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2 Fused Deposition Modeling (FDM) of Pharmaceuticals 77
Fig. 2.20 A detailed overview of orally administered dosage forms. (Reprinted with permission
from Gioumouxouzis et al.
2019)
Weietal. (2020) constructed tablets containing carvedilol and haloperidol in a
polyvinyl alcohol matrix. Pereira et al. (
containing up to 4 different drugs for cardiovascular treatment (Pereira et al.,
2019) constructed a multi-layered tablet
2019).
Other innovative tablet designs include for example a two-compartment dosage
form, the DuoCaplet, which represents a smaller caplet containing paracetamol
within a larger one containing caffeine. The idea is to enable the production of a
controlled release tablet where the encapsulated drug is released after a certain lag
time needed to dissolve the outer layer (Goyanes et al.,
2015).
2.5.1.2 Paediatric Dosage Forms
Due to the flexibility in size and shape, FDM 3D-printing proves to be exceptionally
suited for the production of paediatric medicines. Scoutaris et al. (
2018)havedevel-
oped drug-loaded sweet-like chewable tablets (“Starmix”) utilizing indomethacinloaded HPMCAS filaments (Scoutaris et al.,
2018).
78 S. Henry et al.
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2.5.1.3 Targeting Specific Release
The flexibility of 3D-printing allows the exploitation of different tablet designs to
target a specific drug release profile, optimally suited for the proposed treatment
strategy. Investigated modifications of the tablet include the construction of a
specific porosity level, pore structure, surface area or polymeric composition.
Porosity
In comparison to direct compression, porosity and tablet dimensions are not correlated, as indicated by studies which reported the construction and characterization
of tablets with identical size but varying porosity (Kempin et al.,
2018; Henry et al.,
2021c). This enables the production of dosage forms with a wide variety of release
rates. For example, Henry et al. (2021) constructed dosage forms with an infill level
varying from 20% to 90%. This altered the time needed to dissolve 63.2% of the
API from 60 to 176 min (Henry et al.,
2021c). Another study noted a decline in
percentage of itraconazole released after 45 min from 96.9% to 80.9% when the
infill was decreased from 67.2% to 39.9% (Jamroz et al.,
2020).
Moreover, the porosity of FDM 3D-printed products can be freely chosen which
enables the production of hollow products. As a result, some studies have focused
on the development of gastro-retentive floating tablets (GRFTs) to enhance the
bioavailability of certain drugs. Giri et al. (
consisting of theophylline and hydroxypropyl cellulose (Giri et al.,
et al. (
2022) prepared floating tablets containing a drug-loaded core and hollow air
cell for the sustained release of venlafaxine (Zhao et al.,
2020), for example, developed a GRFT
2020). Zhao
2022). Vo et al. (2020)
developed floating tablets utilizing hydroxypropyl cellulose and vinylpyrrolidone
vinyl acetate containing cinnarizine (Vo et al.,
2020). Chai et al. (2017)have
developed a floating tablet containing hydroxypropyl cellulose to increase the
bioavailability of domperidone (Chai et al.,
2017).
Pore Structure
Next to the degree of porosity, the pore structure can also be tailored utilizing
different infill patterns. An example is given by Nukala et al. (
2019a), who compared
two infill patterns (hexagonal and diamond) and their effect on the mechanical
strength and dissolution kinetics. They found significant differences between the
patterns, even when the same level of infill was used (Nukala et al.,
2019a).
Surface Area
Another way to control the dissolution behaviour is tailoring the surface area of
the tablet. Viidik et al. (
2021) designed tablets with an outer honeycomb lattice to
increase the outer surface area and enhance the drug dissolution rate of theophylline
(Viidik et al., 2021). In another study, Prasad et al. (2019) have developed circular
and rectangular tablets with varying surface area to investigate the effect on
dissolution (Prasad et al.,
2019). Adaptations of the standard tablet design to achieve
a certain release behaviour are easily made by modification of the digital design.
2 Fused Deposition Modeling (FDM) of Pharmaceuticals 79
Fig. 2.21 Radiator-like oral solid dosage forms with varying inter-plate spacing to boost and
control drug release. (Reprinted with permission from Isreb et al.
2019)
Sadia et al. (2018) incorporated channels in the tablet to promote dissolution kinetics
by increasing the tablets’ surface area (Sadia et al.,
tablets have been prepared by Ayyoubi et al. (
(Ayyoubi et al.,
2021). Radiator-shaped tablets utilizing polyethylene oxides with
2018). Solid and channeled mini-
2021) to tailor the release of nifedipine
varying inter-plate spacing were produced to boost and tailor the release profile of
theophylline, as can be seen in Fig.
2.21 (Isreb et al., 2019). Tidau et al. (2019)
investigated the release from cylinders, rings and balls loaded with theophylline
(Tidau et al., 2019).
Polymeric Composition
Modifying the ratios between the components in a formulation or changing the
additives could also be employed to obtain a specific release pattern. Tan et al.
(
2020) developed a dosing platform containing theophylline with a polymeric
composition of hydroxypropyl cellulose, Eudragit RL PO and polyethylene glycol.
They stated that different sustained release properties could be achieved when the
ratio of these polymers was varied (Tan et al.,
dissolution behaviour was discussed by Shi et al. (
2020). Another approach to tailor
2021) as they developed a dosing
platform containing ibuprofen (20%), ethyl cellulose (60%) and a release modifier
(20%). The release modifier was either poly(vinyl alcohol), Soluplus, PEG 6000,
Eudragit RSPO, Eudragit RLPO, HPMC, Kollidon 17 PF, Kollidon 30 or Kollidon
VA64. The nature of the release modifier influenced the dissolution kinetics of the
model drug, hence controlling the zero-order release behaviour (Shi et al.,
2021).
2.5.1.4 Amorphous Solid Dispersion
Poorly soluble drug molecules are troublesome to formulate as they often display
poor bioavailability. Transforming t he formulation to an amorphous system, molecularly dispersed within its polymeric carrier could provide a solution. Hot-melt
extrusion and consequent FDM 3D-printing will provide the necessary energy to
overcome the crystal lattice energy of the drug (Kolter et al.,
was exploited by Omari et al. (
2022), who produced immediate release tablets
2012). This mechanism
of loratadine, a poorly soluble compound that was solubilized in hydroxypropyl
cellulose (Omari et al.,
2022). Parulski et al. (2022) could also produce stable (up
to 52 weeks) amorphous dispersions of itraconazole, a poor soluble compound, in
80 S. Henry et al.
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Fig. 2.22 Various designs of mini floating polypills for Parkinson’s disease. (Reprinted with
permission under the open access CC BY 4.0 license from Windolf et al.
2022)
a Kollidon VA64-HPMC matrix. The produced tablets showed a highly improved
dissolution rate (Parulski et al.,
2022).
2.5.1.5 Complex Oral Dosage Forms
The unlimited versatility of FDM 3D-printing can be used to construct a wide
variety of complex dosage forms. An example is the polypill developed by Windolf
et al. (
2022) as can be seen in Fig. 2.22. The floating pill contained levodopa,
benserazide and pramipexole for the treatment of Parkinson’s disease, addressing
both prolongation of levodopa absorption and personalization of the treatment
since the drugs possess a narrow therapeutic range (Windolf et al.,
2022). Another
example was the construction of abuse deterrent egg-shaped tablets (“egglets”) from
PVA by Nukala et al. (2019b), which could prevent snorting and injection abuse
(Nukala et al.,
2019b). Zhang et al. (2022) developed combi-pills of tranexamic acid
and indomethacin by coupling semi-solid syringe extrusion with FDM to achieve
both an immediate and a sustained-release profile with the same pill (Zhang et al.,
2022).
2.5.1.6 Print and Fill Technology
Certain oral dosage forms are produced using the “print and fill” technology
(Cailleaux et al.,
2021). An outer, hollow shell is printed using a commercially
available or self-made filament. During or after the printing process, it is filled
with a drug or other substance. For example, Markl et al. (
2017) constructed
hollow compartmental tablets of polyvinyl alcohol. Halfway through, the printing
process was stopped to enable manual filling with carbamazepine powder or selfnanoemulsifying liquids. After this filling step, the printing process was resumed
(Markl et al.,
2017). Linares et al. (2019) developed an automated sequence
combining FDM 3D-printing and injection volume filling to produce “Printfills”
as can be seen in Fig.
2.23. A porous structure is printed utilizing PLA, after which
the process is automatically stopped and the structure filled with a drug-loaded ink
consisting of a theophylline-loaded hydro-alcoholic gel (1% HPMC gel: ethanol
in a 25:75 ratio). Consequently, printing is resumed and a pH sensitive polymer
dispersion injected into the top layer (Linares et al.,
2019).
Stopping the process mid-print could however cause anomalies in the printed
structure as was noted by X
. μCT analysis (Markl et al., 2017). A solution could be
to only fill the print after its production is finished, as was demonstrated by Maroni
2 Fused Deposition Modeling (FDM) of Pharmaceuticals 81
Fig. 2.23 An illustration of how injection volume filling (IVF) and FDM 3D-printing can be
combined to create printfills (a). First, a porous structure is printed (b) which is automatically
filled with a drug-loaded ink (c). Next, 3 additional layers are printed on top of the drug-loaded
structure. Finally, the top layer is injected with a pH-sensitive polymeric dispersion to allow colontargeting (d) and the final printfill is obtained (e). (Reprinted with permission from Linares et al.
2019)
et al. (2017). They printed two hollow halves and joint structure. The hollow halves
were manually filled with acetaminophen or dye-containing Kollicoat powder.
Subsequently, the halves were manually assembled by means of the joint structure
in between. This joint structure enables the two hollow parts to form a closed device
but additionally also serves as separation between the two chambers. The produced
capsular devices hence contained different compartments which could possess other
thicknesses or compositions to produce two-pulse release patterns. Additionally, this
device could contain different APIs or formulations (Maroni et al.,
example is provided by Okwuosa et al. (
2018) who printed polymethacrylate shells
2017). Another
which were filled with a theophylline solution or dipyridamole suspension in a
single print step (Okwuosa et al.,
2018).
The print and fill technology can also be used to build additional functionalities
into the dosage forms as demonstrated by Palekar et al. (
2022) who devel-
oped aversion liquid-filled capsules (“3D-RECAL”). A capsule shell consisting of
metformin-loaded polyvinyl alcohol was printed and manually filled with aversion
liquid. The aversion liquid consists of pigment and starch in an oil base and its
presence within the capsule did not interfere with drug release. However, this
dark and viscous aversion liquid is released from the shell upon attempted solvent
extraction or manipulation, engulfing the drug particles and forming swollen and
non-snortable particles (Palekar et al.,
2022).
82 S. Henry et al.
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2.5.2 Transdermal and Transmucosal Films
FDM 3D-printing has also been used to produce transdermal and transmucosal
films, as an alternative to the traditional oral treatment. Investigated dosage forms
include fast-dissolving oral films, mucoadhesive buccal formulations, skin patches
or microneedle patches.
2.5.2.1 Fast-Dissolving Oral Film
Fast-dissolving oral films (FDFs) could improve customer acceptance by fast dissolution in the mouth without the need for water. Ehtezazi et al. (
2018) demonstrated
its potential by printing single- and multi-layered FDFs containing both tastemasking and drug layers (Ehtezazi et al., 2018).
2.5.2.2 Buccal Film
Mucoadhesive buccal films could achieve local and systemic delivery while avoiding passage through the gastro-intestinal tract and the first-pass effect. Eleftheriadis
et al. (
2020), for example, have prepared mucoadhesive films using hydroxypropyl
methylcellulose loaded with ketoprofen, for the local treatment of inflammation
associated with periodontitis. A back layer of ethyl cellulose was created to ensure
unidirectional release (Eleftheriadis et al.,
2020). Elkanayati et al. (2022)have
printed immediate-release buccal films consisting of xylitol and adipic acid in a
polyethylene oxide carrier to treat xerostomia or dry mouth (Elkanayati et al.,
2022).
2.5.2.3 Skin Patch
Skin patches could be an interesting alternative to oral treatment for drugs displaying bitter taste, poor solubility and/or instability in the gastro-intestinal tract
(Oliveira et al.,
2021). Chaudhari et al. (2021) have 3D-printed skin patches for
transdermal delivery from polyvinyl pyrrolidone containing amorphous quercetin
to increase its bioavailability. The patch contained an impermeable back layer of
Eudragit RS PO (Chaudhari et al.,
2021). Another example is montelukast, a drug
suffering from extensive first-pass metabolism resulting in limited bioavailability.
Azizo˘glu and Özer (
2020) have developed 3D-printed transdermal patches for skin
delivery of montelukast, aiming to increase its bioavailability (Azizo˘glu and Özer,
2020).
Alternatively, skin patches could be tailored in size and composition based
on the region of interest and necessary treatment. Anatomically adaptable wound
dressings containing the antimicrobial metals silver, copper and zinc were produced
by Muwaffak et al. (
2017). Another study reported the use of composite materials from PLA and
et al.,
2017) after 3D-scanning of the region of interest (Muwaffak
lignin which were utilized to produce meshes with antioxidant properties for wound
treatment (Domínguez-Robles et al.,
2019). Goyanes et al. (2016) have developed
anti-acne drug-loaded patches for topical delivery of salicylic acid utilizing 3Dscanning to construct a 3D-model based on the physical characteristics of a
volunteer. Both polylactic acid and polycaprolactone were investigated as printing
matrices (Goyanes et al.,
2016).
2 Fused Deposition Modeling (FDM) of Pharmaceuticals 83
Fig. 2.24 Microneedle patches for galantamine delivery at x24 magnification (a), x200 magni-
fication (b) and x335 magnification (c). (Reprinted with permission from Antonara et al.
2022)
2.5.2.4 Microneedle Patch
Microneedle patches contain small needles usually of a height below 1000 . μm.
They have been investigated for transdermal delivery of drugs to improve patient
compliance, reach constant systemic drug levels and reduce dosing frequency.
The needles will disrupt the stratum corneum, hence allowing diffusion of the
drug directly into the deeper skin layers and consequently the blood circulation.
Antonara et al. (
after which these were infused with a galantamine solution (Fig.
et al.,
2022). Wireless controlled devices for wound delivery of vascular endothelial
growth factor have been reported by Derakhshandeh et al. (
2022), for example, printed polylactic acid microneedle scaffolds,
2.24) (Antonara
2020), who produced
polymeric miniaturized needle arrays utilizing a desktop FDM printer. These arrays
were consequently loaded with the drug and placed into a programmable smart
bandage (Derakhshandeh et al.,
2020).
84 S. Henry et al.
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2.5.3 Implants
Implants might be preferred over oral formulations since they deliver the drug at a
specific site, hence potentially lowering the systemic concentration. As a result, side
effects are reduced and patient compliance increased. 3D-printing could enable the
production of tailored implants, with a shape modified to the needs of the patient
(Domsta and Seidlitz,
2021). Kempin et al. (2017) have demonstrated the use of
different polymers to create implants loaded with quinine. They obtained excellent
drug homogeneity within the constructed implants whereby the drug release rate
depended on the polymer or drug loading (Kempin et al.,
2017).
2.5.3.1 Antiplatelet Therapy
Antiplatelet vascular grafts containing dipyridamole have been prepared using
thermoplastic polyurethane. The grafts showed effective antiplatelet activity and
could provide sustained release for 30 days. Double-layered tubular grafts containing additional rifampicin with antimicrobial activity have also been prepared
(Domínguez-Robles et al.,
2022).
2.5.3.2 Anticonception
Intrauterine devices and subcutaneous rods with sustained release were produced
using indomethacin as model drug in ethylene vinyl acetate carriers (Genina et al.,
2016) or polycaprolactone (Holländer et al., 2016). Vaginal rings with personalized
shapes (O-, Y- or M-shaped) for controlled progesterone release have been produced
by Fu et al. (2018) as can be seen in Fig. 2.25 (Fu et al., 2018). Urethra pessaries
with personalized geometry to fit the anatomy of an individual vaginal cavity
were produced by Spoerk et al. (
2021), utilizing a novel polyester-based elastomer.
The mechanical properties could be changed based on the patient requirements by
adapting the in-silico model (Spoerk et al.,
2021). A biodegradable projectile made
from polylactic acid containing progesterone for contraception of wild life without
the need to restrain the animal was constructed by Long et al. (
2018).
2.5.3.3 Scaffold
Sustained release scaffolds containing ibuprofen were prepared by Yang et al.
2022) utilizing polycaprolactone. The addition of chitosan acted as a plasticizer
(
and induced the formation of channels within the implant, hence controlling diffusion rate (Yang et al.,
2022). Polycaprolactone scaffolds with gold nanoparticles
immobilized on their surface using plasma polymerization have been produced for
tissue regeneration by Joseph et al. (
2021).
2.5.3.4 Biodegradability
Most implants are constructed utilizing non-biodegradable polymers, hence necessitating surgical removal after completion of the therapy. Stewart et al. (
2020)have
2 Fused Deposition Modeling (FDM) of Pharmaceuticals 85
Fig. 2.25 CAD files (a–c) and 3D-printed (d–f) vaginal rings for progesterone release with
tailored “O”, “Y” and “M” shapes. A cross-section is depicted in figure J. Reprinted with
permission from Fu et al. (
2018)
developed different sizes of a biodegradable implant from either PVA or PLA after
which the implants were filled directly with a powdered model drug, ibuprofen.
They also investigated the effect of implant coating on the release characteristics
(Stewart et al.,
2020).
86 S. Henry et al.
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2.6 Challenges and Future Perspectives
Fused deposition modeling in pharmaceuticals could be a technique exploited in
Industry 5.0, a new industrial revolution anticipating to merge human creativity and
industrial accuracy to enable mass personalization. Smart additive manufacturing
(SAM) is one of the keystones of Industry 5.0 due to its potential for sustainable and cost-effective production. Applications of SAM and more specifically
FDM in healthcare could be prescription of personalized doses, manufacturing
of personalized implants, assistive technology, smart medical education or disaster management. However, before these techniques can be exploited to provide
decentralized manufacturing, the production life cycle will have to be digitized
and innovated. Development of cloud manufacturing platforms could enable access
control and intellectual property protection for designers, while the actual manufacturing occurs at a decentralized production site. Since fused deposition modeling
is a digitized, computer-based technique, a high level of security in data s torage
and handling is required to guard patient privacy. Authentication, integrity of
stakeholders, restricted access control and auditability of these digital processes
could mitigate this risk. Additionally, decentralized production requires optimized
supply chain management, which could be achieved by for example predictive
analytics anticipating disruptions (Kumar et al.,
Understanding and controlling all production process variables from digital
design to printed product is vital prior to implementation in healthcare. At the
moment, most pharmaceutical research focuses on the use of non-GMP desktop
printers from various brands in combination with different slicer programs like
Cura, Makerware or PrusaSlicer. These programs convert stereolithography files
to g-code, a sequence of instructions utilized by the printer. The conversion itself
might vary between different programs, utilizing a different user interface, model
settings and algorithms. Next to the program itself, different printer brands also
introduce variability. Changes in nozzle length, feed mechanism or filament diameter tolerance for example might influence processability and jeopardize standardized
results (Cailleaux et al.,
2021; Henry et al., 2021a). Another critical aspect related
to the design of a GMP printer is the importance of cleanability. In pharmaceutical
research, different cleaning protocols utilizing high temperatures, brass brushes,
immersion in solvents or flushing with cleaning polymers like cellulose-based
derivatives have been investigated (Henry et al.,
acceptable medical printer should have easily cleanable parts, should be made from
pharmaceutical grade material to avoid leachables in the drug product and should
be in cleanroom (Trenfield et al.,
2018). Application of the printing technique in
healthcare however necessitates the use of biocompatible starting material (Awad
et al.,
2018) and the development of pharmaceutical-class printers including the
use of inert contact parts, easily cleanable and enabling pharmaceutical process
validation checks (Crowley et al.,
2007).
At the moment, only a limited number of materials are suitable for pharma-
ceutical FDM 3D-printing due to constraints in terms of mechanical, thermal
2022).
2021a; Melocchi et al., 2016). An
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