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j.ijpharm.2018.11.044
Inkjet and Binder Jet Printing
in Pharmaceuticals
Thomas G. West and Jaedeok Yoo
Abstract
After three decades of foundational work, global interest remains ascendant for
additive manufacturing (AM) of pharmaceuticals. At the forefront of this interest
is binder jetting onto powder, which holds a unique position due to the early
regulatory precedents established using this technology and also the diversity of
materials it can process.
To date, binder jetting is the only type of additive manufacturing worldwide to
be part of an approved drug application, first achieved with SPRITAM
This milestone echoes the prior use of binder jetting in regulated life sciences via
clearances for implantable medical devices in 2003 and 2004. These examples
cement the early commercial implementation of binder jetting in centralized
manufacturing configurations under the extant regulatory frameworks.
Conceptually, any pharmaceutical powder can be considered for binder
jetting. A diverse body of research has prototyped a range of immediate and
controlled release dosage forms, predominantly for oral use, along with a few
implantable examples. As with other AM processes, strategies for decentralization and part customization are actively contemplated.
This chapter will provide a technical foundation for binder jet printing of pharmaceuticals, with particular emphasis on its application to novel pharmaceutical
dosage forms and future perspectives on the field.
®
in 2015.
6
T. G. West ()
Independent Consultant, Lawrenceville, NJ, USA
J. Yoo
FoundationLayers LLC, Princeton, NJ, USA
e-mail:
jdyoo@alum.mit.edu
© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023
S. Banerjee (ed.), Additive Manufacturing in Pharmaceuticals,
https://doi.org/10.1007/978-981-99-2404-2_6
201
202 T. G. West and J. Yoo
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Keywords
Additive manufacturing · 3D printing · Binder jetting of pharmaceuticals ·
Drug delivery
6.1 Nomenclature
This chapter follows the high-level process category definitions for Additive
Manufacturing (AM) promulgated under ISO/ASTM 52900:2021(E). Accordingly,
the phrase binder jetting refers to the form of AM in which a liquid is selectively
deposited in order to join powder materials to form parts. As such, the use of both
powder and liquid is required by this form of AM. The term inkjet is not included
in the standard and is treated here as a synecdoche of binder jetting, using a part to
label the whole. Other terminology may deviate from that of ISO/ASTM in order
to aid communication to the reader. This includes use of binder jetting conventions
already established or used elsewhere for the pharmaceutical context.
6.2 Historical Progression of Binder Jetting for
Pharmaceuticals
6.2.1 Origins at M.I.T
Binder jetting was invented at Massachusetts Institute of Technology (M.I.T.) in
the late 1980s resulting in filing of the first patent application for binder jetting in
1989 (Sachs et al.
1993).1 Its initial purpose was more generalized and not at all
pharmaceutical. While other Additive Manufacturing (AM) had already come into
usage, the binder jetting process represented a new form of AM able to fabricate
objects by selective deposition of a liquid binding material onto powder material,
in order to bind particles of the powder material together, layer by layer. After
binder jetting, the parts are dried and separated from loose unprinted powder. This
process was initially named Three-Dimensional Printing (3D printing, or 3DP) by
its inventors. In recent years, the 3D printing name has moved into generic usage
as an umbrella term across multiple forms of AM instead of solely the liquidonto-powder process. As with other AM processes, the first applications of binder
jetting were aimed at industrial use to provide faster and more agile design and
prototyping of mechanical parts, tooling, and molds, reducing overall time and cost
for development of products made from metals and ceramics (Sachs et al.
1992).
In the early 1990s, the work at M.I.T. extended to binder jetting for medical
applications in tissue engineering and drug delivery (Cima and Cima
1
Authors note that a complete review of patents is beyond the scope of this chapter. Selected
patents are cited only as needed to show specific advancements in binder jetting technology. This
chapter should not be construed as legal advice, and the reader is directed to seek competent
counsel for such purposes.
1996a, b;
6 Inkjet and Binder Jet Printing in Pharmaceuticals 203
Cima et al. 1994) A core tenet of this work was spatial compositional control,
enabled by the ability of the one or more jetted liquids to deliver certain ingredients
into precise positions within the part, and in prescribed amounts, as chosen by the
user. This capability is an early distinction for binder jetting versus other forms of
AM. The research at M.I.T. also explored materials and part architecture that would
be advantageous for fabrication of implantable tissue scaffolds and drug delivery
devices exhibiting complex release patterns over time, including contemplation
of other AM techniques. Significant attention was given to the role of structural
elements to help maintain the mechanical integrity of degradable or erodible parts
over time, allowing for tissue growth and/or drug delivery to proceed unimpeded by
breakdown of the part’s matrix.
This stage included early studies on the mechanical properties of binder jetted
parts as a function of the amount of liquid deposited, including evaluation with
subsequent cold isostatic pressing (Giordano et al.
1996). It showed that significant
densification could be obtained in parts relative to the tapped density of the starting
powder. Companion work in drug delivery demonstrated that the release time and
release rate of model dyes can be controlled by specifying the spatial position
of dye within the part geometry and by controlling the local composition and
microstructure, resulting in perhaps the most cited publication for binder jetting of
pharmaceuticals (Wu et al.
1996). This foundational work dovetailed with the initial
license of M.I.T.’s binder jetting technology for medical applications, as reflected
in acknowledgments to Therics Inc. and J&J Development Corporation.
6.2.2 Elaboration of Binder Jetting as Licensed Technology for
Medical Applications
6.2.2.1 License to Therics, Inc.
M.I.T. first licensed its binder jetting technology for medical applications on
an exclusive worldwide basis to a startup company named Therics, Inc., which
continued to sponsor collaborative research at M.I.T. Therics commenced activities
as a virtual company in 1993 and transitioned to engineering and laboratory
operations in mid-1996. Its technical scope was considerable, encompassing product
and process R&D for both pharmaceutical and tissue engineering applications, as
well as in-house design and assembly of novel machines and related software needed
to support the product and process R&D. Therics pursued its own patents in addition
to the licensed estate. Therics delineated its version of binder jetting machines and
process using the TheriForm brand name.
2
Initial TheriForm machine development focused on developing small systems
with automated powder feeding, spreading, and raster-style printing using a 6
2
Although the trademark is no longer active, the TheriForm name is only accurately used in
reference to the machines made by Therics as the source of those machines. It is essentially a
historical term now.
x
204 T. G. West and J. Yoo
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6build area—these attributes having roots in the early M.I.T. machines. Print
head and spreader translation were provided by a top-mounted XY gantry that
moved above fixed powder feed bed and powder build bed assemblies. The feed and
build beds were stationary during operation, save for movable Z-axis piston within
each. The earliest TheriForm machines used a simple single-nozzle continuous
jet (undeflected) print head in tandem with print masks (i.e., stencils) to dictate
the print pattern. Subsequent research involved continuous jets with deflection,
including organic solvent applications. In its larger body of machine work, Therics
developed its own drop-on-demand (DOD) print head design incorporating solenoid
microvalve technology, progressing in steps from single nozzle to 8 nozzle capability on its small and pilot scale machines, with the ability to handle multiple fluids in
the same build. Pilot scale build area doubled to 6
x12per machine. Overall, the
machine designs reflected increased attention to occupational safety, cleanability,
and eventual cGMP operations. Collectively, these machines formed the foundation
for the majority of the publicly disclosed work from Therics.
Diverse pharmaceutical applications of binder jetting were explored at Therics.
Unfortunately, published reviews of its work are often incomplete due to the limited
and disparate source material available. Accordingly, this chapter endeavors to
collect most of the main ideas below. Use of a “shell/core” design was a recurring
theme across much of the work, i.e., using binder jetting’s control of material
placement to define at least one drug-containing interior “core” region and a drugfree “shell” region surrounding it. Such designs required concurrent use of two
liquid compositions during the print job. Example applications demonstrated at
Therics include:
• Rapid prototyping of dosage forms. Tablet designs differing in composition
and physical attributes were obtained by use of different print parameters or print
fluid compositions, for example, while using the same powder bed composition
in the same print job (Kumar et al.
1998). After completing prototypes using the
first powder, the feed bed could be replaced and the machines reset for repeating
this approach with the next powder. Techniques like this were used for a variety
of dosage form types at Therics, as well as some tissue/device prototypes.
• Microdosing for high potency drugs and encapsulation of hazardous drugs.
Microdosing was demonstrated via deposition of dilute drug solution to create
an active-containing core region of the dosage form. This approach avoided
potential uniformity issues associated with dry powder blending or potential drug
loss through surface abrasion of the dosage form (Yoo et al.
1997). For hazardous
drugs, an unprinted transition region was used in between the outermost placebo
shell region and the innermost active core region to avoid the possible migration
of drug across the wetted interface during the binder jetting or drying steps
(Payumo et al.
2007).
• Rapidly-disintegrating oral dosage forms. Therics modeled these dosage
forms after classical orally disintegrating tablets (ODTs): small units designed
to disintegrate without water that deliver predominantly low-dose drugs (FDA
Guidance for Industry
2008). Several cough/cold medicines were prototyped
6 Inkjet and Binder Jet Printing in Pharmaceuticals 205
including some fixed dose combinations, with actives delivered through the print
head (Yoo et al.
2002). An example of square-shaped pseudoephedrine HCl
tablets having placebo shell/active core “encasement” design was prototyped
in vertical orientation (i.e., standing on its side) using Therics’ pilot scale
equipment (Wang
2000). Likewise, early optimization of a square shell/core
design of captopril using Box-Behnken design of experiments (DOE) was
published (Lee et al.
2003). Collectively dubbed TheriFlash dosage forms, these
rapidly disintegrating tablets were perhaps the most established application area
of binder jetting for pharmaceutical use at Therics.
• Resorbable implantable dosage forms. This area included primarily pulsatile
and (prolonged) continuous release of drugs from degradable polymer devices.
A conceptual multi-chambered retinal implant prototype showed four separately
timed pulses, one per chamber, of 5-fluorouracil delivered over multiple days
based upon the thickness of each chamber lid, and concurrent continuous release
of diclofenac (Monkhouse et al.
1997). Continuous release of ethinyl estradiol
for 4 months was shown from rod-shaped implants having a central channel of
drug with placebo exterior, including rabbit biostudy data (Kumar et al.
Lin et al.
2001). A generalized design matrix was shown for adjusting release
1999;
of drug-in-chamber devices in response to surface area and wall thickness when
chamber volume is held constant (Wang
2000).
• Oral controlled release (CR) dosage forms. Proof-of-principle was demonstrated for a series of conceptual CR tablet designs using chlorpheniramine
and diclofenac: (1) tablets releasing both via erosion and via diffusion from
respective halves of the same device; (2) tablets using a quick dissolve region
to divide into subunits; (3) tablets targeting two intestinal pulses; and (4) tablets
targeting one stomach and one intestinal pulse (Rowe et al.
2000). Additional
studies demonstrated dose accuracy and the influence of polymer use level
(via print head) on diffusion- or erosion-based release rates, including the
microdosing of fluorescein (Katstra et al.
2000). Core/shell extended release
units were prototyped for isosorbide mononitrate and for 9-nitrocamptothecin
(9-NC, printed via suspension) (Rowe et al.
2002). Near zero-order release of
pseudoephedrine was shown for a diffusion-based multi-chamber tablet design
having a pH-independent release rate tunable via polymer ratio, which included
pilot pharmacokinetic study data in man (Wang et al.
2006).
• Combining binder jetting with a subsequent compression step. Uniaxial
compression was shown to improve volume efficiency, hardness, and surface
smoothness of binder jetted tablets while maintaining the general shape and
internal patterning of active ingredients (i.e., the patterns reduced in length
proportionally along the axis of compression) (Katstra
2001). Erosion-based
tablets exhibiting zero-order release were also prototyped using this technique.
These tablets included radial- and cylindrical-release designs using stepped
concentration gradients of drug delivered via the print head.
Therics’ binder jetting machines were used for medical devices as well as
pharmaceuticals, and it continued scaling its machines to larger build area of
206 T. G. West and J. Yoo
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approximately 16x 24.5and up to 32 nozzle capability for its microvalve-based
print head in order to create capacity for early commercial manufacturing.
By the early 2000s, its largest machines were sufficiently scaled for direct
manufacturing of medical devices requiring lower production volumes at higher
price points than those of most pharmaceutical products. Accordingly, Therics
elected to discontinue work on pharmaceuticals in order to focus fully on medical
devices. As related achievements, in 2003 and 2004 Therics obtained perhaps the
earliest FDA clearances for implantable medical devices made directly by binder
jetting. These devices are described under the section Regulatory “Firsts” for Binder
Jetting. Consequently, Therics’ license from M.I.T. was amended to reflect this
focus on medical devices, returning all pharmaceutical rights to M.I.T. for potential
pharma-specific licensing.
6.2.2.2 License to Aprecia Pharmaceuticals and Further Innovation
Aprecia Pharmaceuticals Company was founded in 2003 with the explicit goal of
attaining production rates suitable for centralized manufacturing of the novel pharmaceutical dosage forms enabled by binder jetting. It promptly licensed M.I.T.’s
technology on an exclusive worldwide basis for all pharmaceutical applications.
Aprecia would also build its own patent estate over time, filing its first application
in 2007 for dosage forms having patterned internal chemical markers to aid dosage
form authentication (Yoo et al.
realized in 2015 with the FDA approval of SPRITAM
2014a). Aprecia’s founding raison d’être was first
®
, now a cornerstone in
the AM of pharmaceuticals. SPRITAM (levetiracetam) tablet for oral suspension
became the world’s first approved pharmaceutical product made using AM, and it is
manufactured at scale in a centralized plant. It has been sold in the U.S. since 2016.
As noted in FDA’s “Orange Book” database, it is a patented product (Orange Book
n.d.).
An extensive discussion of SPRITAM is provided in a prior book chapter
describing the technology development and regulatory positioning leading to its
approval (West and Bradbury
relied upon for its approval (Boudriau et al.
2019). A journal publication details the biostudies
2016). The present chapter discusses
SPRITAM further under the section Regulatory “Firsts” for Binder Jetting.
SPRITAM is part of Aprecia’s family of high-dose “fast melt” formulations
known as ZipDose
®
Technology. These formulations incorporate high-dose active
ingredients via the powder blend used for binder jetting and can deliver hundreds
of milligrams of drug. Unlike legacy ODTs, ZipDose formulations often exceed
275 mg of drug loading and 500 mg of total tablet weight and are designed to
disintegrate directly in the mouth in seconds when taken with a sip of liquid.
Hydrophobic drugs (e.g., micronized and granulated)(Jacob et al.
having hydrophobic coatings (Jacob et al.
2016b) have been exemplified, in addition
2016a) and drugs
to hydrophilic drugs.
To enable centralized manufacturing of pharmaceutical parts, Aprecia designed
from a “clean sheet” to create a novel “open bed” form of binder jetting. This
technology significantly removes or reduces the wait times in the component steps
6 Inkjet and Binder Jet Printing in Pharmaceuticals 207
of binder jetting while also increasing the total effective build bed area. Both
the powder blend and the printing fluid are added essentially continuously and
simultaneously during the run time of the print job. In effect, the technology marks
a cumulative scale evolution from early AM prototyping of perhaps ten parts at a
time to manufacture of functional pharmaceutical parts in the thousands at a time.
Compared to the largest prior Therics machines, and adjusting for the much larger
tablets targeted by Aprecia, it represents more than an order of magnitude boost to
binder jetting production rate (West and Bradbury
on this technology issued in 2014 (Yoo et al.
2019). The first of several patents
2014b). It is now branded under the
name Z-Free.
It is worth noting that Aprecia’s “open bed” (Z-Free) machines are not TheriForm
technology and should not be referred to by that name. The two are often conflated in
recent journal publications without substantiation. In contrast, based on the present
authors’ firsthand knowledge of each, the apparatus in fact differ substantially in
their respective size, shape, construction, operational motions, controls, software,
method of powder addition, and print head design, with virtually no componentry
in common and with ownership by distinct corporate entities.
Recently, Aprecia introduced in-cavity (print-in-blister) technology. This technology adapts the principles of binder jetting to the formation of tablets directly
inside of pharmaceutical packaging, such as unit-of-use blister packs. In this way,
it avoids the presence of loose unprinted powder that customarily surrounds wet
parts during forming on binder jetting systems to this point. One benefit is that use
of two or more powder blends to form distinct regions of the same part becomes
more practical, as it avoids the mixing of excess powder that would occur during
recycling of unprinted powder from prior binder jetting systems. The first patent
on this technology area issued in early 2022 (Beach-Herrera et al.
2022). In October
2022, Aprecia unveiled its Z-Form Flex machine design based upon the technology.
In 2021, Aprecia also introduced ZipCup™ (Z-Fill) dosage form technology.
These dosage forms can be filled like two-piece capsules and disintegrate in seconds
when exposed to a small amount of liquid. ZipCup units can be made in situ
using print-in-blister technology or can be made as two-piece shells for subsequent
filling and assembly on separate equipment (or manually). The two-piece shells can
be made on Aprecia’s open bed (Z-Free) equipment and offer the most payload
flexibility for two key reasons: (i) the fill material experiences less process stress, as
it is not exposed to the wetting and drying steps of binder jetting; (ii) the fill material
can differ significantly in particle size from the powder blend used to make the twopiece shells (Pollinger and West
2021). Accordingly, one or more populations of
engineered particles can be considered, as well as amorphous solid dispersions, cocrystals, effervescent blends, or other moisture-sensitive payloads that would benefit
from dry filling conditions. The first patent on this technology area issued in late
2022 (Yoo et al.
2022b).
208 T. G. West and J. Yoo
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6.2.3 Broadening of Research Interest Globally
An impediment to wider practice of the pharmaceutical binder jetting field was,
and to some degree still is, the relative unavailability of off-the-shelf purpose-built
binder jetting equipment designed for pharmaceutical practitioners. Consequently,
as interest in the technology started to grow, much of the research made use of the
readily available non-pharmaceutical equipment, or lead to the assembly of new
custom equipment.
In 2007–2009, authors from Donghua University (Shanghai, China) and
Huazhong University of Science and Technology (Wuhan, China) published
perhaps the earliest research in pharmaceutical binder jetting outside of M.I.T.
and its licensees. Their apparatus was made by Fochif Mechatronics Technology
Co, Ltd. (Shanghai, China). This body of work corroborates and extends the
underlying pharmaceutical binder jetting field across a range of applications. Fast
disintegrating tablets were demonstrated with acetaminophen incorporated via
powder blend and using excipients proven for this application (Yu et al.
b). For oral controlled release, printed concentration gradients of ethyl cellulose
and other release modifying agents were used to achieve zero-order release of
acetaminophen in disc-shaped (Yu et al.
2007) and doughnut-shaped tablets (Yu
et al. 2009c). Degradable implants were formed that show bimodal release of
levofloxacin from cylindrical shapes (Huang et al.
2007) and sequenced release of
isoniazid and rifampicin from cylinders having four concentric regions of printed
drug (Wu et al.
2009). Additional groups in China later contributed research with
the Fochif Mechatronics system. In 2014, a multilayer cylindrical implant with
axial through-hole demonstrated slow release of isoniazid (Wu et al.
2018, orally disintegrating tablets were prototyped containing the anticoagulant
warfarin sodium (1% w/w of powder blend) while modifying the total number of
printed layers to demonstrate patient-based dose adjustment (1, 2, or 3 mg) (Tian et
al.
2018).
In 2019, University of Sussex (UK) prototyped placebo oral tablets using a ZCorp printer (3D Systems, USA) and modeling powder, subsequently loaded with
model anticancer drug 5-fluorouracil (5-FU) in hot solution via micropipette (Shi et
al.
2019). This work echoes the manual deposition of 5-FU solution onto already-
formed binder jetted implant prototypes by Therics two decades earlier,(Monkhouse
et al.
1997) adapted to an oral dosage form made on newer equipment.
In 2020, the University of Connecticut demonstrated prototype tablets using
aProJet
®
CJP 660 Pro (3D Systems), a printer for non-pharmaceutical rapidprototyping. Low-dose drug loading (0.030 to 1.75 mg) of binder jetted tablets
was studied anew using CNS drug amitriptyline hydrochloride as model compound
deposited through the printing fluid (Sen et al.
2020). Also, a range of powder and
fluid properties were reviewed in the course of prototyping rapidly disintegrating
tablets incorporating indomethacin via the powder blend (5% or 10%), leveraging initial observations from the supplier’s non-pharmaceutical modeling powder
®
VisiJet
PXL Core (Chang et al. 2020). In 2021, prototyping of indomethacin
2009a,
2014). In
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