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2 Fused Deposition Modeling (FDM) of Pharmaceuticals 57
Tab le 2 .2 Examples of printing failures observed due to flowability issues related to thermal and
rheological properties with their characterization test
Failure mode Observation Screening parameter Reference
Excessive
viscosity
Non-Maxwellian
behaviour
Excessive flow
energy
Insufficient
viscosity
SAOS. = Small amplitude oscillatory shear, .w = angular frequency (rad/s)
Nozzle blockage Dynamic viscosity Henry et al. (2021a)
(temperature sweep, SAOS)
(frequency sweep, SAOS) Elbadawi et al. (2020),
Melt flow index Samaro et al. (2020),
Poor print
quality
Insufficient flow Moduli .∼ w Henry et al. (2021a)
Print speed
limitation
Deposition of
droplets
Excessive
material
deposition
Melt flow index Alhijjaj et al. (2019)
Max/min. ratio (frequency
sweep, SAOS)
Arrhenius activation energy
(frequency sweep, SAOS)
Melt flow index Genina et al. (2016)
Complex modulus
(temperature sweep, SAOS)
Zhang et al. (2019), Novak
al. (2018)
et
Genina et al. (2016)
Samaro et al. (2021)
Henry et al. (2021a)
Lima et al. (2022)
when the filament was stored for three months at 40◦C and 75% relative humidity.
In comparison, filament stored in a refrigerator at 0% humidity displayed stability
over the whole investigated time frame (Viidik et al., 2021). Ayyoubi et al. (2021)
ha
ve shown recrystallization of nifedipine when a mini-caplet made from ethyl
cellulose was stored at higher humidity levels (Ayyoubi et al., 2021). In conclusion,
optimization
of storage conditions is vital to ensure stability of the produced
feedstock materials and reproducibility of the produced dosage forms.
2.2.3.4 Enhancing Printing Performance
The constraints placed on the materials compatible with FDM 3D-printing limit
the portfolio of processable pharmaceutical polymers. Several approaches have
been investigated to overcome these limitations. Firstly, adaptations of the feeding
mechanism might reduce the force applied on the filament resulting in less stringent
constraints on the mechanical properties. For example, the construction of a rigid
polylactic acid (PLA) guide combined with its use as a piston enabled printing
of very brittle polymers (Gottschalk et al., 2021). Another adaptation involved a
change
of the original, high-pressure gear wheels by smooth and toothless 3Dprinted ones as can be seen in Fig. 2.6, hence enabling the printing of brittle
materials
(Abdelhamid et al., 2022). Secondly, decreasing the pressure drop by
58 S. Henry et al.
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Fig. 2.6 Illustration of fractured feedstock material utilizing unmodified printer equipment (a)
with the original (b, left) gears in comparison with the adapted, toothless gears (b, right).
(Reprinted with permission from Abdelhamid et al. (
2022))
optimizing process temperature, nozzle size and production speed might enable
printing of troublesome materials (Henry et al.,
2021a; Koutsamanis et al., 2021)
Thirdly, blending of carrier polymers or the addition of processing aids might
dramatically influence the mechanical properties and flow behaviour of the melt
(Azad et al.,
2020), as will be discussed in the next section.
2.2.4 Alternative Feedstock Materials
The FDM or FFF technique requires filaments with acceptable mechanical and
optimal rheological properties which limit the materials compatible with this
technique (Henry et al.,
section might broaden the portfolio of printable materials, limitations still exist.
For example, Prasad et al. (
filaments containing 25–45 wt% paracetamol due to softness of the filaments
(Prasad et al.,
2019). Samaro et al. (2021) noticed print failures of ethylene-vinyl
acetate filaments with 9 or 25% vinyl acetate content due to a high initial viscosity
and a high viscosity variation in a frequency sweep (Samaro et al.,
Various efforts were made to develop innovative extruder heads for direct
extrusion additive manufacturing (DEAM), using alternative feedstock materials
like powder and pellets with less material restrictions. For example, Goyanes et al.
(
2019) utilized a FabRx single-screw powder printer (Fig. 2.7) to process amorphous
dispersions of itraconazole in different grades of hydroxypropyl cellulose (Goyanes
et al.,
2019). Boniatti et al. (2021) utilized the DEAM technology to produce
2021a). While the approaches mentioned in the previous
2019) noticed printing failures with Affinisol™15LV
2021).
2 Fused Deposition Modeling (FDM) of Pharmaceuticals 59
Fig. 2.7 FabRx direct single-screw powder extruder designed to enable single-step 3D-printing,
avoiding filament fabrication. (Reprinted with permission from Goyanes et al.
2019)
praziquantel-loaded Kollidon VA64 printlets from both powder, pellets and milled
™
pellets on the M3DIMAKER
Thommes (
2021) have developed a single-screw extruder head to successfully print
printer (Boniatti et al., 2021). Feuerbach and
pharmaceutical grade polymers in powder form, which were troublesome to process
on a traditional printer (Feuerbach and Thommes, 2021). Samaro et al. (2021)
investigated the use of DEAM using powder and pellets of ethylene-vinyl acetate
with 50% wt metoprolol tartrate. It was noticed that material flowability presented a
restricting factor for successful printing at higher drug loads (Samaro et al.,
2021).
The direct extrusion process using powders will have to overcome some challenges
like dealing with poor powder flowability, electrostatic forces, insufficient userfriendliness or difficulty in cleaning of all printer parts (Samaro et al.,
et al.,
2021). In addition, direct extrusion using pellets might suffer from non-
continuous flow with inconsistent pellet size (Boniatti et al.,
2021; Boniatti
2021). More in-depth
studies investigating a wider range of materials utilizing the DEAM technology are
certainly needed.
Triastek has developed a novel 3D-printing technique called melt extrusion
deposition (MED™), avoiding the need for filament production as it integrates a hotmelt extruder and 3D-printer to produce printed dosage forms in one step. Multiple
printing stations can be used to develop compartmental core-shell structured tablets,
a concept called 3D-printing formulation by design (3DPFbD) (Zheng et al.,
2021).
A similar approach to the melt extrusion deposition was utilized to produce tablets
containing mefenamic acid dispersions in Soluplus (Prasad et al., 2020).
Another printing technique, Arburg plastic freeforming or droplet deposition,
combines principles from both material extrusion and material jetting and has
recently been used to produce pharmaceutical dosage forms. The starting material
60 S. Henry et al.
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can either be pellets or dried granules produced by wet granulation methods
(McDonagh et al.,
dapivirine-releasing vaginal rings from polyurethanes (Welsh et al.,
2022). The technique has successfully been used to produce
2019), tablets
containing hypromellose acetate succinate, polyethylene oxide and paracetamol
(Zhang et al.,
(McDonagh et al.,
2021) and printlets from Eudragit EPO loaded with paracetamol
2022).
2.3 Materials Used in Fused Deposition Modeling 3D-Printing
The starting material for a pharmaceutical FDM process is a drug-loaded filament,
generated by either filament impregnation or extrusion. Filament impregnation
incorporates the drug or active pharmaceutical ingredient (API) into commercially
available polymeric carriers by means of soaking the carrier into a saturated API
solution or dispersion before printing (Tagami et al.,
performed to load drugs directly into printed, polymeric tablets (Beck et al., 2017).
However, the impregnation method suffers from numerous drawbacks like the use
of toxic solvents, limited drug loading capacity and long duration of the process
(Shaqour et al.,
2020).
A major advantage of hot-melt extrusion is the fact that the use of solvents or
water is optional (Crowley et al.,
2007). Therefore, most reported studies employ
hot-melt extrusion (HME) to transform a polymer/drug mix into a printable filament
(Shaqour et al.,
2020). Either powder or pellets are selected as staring material and
fed to the extruder, where heat is utilized to melt the material. A ram or screws are
used to push the material towards a die, as illustrated in Fig. 2.8. Ram extrusion
utilizes a movable arm or ram to generate pressure and push the product through
the die of the hot-melt extruder (Kempin et al.,
extrudates with highly consistent diameter but generally suffers from poor mixing
capability.Screw extrusion, on the other hand, utilizes a single or twin rotating screw
and generates more shear stress, resulting in more intense mixing (Crowley et al.,
2007). In pharmaceutical production processes, the use of a twin screw extruder is
generally preferred over a single screw since the latter provides less mixing. Hence,
employment of a single-screw extruder necessitates excellent homogenization of
the powder blend using for example grinding and mixing, solvent casting or melt
mixing (Shaqour et al.,
2020; Martin, 2016; Goyanes et al., 2015). Twin screws can
have a non-intermeshing or intermeshing set-up made for co- or counter-rotation
and are generally modular with different sections facilitating feeding, melting and
metering. The possibility to change the screw design enables selecting appropriate
process conditions based on the product requirements (Crowley et al.,
FDM 3D-printing is a volume-controlled production technique, and hence a
consistent and correct diameter of the filament feedstock is crucial to fabricate
dosage forms with controlled and consistent mass (Macedo et al.,
to maximize diameter consistency when employing a twin screw extruder, process
settings should be optimized to minimize pressure fluctuations and maximize the
barrel filling degree (Ponsar et al.,
2020; Chamberlain et al., 2022). Additionally, a
2019). The same approach was
2017, 2018). This method generates
2007).
2022). In order
2 Fused Deposition Modeling (FDM) of Pharmaceuticals 61
Fig. 2.8 Illustration of an extrusion set-up utilizing powdered or pelletized starting material to
create drug-loaded filaments which are consecutively used in FDM 3D-printing. (Reprinted with
permission from Cailleaux et al.
2021)
melt pump between barrel and die might optimize filament diameter consistency by
stabilizing melt fluctuations (Quodbach et al., 2021; Fuenmayor et al., 2018). The
production of a filament with a correct diameter might be impaired by a process
called die swell. Most polymers undergo die swell upon leaving the extruder die
since the polymer chains are compressed and forced through this narrow die, after
which the melt relaxes and swells to a larger-than-desired diameter. The extent of
die swell depends on the process settings of the extruder and on the viscoelastic
material characteristics of the specific polymer. Die swelling can be reduced by
decreasing the shear to which the polymer is subjected for example by increasing
the die temperature. In most cases, however, a self-winding roller is placed after the
die to wind and stretch the melt in order to achieve a correct diameter (Quodbach
et al.,
2021; Samaro et al., 2020).
2.3.1 Carrier
Most research focuses on the use of polymer-based excipients for FDM 3D-printing.
Hence, the properties of the formulation are often mainly determined by the material
properties of the polymer in which the API is embedded. The most commonly
used polymers in FDM 3D-printing are listed below with comments on their
processability and possible applications. Blends of different polymers are often
62 S. Henry et al.
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made to enhance the mechanical properties of the resulting filament or to modify
its release behaviour (Shi et al.,
2021).
Other feedstock materials have also been investigated, like lipid-based excipients
which presented technical challenges due to their brittle nature (Abdelhamid et al.,
2022) or novel polyester-based thermoplastic elastomers (Koutsamanis et al., 2021).
2.3.1.1 Cellulose Derivatives
Cellulose derivatives like hydroxypropyl methyl cellulose (HPMC), hydroxypropyl
cellulose (HPC), ethyl cellulose (EC) and hydroxypropyl methyl cellulose acetate
succinate (HPMCAS) are commonly used in FDM 3D-printing as they are biocompatible and generally possess favorable mechanical properties. The material
properties and solubility of these derivatives strongly depend on the type of
modification and substitution degree of the polymer (Zamboulis et al.,
et al.,
2020). Ethyl cellulose for example is insoluble in water and hence could
2022; Azad
be used for sustained-release products. On the other hand, HPMC swells when
in contact with water, resulting in a drug release mechanism relying on diffusion
through the swollen layer in combination with erosion of the hydrated polymer
(Pereira et al.,
2020).
Cellulose derivatives are particularly popular to produce zero-order release
gastroretentive floating devices. For example, Giri et al. (
2020) utilized HPC in
combination with theophylline to create tablets with a floating capability of up to
10 h (Giri et al.,
2020). Zhao et al. (2020) created a floating tablet with air chambers,
utilizing HPMC to create a drug-loaded core surrounded by an insoluble shell of
polylactic acid containing an air chamber as can be seen in Fig.
2.9 (Zhao et al.,
2022).
Fig. 2.9 Intragastric floating sustained-release tablets consisting of a drug-loaded core utilizing
hydroxypropyl cellulose. Different sizes in air chambers resulted in different release windows of
the drug. (Reprinted with permission from Zhao et al.
2022)
2 Fused Deposition Modeling (FDM) of Pharmaceuticals 63
Additionally, cellulose derivatives are also often used in combination with
other, difficult-to-feed pharmaceutical polymers to enable processing in the FDM
apparatus. For example, Vo et al. (
2020) combined polyvinyl pyrrolidone vinyl
acetate (Kollidon VA64) with HPC to enable printing of a cinnarizine-loaded
floating tablet (Vo et al.,
and Eudragit polymers when combined with HPC (Than et al.,
2020). Than et al. (2022) could successfully print Soluplus
2022).
2.3.1.2 Ethylene Vinyl Acetates
Ethylene vinyl acetates are copolymers of ethylene and vinyl acetate monomers,
where the content of vinyl acetate monomers (1–40%) mainly determines the
chemical and physical characteristics of the resulting polymer (Schneider et al.,
2017). This is especially important for FDM 3D-printing, as it has been shown that
EVA grades with a high VA content are too flexible for successful printing (Samaro
et al.,
2021; Genina et al., 2016). EVAs are biocompatible and non-water soluble
hence making them ideal polymeric carriers for the development of sustained release
dosage forms like implants (Schneider et al.,
2017).
2.3.1.3 Kollicoat IR
Kollicoat IR is a co-polymer of polyethylene glycol and polyvinyl alcohol which is
freely soluble in water. As a result, produced dosage forms display an immediate
release behaviour (Kolter et al.,
2012). The feedstock can easily be printed and
successful printing with solid loads of up to 40% has been reported (Samaro et al.,
2020).
2.3.1.4 Polycaprolactone
Polycaprolactone is a biocompatible and biodegradable polyester which is commonly used in 3D-printing. It is easily printable and has been used in many studies
in combination with drugs like indomethacin or theophylline (Viidik et al.,
or with polymers like poly(lactic acid) (Fu et al.,
2018). Drug release occurs
2021)
via diffusion, making it a suitable carrier for sustained release applications like
intrauterine devices as can be seen in Fig.
Fig. 2.10 Intrauterine
devices constructed via FDM
3D-printing of
indomethacin-loaded
polycaprolactone filaments.
(Reprinted with permission
from Holländer et al.
2016)
2.10 (Holländer et al., 2016).
64 S. Henry et al.
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Fig. 2.11 Illustration of different tablet shapes created either from polyethylene oxide (MW
100,000) in formulations PEO15 and PEO15-P or from HPMC with added PEG (MW 8000) in
formulations HPMC15, HPMC35 and HPCM50. (Reprinted with permission under the open access
CC BY 4.0 license from Tidau et al.
2019)
2.3.1.5 Polyethylene Oxide
Polyethylene oxide (PEO) is a linear polymer made from ethylene oxide monomers.
Low molecular weight PEOs (
. <20,000 Da) are generally referred to as polyethylene
glycol (PEG) and are often added to a formulation to act as plasticizers or pore
formers. PEGs have been successfully combined with for example polycaprolactone
(Elbadawi et al.,
2020) or cellulose derivatives (Omari et al., 2022). Higher
molecular weight PEOs can be used as such for extrusion and printing but are
generally only processable at molecular weights above 100,000 Da since polymers
with a lower molecular weight show brittle behaviour (Ehtezazi et al.,
et al.,
2019). For example, Fig. 2.11 presents a case where PEGs have been added
2018; Isreb
to hydroxypropyl methylcellulose to enable printing, while PEO has been used
separately to construct tablets (Tidau et al.,
2019).
PEOs possess a rather low melting point in the range of 60 to 70◦C. The resulting
filaments are slightly hydrophilic and they form a gel layer upon contact with water.
The resulting release behaviour might be zero order or immediate, depending on the
molecular weight and tablet design (Isreb et al.,
2019; Tidau et al., 2019).
2.3.1.6 Polylactic Acid
Polylactic acid is a biocompatible and biodegradable polyester commonly used
for FDM 3D-printing due to its favorable mechanical properties. Drug dissolution
generally occurs via diffusion from the polymer matrix (Cerda et al.,
is commercially available and has been used to produce dosage forms which
were subsequently loaded with drugs using the impregnation method. Wu and
Hong (
2019) for example have printed porous PLA scaffolds which were later on
crosslinked with silver nanoparticles to create antibacterial hydrogels for wound
treatment (Wu and Hong,
2019). Cerda et al. (2020) have used passive diffusion of
nifedipine in commercially bought PLA to print oral dosage forms (Cerda et al.,
2020).
2020). It
2 Fused Deposition Modeling (FDM) of Pharmaceuticals 65
2.3.1.7 Polymethacrylates
Polymethacrylates are synthetic polymers consisting of dimethylaminoethyl
methacrylates, methacrylic acid and methacrylic acid ester monomers. A wellknown brand is Eudragit, comprising a portfolio of methacrylates with varying
substitutions which can be neutral, anionic or cationic. They have been used as
matrix excipients for immediate, delayed and controlled release (Dos Santos et al.,
2021). While these polymers are popular in FDM 3D-printing, they are too brittle
and need plasticizers or blending with other polymers to enable feeding (Sadia
et al.,
2018; Henry et al., 2021b).
2.3.1.8 Polyurethanes
Polyurethanes are synthetic polymers consisting of isocyanates and polyols using
urethane linkages as polymer backbone. The chemical nature of the building blocks
will determine their mechanical properties which can vary greatly. Polyurethanes
are biocompatible and non-water soluble, and hence they have been used to produce
sustained release implants (Domínguez-Robles et al.,
polyurethanes are not approved for oral administration, although different studies
have highlighted its compatibility with the FDM 3D-printing technique and its
potential in the production of oral solid dosage forms (Verstraete et al.,
et al.,
2021a).
2022). At the moment,
2018; Henry
2.3.1.9 Polyvinyl Alcohol
Polyvinyl alcohol (PVA) is a semicrystalline material composed of linked vinyl
alcohol monomers. The polymer is water soluble and hence used to formulate
immediate release tablets. The resulting filament is printable but generally brittle
when combined with higher contents of crystalline drugs (>20%) requiring plasticizers to enable processing (Nukala et al.,
the filament is hygroscopic and susceptible to moisture uptake, which renders the
filament more flexible (Macedo et al.,
a filament with a consistent diameter. Drug loading is therefore often achieved
utilizing passive diffusion as reported for example by Ayyoubi et al. (
impregnated PVA filament with a nifedipine-ethanol solution prior to printing mini
tablets (Ayyoubi et al.,
2021).
2019a; Macedo et al., 2020). Moreover,
2020). PVA is commercially available as
2021)who
2.3.1.10 Polyvinyl Pyrrolidone
Polyvinyl pyrrolidone (povidone) represents a class of water soluble polymers
consisting of linked vinylpyrrolidone monomers. As these polymers are freely water
soluble, they are designed for immediate release dosage forms. Co-polymers of
povidone and vinyl acetate (e.g. Kollidon VA64) have also been used in 3D-printing.
The vinyl acetate moiety is water insoluble, but the ratio of monomers still enables
free dissolution of the resulting co-polymer (Kolter et al.,
Both povidone and its co-polymer are rather brittle with limited feedability,
hence requiring the addition of plasticizers (Kollamaram et al.,
with other polymers (Shi et al.,
2021). Moreover, the hygroscopicity of these
2012).
2018) or blending
66 S. Henry et al.
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formulations necessitates correct storage to avoid stability issues of the resulting
filaments (Henry et al.,
2021b).
2.3.1.11 Soluplus
Soluplus is a polyvinylcaprolactam –polyvinyl acetate– polyethylene glycol copolymer. Due to its amphiphilic behaviour, it is capable of solubilizing poorly
soluble drugs to increase their bioavailability while displaying an immediate release
behaviour (Kolter et al.,
requires the addition of a plasticizer (Melocchi et al.,
2012). Soluplus is too brittle to enable direct printing and
2016).
2.3.2 Active Pharmaceutical Ingredient
The active pharmaceutical ingredient (API) drives the choice of carrier polymer and
process conditions since shear and thermal degradation should be avoided. HME
and FDM are both anhydrous production processes, avoiding hydrolytic degradation
pathways of the API (Crowley et al.,
be challenging to process via HME and/or FDM 3D-printing, as was shown by
Weietal. (
2020) who noticed sublimation of carvedilol upon production of 3D-
printed tablets with polyvinyl alcohol (Wei et al.,
polymeric carrier could however enable processing of thermo-sensitive drugs as was
proven by Kempin et al. (2018) who could effectively utilize pantoprazole s odium
at temperatures below 100
◦
C (Kempin et al., 2018).
The API might be dissolved, dispersed as undissolved particles or a combination
of both within the carrier matrix depending on the chemical, thermal and physical
properties of both the drug and the carrier. The created system greatly influences the
stability and processability of the resulting formulation. In general, a dispersion
could be favorable due to its superior stability, while a solution system could
enhance the bioavailability of the drug. The Hansen solubility parameters are a
way to predict drug–polymer miscibility and hence which system will be generated
(Kolter et al.,
2012). Solanki et al. (2018) for example have prepared an amorphous
solid dispersion (ASD) of the poorly soluble haloperidol for processing via 3Dprinting, this resulted in complete drug release at higher pH (Solanki et al.,
In another study, Chaudhari et al. (
filaments to produce skin patches with improved solubility (Chaudhari et al.,
The presence of crystalline drugs in the feedstock filament might hamper
printability. First of all, the presence of crystalline particles within the carrier might
interfere with the mechanical properties of the blend and hence the compatibility
with the printers’ feeding gears. Both an increase and a decrease of the feedability
have been mentioned based on drug content (Palekar et al.,
2020). Secondly, crystalline drugs might alter the rheological properties of the melt.
Than et al. (
2022) found that a higher theophylline content drastically increased
the viscosity of the formulation, requiring a higher process temperature since the
drug was not dissolved within the polymeric carrier and acted as a crystalline
filler (Than et al.,
2022). Thirdly, large clusters of crystalline material might block
2007). Thermo-sensitive drugs might however
2020). A careful selection of the
2018).
2021) have made amorphous quercetin-PVP
2021).
2022; Samaro et al.,
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