototype of an FDM printer was
developed by Stratasys in 1992. The machine, the so-called 3D Modeler, utilized
only plastics and waxes as starting material. In 2011, one of the first reports of
pharmaceutical FDM 3D-printing appeared, when wound dressings containing an
48 S. Henry et al.
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Fig. 2.2 On the left, an overview of the set-up of a generic FDM 3D-printer, utilizing a direct
extrusion mechanism. A detailed overview of the extruder with feeding gears and nozzle is
presented on the right. (Reprinted with permission from Parulski et al.
2021)
antibacterial agent were printed and evaluated in vivo (Teo et al., 2011). In 2014, one
of the first reports of FDM 3D-printing for oral drug delivery occurred, describing
the development of a fluorescein loaded polyvinyl alcohol (PVA) tablet (Goyanes
et al.,
2014).
While all FDM printers possess a largely identical working principle, small differences in set-up exist in terms of movement, feedstock diameter, feed mechanism,
print enclosure and number of nozzles. The set-up of a generic FDM 3D-printer
is illustrated in Fig.
2.2, and possible variations on this generic type are discussed
below.
• Movement system: Nearly, all FDM printers used in pharmaceutical research
utilize the Cartesian coordinate system with movement of the extruder head and
build platform along the X-, Y- and Z-axis. Other less common types include a
delta head, polar system or robotic arm.
• Feedstock diameter: Printers are developed to work with a filament diameter
of either 1.75 or 2.85 mm. Smaller filament diameters could be preferred in
pharmaceutical manufacturing due to a shorter residence time inside the liquefier
and nozzle, hence reducing the thermal load on the API (Gottschalk et al.,
and impact of diameter inhomogeneities on the printed dosage form (Quodbach
2021).
et al.,
• Enclosure: Only a small subset of printers is built within a temperature-controlled
enclosure, minimizing thermal gradients and subsequent warping of the printed
object. Smaller scale printers used in pharmaceutical production mostly do not
operate in a full enclosure but utilize only a heated build platform. While this
is cost-effective, this approach impedes the use of materials with high melt
temperatures and the production of large-scale objects.
• Feed mechanism: Two subtypes exist within the class of FDM 3D-printers based
on the feeding mechanism. The first subtype contains a direct drive extruder,
with the feeding gears positioned directly above the extruder head as depicted
2021)
2 Fused Deposition Modeling (FDM) of Pharmaceuticals 49
Fig. 2.3 Set-up of the
Bowden feed mechanism in a
fused deposition modeling
3D-printer. (Reprinted with
permission from Tlegenov
et al. 2018)
in Fig. 2.2. This system provides superior feed control, which is beneficial for
flexible materials. As a result however, the extruder head is somewhat heavier,
resulting in vibrations which might hamper continuous flow from the nozzle and
cause imperfections in the printed object (Fuenmayor et al., 2018). An example
of
a commercialized, non-GMP printer using this principle is the Prusa i3 MK3S.
The second subtype, a Bowden printer, has the driver gears positioned apart
from the extruder head as depicted in Fig. 2.3. This system enables higher print
speeds
with less vibrations but requires more fine-tuning for specialty filaments
(Fuenmayor et al., 2018). An example of a commercialized, non-GMP printer
using
the Bowden principle is the Ultimaker S3. In general, the direct extrusion
mechanism is preferred over the Bowden system to allow for a wider material
selection while minimizing stress on the feedstock material (Prasad et al., 2019;
Lamichhane
made
et al.,
2019; Fuenmayor et al., 2018). However, reports were recently
of modified Bowden printers utilizing a smaller feeding tube, rigid guide
and piston feeding to enable wider material selection (Gottschalk et al., 2021).
• Nozzle: A printer mostly has one nozzle but might consist of multiple extruders
each
with their own nozzle to enable for easy multi-material printing. This principle was used successfully to construct for example a polypill for the treatment
of cardiovascular diseases (Pereira et al.,
multi-material
e
xtruder and nozzle was utilized where different filaments are consecutively fed
printing has been demonstrated by Windolf et al. (2022). A single
2019). Another approach enabling
and washed out by means of a cleaning tower (Windolf et al., 2022).
50 S. Henry et al.
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2.2.2 The Printing Process
The extrusion head of a generic FDM 3D-printer contains a feeding mechanism,
liquefier and nozzle assembled onto a gantry with build platform. The starting
material, a filament, is pinched by roller grips and pushed further inside the extrusion
head. This feeding mechanism might be incompatible with certain feedstock
materials as it might crush or bend filaments due to the exerted pressure. Next, the
feedstock enters the heated liquefier and is molten. The amount of melt inside the
channel will depend on both the feed rate and heat flux. Finally, the melt flows out
of the nozzle due to the piston action of the unmolten filament above the liquefier
zone. Consequently, the melt is deposited on the build platform where it solidifies.
The surface of the build platform is crucial as it should enable sufficient but not
excessive adhesion of the object to the build platform. During melt flow out of the
nozzle, the motion of the extrusion head and build platform are controlled by stepper
motors, enabling the production of a 3D-object. The printing step could be followed
by a smoothing step using mechanical abrasion, chemical smoothing with solvent
vapors or surface coating (Turner et al.,
2014) although this is typically not pursued
when producing biocompatible pharmaceutical dosage forms.
2.2.2.1 Mass Flow During Fused Deposition Modeling 3D-Printing
Feeding of the feedstock filament is controlled by rotation of the roller grips above
the liquefier to obtain a well-defined constant volumetric flow rate. This feed rate
can be expressed as
.v =
Q
W × H
(2.1)
where v is the linear feed velocity of the filament, Q the volumetric flow rate of the
melt, W the road width and H the slice thickness of the deposited strand.
The force required to achieve this volumetric flow by pushing the melt out of the
nozzle depends on the pressure drop (
. P) and cross-sectional area of the feedstock
filament (A):
.F = P × A (2.2)
Since polymer melts generally display pseudoplastic behaviour, their viscosity
depends on the imposed shear rate and temperature of the process. A minimum
process temperature is required for extrusion, since excessive viscosity will lead to
an excessive pressure drop which will consecutively block the extruder.The pressure
drop (
. P) over the extruder head is directly proportional to the viscosity (. η) and
volumetric flow rate (Q):
.P =
8 × Q × L × η
4
D
π ×
2
(2.3)
2 Fused Deposition Modeling (FDM) of Pharmaceuticals 51
where the length of the nozzle (L) and the diameter of the nozzle (D) represent
equipment design variables (Henry et al.,
the size of the nozzle is an important process variable, since it controls the pressure
drop and hence the resolution, occurrence of print failures and acceptable process
conditions of a specific formulation (Henry et al.,
determines the mass average of the printed object and its mass variation (Macedo
et al.,
2022).
2021a). From Eq. 2.3, it becomes clear that
2021a). Moreover, nozzle size
2.2.3 Material Processability
As mentioned previously, the 3D-printing process utilizes roller grips to pinch and
push the filament forward through the extruder. The flow behaviour of the melt
exiting the extruder is in turn mainly dictated by its rheological behaviour. As a
result, this printing technique inherently poses limitations on the materials that can
be used as feedstock.
2.2.3.1 Feedability
In terms of feedability, constraints are mainly related to the mechanical behaviour
of the feedstock. The filament should be able to withstand the loads imposed by the
feeding gears with minimal deformation. If the filament is incompatible with the
printing gears, passage towards the heated nozzle is impeded which results in the
occurrence of print failures as can be seen in Fig.
2.4.
Feeding Failures
Print failures due to feedability issues can be classified into brittleness, flexibility
and softness. Brittleness occurs when filaments break inside the print head due
to the transversally applied stress of the gears, as noted when (Korte et al.,
attempted to print theophylline-loaded Eudragit RL (Korte et al.,
of the filament becomes an issue when the filament is not deformed or broken
between the gears but buckles above the liquefier, hence impeding the piston action
of the filament to push the melt out of the nozzle. This was observed by Genina
et al. (
2016) when attempting to print elastic ethylene vinyl acetate grades (Genina
et al.,
2016). Problems regarding filament softness are observed when the filament
is deformed and flattened between the gears, often occurring for higher drug-loaded
filaments in combination with increased process temperature. This was observed
by Aho et al. (
indomethacin at higher temperatures (Aho et al., 2019). This phenomenon seems
especially problematic when the filament has a low glass transition temperature
and/or melting temperature and if high pressure is required to advance the filament
towards the nozzle (Henry et al.,
2019) when attempting to print polycaprolactone with 70% (m/m)
2021a).
2018). Flexibility
2018)
52 S. Henry et al.
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Fig. 2.4 Illustration of an FDM extruder head, presenting the feeding mechanism by means
of roller grips and highlighting (a) defective feeding due to low toughness and subsequent
deformation, (b) defective feeding due to brittleness and (c) flawless passage through the gears.
(Reprinted with permission from Lima et al.
2022)
It must be noted that different nomenclature was sometimes used in research
articles. The nomenclature used in the first column of Table
2.1 refers to the
failure modes described in the cited articles, rather than the measured mechanical
parameters.
Screening Tests
Several tests have been developed to screen formulations, enabling to test their feedability without the need to go through trial-and-error iterations on the printer. Most
of these tests utilize a texture analyser, generating a force–displacement curve which
is mostly converted towards a stress–strain curve taking into account the diameter
and length of the investigated specimen. Zhang et al. (
2017) utilized a 3-point bend
test to investigate brittleness, expressed as stiffness, which was the ratio between the
breaking stress and breaking distance (Zhang et al., 2017). This 3-point bend test is
most commonly used to evaluate the feeding behaviour by comparing the breaking
stress and flexural modulus (Prasad et al.,
2019; Than and Titapiwatanakun, 2021).
Alternative tests have also been developed like elongational tests (Goyanes et al.,
2016; Henry et al., 2021a; Samaro et al., 2020; Macedo et al., 2020), compressive
fracturability tests (Gültekin et al.,
tests (Gioumouxouzis et al.,
2019; Nasereddin et al., 2018) and indentation
2020). Different screening parameters can be deducted
from these mechanical tests and compared between formulations to predict printing
failures, as summarized in Table
2.1.
2 Fused Deposition Modeling (FDM) of Pharmaceuticals 53
Tab le 2 .1 Examples of printing failures observed due to feedability issues between the gears and
their characterization test
Failure mode Observation Screening parameter Reference
Brittleness Breakage Distance at break (3PB) Korte et al. (2018), Gottschalk
Distance at break
(compression)
Bending force
(compression)
Strain at break (elongation) Macedo et al. (2020)
Breaking force (3PB) Zhang et al. (2017), Prasad et al.
Breaking force (elongation) Isreb et al. (2019)
Indentation hardness (DMI) Gioumouxouzis et al. (2018)
Tensile energy (elongation) Henry et al. (2021a)
Flexibility Bending and
blocking
Softness Deformed
filament
3PB. = three-point bend test, DMI . = dynamic micro indenter, AUC . = area under the curve
Flexural modulus (3PB) Samaro et al. (2021), Omarietal.
Breaking force
(compression)
Breaking force (elongation) Lima et al. (2022), Yang et al.
Elastic modulus
(elongation)
Elastic modulus (DMI) Gioumouxouzis et al. (2018)
Maximal stress (modified
3PB)
Toughness (AUC, modified
3PB)
et al. (2021), Wei et al. (2020)
Gültekin et al. (2019)
Oladeji et al. (2022)
(2019)
(2022), Ilyés et al. (2019)
Oladeji et al. (2022)
(2018)
Verstraete et al. (2018), Henry
et al. (2021a)
Zhang et al. (2019), Cri¸san et al.
(2022)
Xu et al. (2020)
In general, a load is applied to a material during a screening test and its
deformation measured. Initially, the material will behave elastically, meaning it will
return to its original shape if the load is removed. The modulus of elasticity or
Young’s modulus represents the stiffness of the material and is the ratio between
stress and strain in this initial linear portion of the stress–strain curve. Printing
failure due to flexibility is associated with a low elastic or flexural modulus. After the
elastic deformation, plastic deformation will be initiated. The ductility of a material
represents the ability for plastic deformation prior to fracture (Samaro et al., 2020).
Brittleness
failure is usually associated with low distance (or strain) and force (or
stress) at break (Korte et al., 2018). Additionally, a low indentation hardness could
re
veal brittle fracture (Gioumouxouzis et al., 2018). The toughness is calculated
from
the area under the curve until fracture and represents the energy needed to
fracture the material (Xu et al., 2020).
In
conclusion, an acceptable filament should possess adequate mechanical
properties which means a sufficient stiffness, toughness and ductility (Samaro et al.,
54 S. Henry et al.
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2020). It is unfortunately difficult to stipulate universally applicable numerical val-
ues for these screening parameters, distinguishing between (non-)feedable filaments
due to the variety of applied tests, variety of utilized printers and modifications of
the printer as reported among research articles. To this end, artificial intelligence
has been exploited to build a predictive tool for feedability and ideal production
parameters, utilizing a balanced dataset of 1594 drug-loaded formulations from inhouse and literature-mined data (Ong et al.,
2022; Elbadawi et al., 2020).
2.2.3.2 Flowability
Following successful passage through the printer gears, the polymer is fed towards
the heated liquefier and nozzle. Here, the polymer melts and the resulting molten
strand is deposited onto the build plate. Successful melting and deposition requires
adequate rheological and thermal properties to achieve consistent melt flow at
acceptable process temperatures, hence ensuring qualitative end-products (Pietrzak
et al.,
2015). The thermoplastic polymers employed as feedstock for FDM 3D-
printing are either amorphous, characterized by a glass transition temperature (Tg),
or semi-crystalline, containing an additional melting temperature (Tm) (Parulski
et al.,
2021). Apart from the Tg and Tm, other material parameters like thermal
conductivity and specific heat capacity are equally important for the printing process
(Azad et al.,
layer fusion and bonding mechanisms (Parulski et al.,
2020). Part strength of the end-product, for example, will depend on
2021).
Flowability Failure
The process temperature will have to be sufficiently high, to ensure that the polymer
is in a molten state, but preferably it also remains below the degradation temperature
of all formulation constituents (Pietrzak et al.,
2015). As described in Eq. 2.3,the
required pressure to push the melt out of the nozzle depends on the viscosity of
the melt, which in turn depends on the process temperature (Solanki et al.,
2018).
As a result, the minimal processing temperature depends on the maximum pressure
attainable within the 3D-printer head, which is generally higher than the processing
temperature on a hot-melt extruder. This results from the smaller nozzle opening,
shorter residence time and absence of shear mixing in the printer head (Azad et al.,
2020).
During the printing process itself, the melt is subjected to relatively high shear
at the narrow print nozzle, and as a result, the shear rate dependency of the melt
viscosity is crucial (Turner et al.,
2014). This shear rate dependency is described by
the degree of (non-)Newtonian behaviour. In general, polymers utilized for HME
and FDM ideally display non-Newtonian shear-thinning behaviour, meaning their
viscosity decreases at higher shear rate. This behaviour is beneficial since it enables
the melt to be pushed through the nozzle while regaining its structural properties
after deposition on the build plate (Azad et al.,
2020). The viscosity of the melt after
deposition should indeed be sufficient to support the weight of the consecutively
deposited molten layers, which is problematic if the polymer has a too low viscosity
as was noted by Kempin et al. (
2018).
et al.,
2018) when attempting to print PEG 6000 (Kempin
2 Fused Deposition Modeling (FDM) of Pharmaceuticals 55
After forcing the polymer melt through the narrow print nozzle, the polymer
chains will relax elastically and die swelling will occur. Die swell means that the
road width of the molten strand will expand above the nozzle diameter. If this
expansion of the road width is considerable, it has a detrimental effect on the
resolution and topography of the printed object. The extent of die swell is a material
property depending on for example molecular weight (Ilyés et al.,
2019) and prior
knowledge might help to optimize process conditions in order to minimize this die
swell (Elbadawi,
2018; Aho et al., 2019).
Screening Tests
Different tests are available to characterize the thermal and rheological behaviour of
the melt. The glass transition temperature and melt temperature can be determined
using differential scanning calorimetry (DSC) or thermal gravimetric analysis
(TGA). The rheological behaviour of the material describes its resistance to flow
(Azad et al.,
2020) and can be investigated using various tests like a melt flow index
analyser, a capillary rheometer or rotational rheometer.
• Melt flow index analyser: A melt flow index analyser is a simple measurement
providing information about the amount of melt flowing out of a heated capillary
at a certain temperature but provides limited additional information (Samaro
et al.,
2020) and might not represent the true value of the viscosity especially for
polymers displaying considerable non-Newtonian behaviour (Aho et al.,
2015).
• Capillary rheometer: A capillary rheometer can provide more detail of the
polymer melt flow behaviour at a high shear rate regimen, although corrections
are needed to achieve true shear stress and viscosity values (Aho et al., 2015).
• Rotational rheometer: Rotational rheometers with a parallel-plate or cone-plate
geometry are the most popular rheological instrument. They can be run in either
rotation (steady-state rotational shear (SSRS)) or oscillation (small-amplitude
oscillatory shear (SAOS)) mode (Aho et al.,
2015). Dependency of the viscosity
on the applied shear can be investigated using SAOS experiments although
the high-shear regimen as assessed during 3D-printing cannot be attained.
Combining SSRS and SAOS experiments by means of the Cox–Merz principle
might deliver information of higher shear rate regimes up to 700 s
−1
.
(Azad et al.,
2020). Oscillatory frequency sweep experiments revealed that the viscosities
should be in the order of 10
3
.
Pa.s at the shear rate of printing (Elbadawi et al.,
2020). An oscillatory temperature sweep could also provide information about
the dependency of the viscosity on the processing temperature (Azad et al.,
2020).
In addition, polymers ideally display Maxwellian behaviour, which means the
polymer melt behaves mainly as a viscous liquid with negligible elasticity. To this
end, the behaviour of the storage and loss moduli in function of the angular shear
rate should be investigated. Maxwellian behaviour means the storage modulus (G
is directly proportional to the angular shear rate (w) at low frequencies and the
.
)
56 S. Henry et al.
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Fig. 2.5 Illustration of
printing failures associated
with high min/max ratio of
the viscosity (i.e.
non-Maxwellian behaviour)
with resulting tablet quality.
(Reprinted with permission
from Samaro et al. 2021)
elastic modulus (G. ") proportional to . w2. Non-Maxwellian behaviour means the
melt displays marked elasticity and the moduli are less dependent on the angular
shear rate. As a result of non-Maxwellian behaviour, the difference between the
minimal and maximal viscosities during the frequency sweep is high. As the shear
rate fluctuates rapidly during 3D-printing, this correlates with a high variation in
viscosity changes and resulting required pressure drop, a phenomenon that has
been associated with printing failures as can be seen in Fig.
2.5 (Samaro et al.,
2021; Serdeczny et al., 2020). Ambiguity exists in the literature, as sometimes
the
opposite was mentioned, stating non-Maxwellian behaviour being advantageous
(Cicala et al.,
In
conclusion, the interplay of thermal and rheological properties governs the
2018).
flowability of a certain feedstock material. A series of printing failures associated
with these properties with their screening test are mentioned in Table
printable
formulation ideally combines Maxwellian behaviour with acceptable flow
2.2.A
energy and viscosity at the printing temperature.
2.2.3.3 Stability
Storage conditions might alter printability of the filaments due to absorption
of moisture. As water acts as a plasticizer, it might render filaments suddenly
(un)printable or can alter drug–polymer interactions initiating for example recrystallization in an amorphous solid dispersion (Henry et al., 2021a; Macedo et al., 2020).
W
ater in the filament can also evaporate during the printing process generating air
bubbles which distort the object. Additionally, a large amount of water content could
also induce microbial contamination (Chaudhari et al.,
2021).
Some examples include the reporting by Tan et al. (2020) of brittleness in
h
ydroxypropyl cellulose filament if left unprotected from moisture (Tan et al.,
2020). Viidik et al. (2021) also stressed the need for proper storage of the feedstock
material
as they noted changes in crystallinity of indomethacin and theophylline
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