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3 Stereolithography (SLA) in Pharmaceuticals 107
diameter. Compared to solid geometries, the torus allows for higher surface area and
hence superior drug release performance. SLA 3D printing is traditionally restricted
to fabricating objects using a single material per printing operation because the
vat can only contain a single resin at one time. Fixed dosage combination (FDC)
products containing at least two different active pharmaceutical ingredients are
especially attractive for poly-medicated patients given that adherence is enhanced
and pill burden is reduced (Fernández-García et al.
2020). However, the combination
of multiple drugs within the same pill can bring a multitude of physicochemical
and pharmacodynamic interactions. Researchers in the pharmaceutical domain
have devised techniques to allow the fabrication of pills with different material
formulations. Curti et al. modified a Formlabs Form 2 3D printer to 3D print with
up to 12 different materials (Fig.
required for printing by 20-fold (Curti et al.
3.6), reducing the volume of minimum resin
2021). This innovative setup allowed the
high throughput screening of 156 photopolymer formulations which improved the
turnaround time by 91.7% and cost by 95%. This is important given the relatively
high cost of synthesizing even modest volumes of pharmaceutical grade photopolymer formulations. The fabrication of a single excipient with 6 different drug-loaded
materials (polypill) (Xu et al.
2020) was performed using a Formlabs Form 1+
3D printer with the OpenFL version of PreForm and manual swapping of the vat
by pausing the print job. The 6 drugs included paracetamol, caffeine, naproxen,
chloramphenicol, prednisolone, and aspirin (Fig.
fabricated a polyprintlet with 4 different hypertensive drugs (Xu et al.
3.7). A different research group
2020). The 4
hypertensive drugs included irbesartan, atenolol, hydrochlorothiazide, and amlodipine (Fig.
3.8). An unexpected Michael addition between the diacrylate group of the
photoreactive monomer and the primary amine group of amlodipine was confirmed
Fig. 3.6 (a) The original Form 2 SLA 3D printer and (b) the novel setup which allows testing
with up to 12 different photopolymer formulations, simultaneously. Reproduced from (Curti et al.
2021)
108 P. Ravi and P. Patel
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Fig. 3.7 A polypill with 6 different drug-loaded regions in cylindrical and ring geometries.
Reproduced from (Robles-Martinez et al.
2019)
Fig. 3.8 Scanning electron microscope cross-sectional image of the polyprintlet loaded with (top
to bottom) amlodipine, atenolol, irbesartan, and hydrochlorothiazide. Reproduced with permission
from (Xu et al.
2020)
in the hypertensive drug-loaded polyprintlet using FTIR and NMR spectroscopy.
This intriguing finding highlights the importance of carefully selecting photocurable
resins for the manufacture of drug-loaded oral dosage forms. The compatibility of
photocurable resins and drugs should be ensured via rigorous studies to avoid such
unwanted chemical reactions that could potentially have a detrimental effect on the
patient (Seoane-Viaño et al.
2021).
Tablets with multiple drugs may improve patient compliance because of the
reduced pill burden and may yield superior clinical outcomes for the patients. For
instance, patients with end-stage renal disease undergoing dialysis often have other
comorbidities such as diabetes or hypertension and can be required to take multiple
pills throughout the day which can reduce compliance, thereby negatively affecting
patient outcomes. Karakurt et al. encapsulated ascorbic acid in a poly(ethylene
glycol) dimethacrylate-based polymer network with riboflavin as a photoinitiator
and 3D printed co-axial annulus with 4-circle and honeycomb pattern geometries
with surface area to volume ratios of 0.6–1.83 using an Anycubic Photon 3D printer
3 Stereolithography (SLA) in Pharmaceuticals 109
(Karakurt et al. 2020). The fluorinated ethylene polypropylene (FEP) membrane
separating the liquid photopolymer from the LCD masking screen was replaced with
a 2 mm thick glass due to sticking and ripping of hydrogel on the FEP. Krobabic
et al. used a Wanhao Duplicator 7 DLP 3D printer for fabricating cylindrical
tablets that were 8 mm diameter and 2 mm thick using atomoxetine hydrochloride
(ATH) photoreactive suspensions. PEGDA 700 and poly(ethylene glycol) PEG
400 (base polymers), DPPO (photoinitiator) and atomoxetine hydrochloride (active
ingredient) photoreactive suspensions were used. The print time was 11–13 min
for 5 tablets which highlights the much lower throughput compared to industrial
manufacturing. Stanojevic et al. applied artificial neural network (ANN) with DLP
3D printing to tailor ATH release from immediate to prolonged by varying the
drug loading and tablet thickness (Stanojevi´cetal.
2020). The ANN model was
developed to predict the ATH release rate. The model drug was ATH because it is
employed in a range of doses within children with attention-deficit hyperactivity
disorder (ADHD) making it a fitting candidate for personalized therapy. In their
research, PEGDA (52.4–63.7% w/w) with PEG400 (17.5–21.2% w/w), water (10%
w/w), DPPO photoinitiator (0.10% w/w), and ATH (5–20% w/w) was used as resin
on a Wanhao Duplicator 8 DLP 3D printer with Chitubox software, a communitybased slicing software. A summary of the SLA-based 3D printers utilized and
pharmaceutical research and the drug excipients printed are provided in Tables
3.1
and 3.2.
In addition to primarily rigid pills and excipients, elastic devices loaded with
lidocaine hydrochloride (Fig.
delivery (Xu et al.
2021b). Elastic resin was used to fabricate the bladder device,
3.9) were also fabricated for targeted bladder drug
and lidocaine hydrochloride was mixed into the resin in 3 ratios—10%, 30%, and
50% w/w. Common drug compounds such as paracetamol, caffeine, naproxen,
chloramphenicol, prednisolone, and aspirin have been successfully used to fabricate
pills using SLA 3D printing. Additional compounds including 4-ASA, aspirin,
ibuprofen, ascorbic acid, atenolol, hydrochlorothiazide, irbesartan, amlodipine, capsaicin, theophylline, and sulforhodamine B tablets have also been used to fabricate
oral dosage forms using DLP or SLA 3D printing (Xu et al.
2021a). Frequently,
PEGDA is used as the prepolymer with which other materials are mixed or into
which the drug compound is loaded (Ravi et al.
2019). Relatively low-cost desktop
SLA 3D printing systems such as the Formlabs Form1+, Form 2, Form 3/3B,
the Anycubic Photon, the Wanhao Duplicator 7/8, etc. are most frequently used
by researchers due to the vast user-base and online support from the communitybased sharing of knowledge related to 3D printing using these machines. Martinez
et al. fabricated tablets with multiple geometries such as a cube, disc, pyramid,
sphere, and torus using SLA 3D printing, and it was found that tablets with a
constant surface area to volume ratio release drug at the same rate, whereas tablets
with constant surface area but different volumes released drug at different rates
(Martinez et al.
2018b). The group used PEGDA 700 as monomer, diphenyl(2,4,6-
trimethylbenzoyl) phosphine oxide (TPO) as photoinitiator, and paracetamol as
model drug with a Formlabs Form 1+ 3D printer. To overcome very slow and
incomplete drug release from tablets fabricated by DLP 3D printing, Krkobabic et
110 P. Ravi and P. Patel
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´
cetal.(2019), Madzarevic et al. (2019)
2020), Sharma et al. (2022)
(
al.
2017); Wang et al. (2016); Tan and Ho (2019), Xu et al.
Economidou et al. (2019), Healy et al. (2019), Uddin et
(2020), Xenikakis et al. (2019)
Krkobabi
Lim et al. (2017)
Caudill et al. (2018), Bloomquist et al. (2018)
) Software References
3
Light Wavelength Power (W) Build volume
SLA 3D printer source (nm) Power (W) (L × W × H;mm
Tab le 3 .1 Major resin 3D printers used in pharmaceutical research applications and their characteristics
Form 1+ Laser 405 0.1 125 × 125 × 165 Preform Robles-Martinez et al. (2019), Martinez et al. (2018b,
Workshop X
Workshop
Envision Labs
software
405 40 115 × 65 × 155 Photon Slicer Karakurt et al. (2020)
DLP 405 30 120 × 68 × 180 Creation
DLP 405 Unknown Unknown Unknown Kadry et al. (2019)
Mask
SLA
SLA 405 0.02 Unknown Unknown Konasch et al. (2019)
Form 2 Laser 405 0.25 145 × 145 × 175 Preform Xu et al. (2021b, 2021c), Pere et al. (2018),
Wanhao
Duplicator 7
Custom DLP
printer
Anycubic Photon
3D
Custom-hybrid
DLP 385 Unknown Unknown FabRx Rodríguez-Pombo et al. (2022)
SLA and inkjet
printer
Volumetric DLP
printer
Pico 2 HD DLP 405 30 71.1 × 40 × 75 Asiga Composer Lim et al. (2021)
Titan 1, Kudo 3D DLP 405 30 191 × 109 × 254 Creation
DLP 365 200 Unknown Unknown Lu et al. (2015)
Custom DLP
CLIP 385 nm Unknown Unknown Carbon printing
printer
Carbon3D M1 CLIP Proprietary Proprietary 141 × 79 × 326 Slic3r Johnson et al. (2016)
S1 CIP Prototype
printer (Carbon)
3 Stereolithography (SLA) in Pharmaceuticals 111
et
(continued)
(2016)
Form 1+ Wang et al.
microscopy (ESEM), X-ray powder
diffraction (XRPD), drug
Tabl et s Environmental scanning electron
Form 2 Pere et al.
concentration using HPLC,
Dissolution
Microneedle Scanning electron microscopy (SEM),
(2018),
Economidou
al. (2019)
Form 1+ Martinez et al.
Circular Dichroism (CD) analysis,
Raman Analysis, MN penetration,
HPLC
Tabl et s SEM, drug loading using HPLC, drug
(2018b)
release, surface area to volume ratio,
swelling
et al. (2019)
Form 1+ Robles-Martinez
Diffraction (XRPD), drug loading
using HPLC, drug release, Swelling
ratio
Tabl et s Raman Spectroscopy, X-ray Powder
(2019)
Form 2 Healy et al.
DSC, Drug release, SEM, Statistical
Tabl et s UV/Vis Spectrophotometry, FTIR,
analysis
Polymer and excipients Drug delivery Characterization techniques 3D printer References
Poly(ethylene glycol) diacrylate,
Active
pharmaceutical
ingredient
Tab le 3 .2 Summary of SLA pharmaceutical 3D printing research
Paracetamol
Poly(ethylene glycol) 300,
diphenyl(2,4,6-
4-Aminosalicylic
acid
trimethylbenzoyl) phosphine oxide
Xylitol,
Mannitol,
Insulin Dental SG resin
Trehalose
(PEGda),
diphenyl(2,4,6-trimethylbenzoyl)
Paracetamol Polyethylene glycol diacrylate
phosphine oxide (TPO)
Polyethylene glycol diacrylate
(PEGda),
diphenyl(2,4,6-trimethylbenzoyl)
Paracetamol,
acetylsalicylic
acid, naproxen,
phosphine oxide (TPO)
chloramphenicol,
Poly(caprolactone) Triol, (PCL
caffeine
prednisolone
Paracetamol,
Triol), Polyethylene glycol
diacrylate (PEGda),
aspirin
diphenyl(2,4,6-trimethylbenzoyl)
phosphine oxide (TPO)
112 P. Ravi and P. Patel
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´
cetal.
(2022)
Madzarevic et al.
(2019)
Kadry et al.
(2019)
Karakurt et al.
(2020)
Krkobabi
(2019)
4100
™
and Omnicure
Form 2 Sharma et al.
Wanhao Duplicator
7
Custom DLP
printer with DLP ® Discovery
s2000 UV source
Form 1+ Xu et al. (2020)
Anycubic Photon
3D
Form 2 SLA Xu et al. (2021b)
Wanhao Duplicator
7
Active
pharmaceutical
Tab le 3 .2 (continued)
chromatography, calipers, friability,
hardness, FTIR, swelling, SEM
Tabl et s Dynamic light scattering,
Polymer and excipients Drug delivery Characterization techniques 3D printer References
TPO
ingredient
Berberine PEGDA, polyethylene oxide (PEO),
apparatus, DSC, Artificial neural net,
kinetic models of drug release
Ibuprofen PEGDA, PEG, Riboflavin Tabl et s UV–Vis spectroscopy, dissolution
water content, drug content,
dissolution apparatus,
Tablets/printlts FTIR, SEM, hardness, swelling ratio,
-(2-hydroxyethoxy)-2-
methylpropiophenone
2-Hydroxy-4
Theophylline PEGDA, PEGDMA,
Nuclear magnetic resonance (NMR)
spectroscopy, dissolution apparatus
Tablets/printlets SEM, XRPD, DSC, HPLC, FTIR,
Hydrochlorothiazide, PEGDA, TPO,
PEG300
Irbesartan,
atenolol,
hydrochloroth-
iazide and
SEM, NMR, UV–vis
spectrophotometry, Diffusion
tablets
amlodipine
Ascorbic acid PEGDA, riboflavin, triethanolamine Hydrogel
apparatus
DSC, XRPD, micro-CT, SEM, drug,
HPLC, dissolution apparatus,
device loaded
Elastic resin from Formlabs Drug delivery
Lidocaine
hydrochloride
mechanical testing, hemolysis
assessment, statistical analysis
with drug
Tabl et s Drug loading using UV/VIS, tensile
Paracetamol PEGDA, PEG400, DPPO, Nacl,
strength, drug release, kinetic
modeling and drug dissolution,
particle size, SEM, DSC, FTIR
Mannitol
3 Stereolithography (SLA) in Pharmaceuticals 113
(continued)
(2017)
Form 1+ Martinez et al.
Form 2 Xu et al. (2021c)
Drug loading, Swelling ratio, water
content, DSC, dissolution apparatus
loading, dissolution, drug release
kinetic profile, drug stability,
statistical analysis
Hydrogel
tablets
Konasch et al.
(2019)
Rodríguez-
Custom-hybrid
SLA and Inkjet
printer
Volumetric 3D
Single and multiple deposition of ink,
diffusion of ink, DDS (drug delivery
system)
tablets
Printlets ESEM, DSC, XRPD, Micro-CT,
Pombo et al.
(2022)
Lim et al. (2021)
printer with
multiple projections
Pico 2 HD from
Asiga
FTIR, HPLC, Dissolution apparatus
drug release, mechanical strength,
Microneedles Rheology, swelling ratio, cytotoxicity,
skin penetration of MNs, in vitro
cellular cytotoxicity, statistical
analysis
(2019)
(2020)
Form 1+ Xenikakis et al.
Form 2 Uddin et al.
vitro permeation, SEM
(OCT), in vitro drug release, atomic
absorption spectroscopic analysis,
skin penetration, cytotoxicity, tumor
development, in vivo antitumor
efficacy
Ibuprofen PEGDA, PEG300, Riboflavin,
TEOHA, DPPO
Ibuprofen PEGDA, PEG400, TPO Ta bl ets Tensile strength, XRD, SEM, drug
PEGDA, LAP, Drug depots in
Bovine serum
albumin
Paracetamol PEGDA 575, PEGDA 700, PEG
300, LAP
BAPO,
AHP-3 PEGDA, vinyl pyrrolidone (VP),
Commercial resin Microneedles Compression test, skin penetration, in
Model dyes (no
drug)
Cisplatin Class I biocompatible resin Microneedles SEM, optical coherence tomography
114 P. Ravi and P. Patel
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Titan 1 Lim et al. (2017)
penetration,
in vitro biocompatibility of resin,
Lu et al. (2015)
Custom DLP
HPLC, data analysis
Microneedles NMR, viscosity, mechanical testing,
printer
in vitro drug release
Microneedles Biocompatibility, skin penetration, Carbon 3D M1 Johnson et al.
(2016)
Caudill et al.
(2018)
S1 CLIP Prototype
printer (Carbon)
optimization, multi-protein
Bloomquist et al.
S1 CLIP Prototype
microneedle patch coating, coating
dissolution in vitro and ex vivo
CLIP process and product
Drug-loaded
(2018)
printer (Carbon)
characterization, SEM, DSC, In vitro
drug release, drug loading,
polymerization kinetics of resins, cell
devices
culture, Cytocompatibility of
leachables and degradation products
Polymer and excipients Drug delivery Characterization techniques 3D printer References
Active
pharmaceutical
ingredient
Tab le 3 .2 (continued)
Diclofenac sodium 3DM Castable Resin Microneedles Test of fracture force, skin MN
diethyl fumarate (DEF), BAPO
TMPTA, poly (ethylene glycol)
dimethacrylate (PEGDMA 550),
polycaprolactone trimethacrylate
(PCL-tMa 1100), acrylic acid, TPO
PEGDMA 350, TPO Microneedles Microneedles coating and
Dacarbazine Poly (ethylene fumarate) (PPF),
Rhodamine B,
fluorescein
Bovine serum
albumin
PEGDMA, poly(ethylene glycol)
methyl ether methacrylate,
di(ethylene glycol) methyl ether
methacrylate (MP2MA),
Docetaxel,
dexamethasone-
Rhodamine B,
2-hydroxyethyl methacrylate
(HEMA), n-propyl methacrylate
(PMA), polycaprolactone
dimethacrylate (PCLDMA), TPO
3 Stereolithography (SLA) in Pharmaceuticals 115
Fig. 3.9 The hollow SLA 3D printed bladder device before (top left) and after (top right) filling
with drug loading mixture; and the hollow device under stretching (bottom). Reproduced with
permission from (Xu et al.
2021b)
al. investigated the effect of PEG 400, salt, and mannitol as hydrophilic excipients
with paracetamol as the model drug, PEGDA as photopolymer, and DPPO as the
photoinitiator (Krkobabi´cetal.
2019). They found that the addition of hydrophilic
polymers increases drug release rate, while PEGDA had the greatest influence on
tensile strength. Martinez et al. successfully 3D printed PEGDA hydrogels loaded
with ibuprofen containing up to 30% w/w water and 10% w/w ibuprofen using
a Formlabs Form 1+ SLA 3D printer (Martinez et al.
2017). The cylindrical
pills 3D printed were 10.5 mm diameter and 3.5 mm tall. Dissolution profiles
were found to be dependent on water content. The hydrogels 3D printed with
riboflavin/triethanolamine as photoinitiator showed superior quality compared to
when DPPO was used as initiator. However, the presence of hydrophilic excipients
can impede printability and formability in SLA 3D printing. Xu et al. used PEGDA
as monomer, TPO as photoinitiator, and ibuprofen as the model drug (Xu et al.
2021c). Tartrazine was used as photoabsorber due to its solubility and non-toxicity.
A separate study by Pariskar et al. also used Tartrazine as photoabsorber to fabricate
highly precise objects (Pariskar et al.
2022). Smaller pellets showed different release
characteristics compared to larger pellets. Konasch et al. developed a hybrid SLA
and inkjet-based printing process where a drug delivery system (DDS) was created
printing (Konasch et al.
2019). For testing, PEGDA samples with integrated depots
116 P. Ravi and P. Patel
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Fig. 3.10 PEGDA-based specimens with (a) single blue ink depot; (b)topand(c) angular view
of specimen with 13 individual depots; and (d) side view of specimen with 2 different ink depots
(blue and pink). Reproduced from (Konasch et al.
2019)
were fabricated and filled with blue and pink solutions (Fig. 3.10). Subsequently,
bovine serum albumin as a model drug was placed inside a DDS.
Januskaite et al. found the visual appearance of DLP printlets to be the most
appealing (61.7%) to pediatric patients compared to printlets fabricated using
selective laser sintering (21.2%), semi solid extrusion (11.7%), and FDM (5.4%)
(Januskaite et al.
2020). The high surface quality of the printed parts is one of
the biggest advantages of resin-based 3D printing (SLA/DLP). An artificial neural
network (ANN) model was developed to predict atomoxetine (ATH) release rate,
a drug used to treat attention-deficit hyperactivity disorder (ADHD), and the drug
release rate was tailored by varying drug loading and tablet thickness. Tan et al.
found that the addition of Alizarin dye to the photopolymer improved resolution
through reduction of light scattering (Tan and Ho
2019).
A fascinating recent development expected to revolutionize SLA in pharmaceuticals is the rapid volumetric 3D printing of paracetamol printlets. Rodriguez-Pombo
et al. fabricated an entire torus-shaped tablet (Fig.
3.11) at once in 17 s from
PEGDA-based resin formulation as opposed to the layer-by-layer fabrication of
SLA 3D printing techniques that can take over 10 min (Rodríguez-Pombo et al.
2022). In the research, PEGDA was the crosslinking monomer, lithium phenyl-
2,4,6-trimethylbenzoylphosphinate (LAP) was the photoinitiator, paracetamol was
the drug, and water or PEG 300 were included as diluents in varying concentrations
to facilitate the drug release. The volumetric 3D printer was based on DLP
composed of a digital mirror device (DMD), a 385 nm UV light source, and UV
optical lenses (f = 210 mm). However, only optically clear resins are suitable
with this technique at present because the photon depth of penetration into the
photopolymer is limited in opaque resins. This is the reason why only small parts
(less than 25 mm) can be 3D printed at present using the volumetric approach,
although this maybe a minor issue given the generally small size of pharmaceutical
pills. Furthermore, the pills still need to be rinsed in IPA and post-cured to fully
establish the mechanical properties of the polymer, and these times are not included
in the reported 17 s 3D printing time. However, the reduction of print speed to
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