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6 Inkjet and Binder Jet Printing in Pharmaceuticals 219
Tab le 6 .2 General attributes of machine groupings. While other combinations are possible, these
designations capture the most common features of the binder jetting equipment used to date
Group Powder feed Print head Build zones Types of motion
A Raising of feed bed
or deposition from
overhead doser
B Deposition from
overhead auger or
curtain feeder
C Raising of feed bed Sized for
Requires repeated
movements to
address the build
area (raster scan).
Sized for
single-pass
coverage of the
build area
single-pass
coverage of the
build area
Single build bed,
typically
stationary
Several moving
build beds
Single moving
build bed
Spreader and printer take
turns, each moving back &
forth over build bed (or
addressing a moving build
bed).
Build beds move
continuously in one
direction under fixed
spreader and fixed printer,
looping around for
repeated presentation.
Feed bed and build bed
move in tandem back &
forth under fixed spreader
and fixed printer, adding
material during forward
pass and resetting on
reverse pass.
by screw/auger or vibratory curtain feeder ahead of a roller assembly. The print
head is sized for full coverage across the entire width of the build bed pathway (i.e.,
orthogonal to the direction of travel), so no reciprocating motions are needed in that
direction.
Group C. This grouping is based on the HuskeyJet printer, which is equipped
with
a feed bed, build bed, roller/spreader, and overhead print heads. Like Group A
this type of machine relies on reciprocating motion for spreading and printing. In
this case, the feed bed and build bed move in tandem beneath a fixed roller/spreader
and fixed print heads, a bit like Group B and the TNO machine of Group A. Also
like Group B, the print heads cover the full width of the build bed pathway, so raster
mode printing is not needed.
A concise comparison of machine groups is provided in Table 6.2. Key features
of
these machines are also illustrated in Figs. 6.2, 6.3, and 6.4.
6.4.4 Key Subcomponent Techniques
Powder deposition. The powder component of binder jetting entails both a delivery
aspect (measurement, metering, and/or feeding) and a leveling aspect. Figure 6.5
illustrates several options for powder delivery, whereas Fig. 6.6 shows two means
for
leveling the delivered powder into a smooth incremental layer ready for liquid
deposition.
A feed bed serves as a pre-filled and leveled powder supply having its own z-
axis
stage. When powder is required, the feed bed z-axis raises to expose a height of
220 T. G. West and J. Yoo
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Fig. 6.2 Key features of Group A binder jetting machines. A counter-rotating roller moves from
feed bed (left) to build bed (right) and back, and a print head moves in a raster mode pattern,
back and forth, to address the desired area of the build bed. These spreading and printing steps are
strictly sequential, as one must wait for the other
Fig. 6.3 Key features of Group B binder jetting machines. Multiple build beds move along a
looping stadium-shaped pathway beneath a powder delivery / spreading zone (right) and a liquid
printing zone (left). The print head is designed for adequate coverage and density across the
printable area without transverse movement. The continuous loop of build beds allows powder and
liquid deposition to occur essentially simultaneously during nearly all of the print job, minimizing
wait times
powder calculated from the desired layer thickness (lowered z-axis) in the build bed.
Alternatively, powder can be fed by overhead means, including a hopper with fill
head (discrete feed) or hopper with fill head (continuous feed) such as an auger
or vibratory curtain. Control of discrete fill is often volumetric, whereas control of
continuous fill may be gravimetric (load cell with feedback control) or based on
displacement rate (RPM of auger or amplitude and frequency of vibratory feeder)
in addition to adjustable slot size for the feeder outlet. After powder is delivered,
6 Inkjet and Binder Jet Printing in Pharmaceuticals 221
Fig. 6.4 Key features of Group C binder jetting machines. A feed bed and build bed move in
tandem left-to-right first under a roller and then under a print head, later returning to the starting
position to reset for the next layer. Like Group B, the print head is designed for adequate coverage
and density across the printable area without transverse movement
a
b
c
Fig. 6.5 Powder delivery approaches: (a) Feed bed for discrete powder delivery; (b) hopper and
fill head for discrete powder delivery; (c) hopper and fill head for continuous powder delivery
powder leveling in the build bed is typically accomplished by a counter-rotating
roller, doctor blade, or other vibratory leveler (not depicted).
Liquid deposition. This section will provide basic summary points on print
heads,
as entire texts have been devoted to the subject. The reader is directed
222 T. G. West and J. Yoo
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ab
Fig. 6.6 Powder leveling approaches: (a) counter-rotating roller; (b) doctor blade
to one such volume for a comprehensive treatment of the topic (Hoath 2016).
Print heads used in binder jetting are diverse in capabilities and tradeoffs and are
primarily grouped as continuous jet or drop-on-demand systems. Some examples
are illustrated in Fig.
6.7. Continuous jet (CJ) systems originate a continuous
source of droplets that must then undergo selection or diversion from deposition
onto the powder bed and into a designated catcher. Droplet breakup occurs by
natural or modulated Rayleigh-Plateau instability (e.g., ultrasonic, electrostatic, or
thermal). The most low-tech approach for drop selection is to use a physical stencil
having holes shaped to the desired print pattern; the stencil is repeatedly positioned
and removed over the powder bed for each layer of printing. More sophisticated
approaches include electrostatically charging and deflecting the unneeded droplets
to a vacuum catcher (gutter). Alternately, a thermally driven CJ (not depicted) can
select by creating differently sized droplets from source and using air pulses to
deflect the smaller droplets. In contrast to CJ, for drop-on-demand (DOD) systems
each droplet (or packet of droplets) is individually commanded and generated.
Droplet generation mechanisms include piezoelectric means, thermal means (bubble
jet), or solenoid valve as the driving element. For piezo DOD, drop formation
is through mechanical deformation via piezoelectric effect. For thermal DOD, it
is from controlled heating and expansion of a bubble within the print fluid. For
solenoid valve, it is by opening and closing the valve in a pressurized fluid line.
In each case, the print head uses discrete electrical signals to impart pressure
waves sufficient to eject droplets from the nozzles that correspond to the respective
commands.
Printing mode. This phrase describes the pathway taken by the print head in
delivering the targeted pattern of droplets onto the powder, as shown in Fig.
6.8,
or the equivalent relative motion by moving a build bed with stationary print head.
Most common is raster scan mode, in which the print head moves in a line across
the build bed in one direction (+X), then makes a short orthogonal movement (+dY)
equal to the line spacing, then moves in a line across the build bed in the reverse
direction (−X), then moves another line spacing (+dY), repeating this reciprocating
movement to progress across the full build area required for the parts. More recently,
6 Inkjet and Binder Jet Printing in Pharmaceuticals 223
ab
Piezo element
modulates droplet
breakoff
Connuous
stream of discrete
droplets
Stencil catches droplets
while allowing desired
droplets to reach target
substrate
Piezo element modulates
droplet breakoff
Charging Cell applies surface
charge to undesired droplets
Deflecon Cell applies
constant voltage, causing
charged droplets to veer
off from vercal path
Guer catches
deflected droplets
Uncharged droplets
reach target substrate
c
Heang element
causing microbubble,
expansion of which
ejects a droplet
Droplets are generated
only when needed
Droplets reach
target substrate
de
Piezoelectric
transducer expands
and contracts to
generate pressure
waves that result in
droplet ejecon
Droplets are generated
only when needed
Droplets reach
target substrate
Electromagnec
coil moves the
plunger to eject
droplets
Droplets are
generated only
when needed
Droplets reach
target substrate
Fig. 6.7 Liquid deposition techniques: (a) continuous jet with stencil; (b) continuous jet with
charging and deflection; (c) drop-on-demand bubblejet; (d) drop-on-demand piezoelectric; (e)
drop-on-demand microvalve
some binder jetting machines are configured to operate in single-pass mode in
which the print head is adequately sized to address an entire build bed with a single
unidirectional movement across the bed.
Build Bed Motion. This phrase refers to the general type of machine movement
during binder jetting, with examples illustrated in Fig.
6.9. The primary types
of movement for binder jetting include use of a stationary build bed, use of a
continuous loop of moving build beds, and use of a reciprocating build bed. It is
also possible to use XY movement of a build bed under a stationary print head to
obtain the same effect as raster mode movement of the print head over a stationary
bed (not depicted).
224 T. G. West and J. Yoo
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ab
Fig. 6.8 Common printing modes: (a) raster mode printing; (b) single-pass printing
Fig. 6.9 Common types of build bed motion: (a) stationary build bed; (b) continuous loop of
moving build beds; (c) reciprocating build bed
6.4.5 Types of Deployment
Potential positioning and use of binder jetting are diverse. Applications range from
small non-GMP prototyping to scaled production of commercial product for the
marketplace. The size, number, complexity, requirements, and cost of binder jetting
apparatus differ significantly based on distance from the patient. This concept is
illustrated in Chap. 1,Fig. 1.2. Unsurprisingly, a centralized plant has different
needs
from those of a community pharmacy or clinical trial site.
6 Inkjet and Binder Jet Printing in Pharmaceuticals 225
Owing in part to its historical development, at this time binder jetting equipment for pharmaceuticals is far more established for centralized operations in
a manufacturing plant or regional hub. Binder jetting’s trajectory contrasts with
that of other forms of pharmaceutical AM which have largely focused on benchscale customization, deferring scale-up considerations until quite recently. Even so,
smaller binder jetting equipment tailored to the clinic or compounding pharmacy
is now taking shape. This type of usage will face case-specific requirements for
system cost, ease of use, safety, reliability, and cost/unit produced while maintaining
product quality and compliance. The utility and value generation potential of these
systems is an active research thrust for today’s scientists and engineers and will be
a fertile topic over the next decade of pharmaceutical binder jetting.
6.4.6 Materials
6.4.6.1 General Considerations
By definition, binder jetting uses a liquid material in order to bind together a
powdered material to form solid parts. The liquid and the powder are rarely
pure substances, as most often they must be formulated compositions for reasons
of processing or performance of a final dosage form. Recent publications have
given significant attention to testing of powder attributes and liquid attributes to
guide binder jetting work,(Antic et al. 2021; Wang et al. 2022; Sen et al. 2021;
K
ozakiewicz-Latała et al. 2022) many of which are compiled below.
Key attributes related to jetting of the liquid are provided in Table 6.3.The
liquid
is typically a solvent, solution, or suspension formulated to enable consistent
jetting from the selected print head. The liquid may also deliver binding agent,
release control agent, drug, flavors, or other substances needed for product function.
When more than one liquid is used within the same part design, the relative count
and positioning of droplets from each liquid can be used to differentiate the local
composition of the final dosage form. As such, spatial placement of liquid-based
ingredients is possible within the part’s architecture.
Tab le 6 .3 Attributes used to evaluate suitability of liquids for binder jetting
Liquid attributes/tests Notes
Viscosity, μ Resistance to flow due to internal friction, related to
Surface tension, σ Tension of surface film of a liquid, related to droplet
Density, ρ Mass divided by volume, indicative of inertia. Used
μ
Ohnesorge number, . Oh =
where L is the characteristic length of the
system (nozzle size or droplet size).
√
σρL
liquid infiltration. Used to calculate Oh.
formation and wetting. Used to calculate Oh.
to calculate Oh.
Dimensionless parameter expressing the balance of
viscous forces to surface forces and inertial forces.
Often guides fluid requirements for specific print
heads.
226 T. G. West and J. Yoo
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Tab le 6 .4 Attributes used to evaluate suitability of powders for binder jetting
Powder attributes/tests Notes
Particle Size Distribution
D10, D50, D90, Span
Particle Shape Via microscopy or dynamic image analysis. Aids
Density (Bulk, Tapped, True) Classical measurement, plus conditioned bulk density
Basic Flowable Energy Powder rheology: energy required to rotate powder in
Specific Energy Powder rheology: energy required for unconfined
Flow Rate Index Powder rheology: sensitivity of powder to changes in
Powder Compressibility Powder rheology: percent volume change in response
Via laser diffraction or dynamic image analysis.
Ingredients need sufficient overlap to maintain
uniformity.
macroscopic observations of flow.
via rheometer.
the test vessel.
powder flow, normalized to mass.
flow rate
to incremental increase in pressure applied to surface
of the powder sample.
The powder is usually a dry mixture, granulation, or collection of engineered
particles. The powder provides the majority of product composition and function on
a mass basis and must also have particle size and powder flow attributes appropriate
to the particular delivery and leveling mechanisms of the binder jetting apparatus
selected. Powder composition is highly application-specific, but can include drugs,
bulking agents, binding agents, release control agents, glidants, disintegrants, or
other customary excipients for oral solid dosage forms or implantable dosage forms.
Importantly, for the vast majority of binder jetting apparatus, the same powder
ingredients will be present throughout each horizontal “slice” of the final part, and
indeed typically throughout the entire part (single-powder systems). Unlike liquid
ingredients, there is no broad capability to spatially place powder ingredients within
selected regions of each layer of the part architecture. Some key powder attributes
for binder jetting are provided in Table 6.4.
Since binder jetting uses two input materials, each must also be formulated to
obtain
a desirable interaction between them with the final product’s function in
mind. Powder–liquid interactions typically focus on suitable wetting and binding
for the material pairing. Since each phenomenon can be influenced through powder
composition or liquid composition, it is important for the formulator to anticipate
potential tradeoffs in material selection given their goals for the end product and the
process requirements of their specific binder jetting apparatus. Some example tests
are provided in Table
6.5.
6 Inkjet and Binder Jet Printing in Pharmaceuticals 227
Tab le 6 .5 Tests for evaluating powder–liquid interactions for binder jetting
Powder–liquid interactions/tests Notes
Drop test Off-machine test allowing observation of
Line test Tests binding of single lines at different drop spacings
Ribbon test Tests binding of single layers at different line
wall test Tests binding of multiple layers at different layer
Saturation (volume occupancy basis)
.S =
dv is droplet volume
dx is drop spacing
dy is line spacing
dz is layer thickness
pf is packing fraction (bulk density/true
density)
dV
dX∗dY∗dZ(1−pf
,where:
)
droplet-on-powder contact angle, wetting, infiltration
time, and dissolution.
(dX) for given droplet size.
spacings (dY), usually after line test.
thickness (dZ), usually after line test and ribbon test.
Dimensionless quantity represents the ratio of droplet
volume to void volume in the powder bed.
Calculation is based on a differential element of build
space. Used to relate the spatial liquid/powder ratio
with desirable process and product outcomes.
(The term “saturation” is also used with calculations
using different quantities and unit basis).
6.4.6.2 Specific Materials
Among the different forms of AM, binder jetting likely has the broadest possible
material set to choose from. While the published literature applying binder jetting to
pharmaceuticals is considerable, it still reflects a fraction of the powdered materials
that might be considered for binder jetting formulations.
Figure 6.10 provides a compilation of the materials used in most of the binder
jetting
references cited for this chapter. This listing is not comprehensive, but is
perhaps the most extensive for binder jetting to date. Ingredients are listed on
the vertical axis, and the reference number with publication year is provided on
the horizontal axis. For compactness, only nonvolatile excipients are included, as
these constituents will also remain part of a final composition for label declaration
purposes. Solvents that are substantially removed by drying, such as water, ethanol,
and chloroform, are not listed. Single material headers can include different grades
of the same substance or multiple members within a related functional grouping
(e.g., polysorbate 20 and polysorbate 80 under “polysorbates”).
Twenty-five (25) active ingredients are listed, excluding dyes or markers that
were
used as model compounds. Over-the-Counter (OTC) drug acetaminophen
(paracetamol) appears most frequently, followed by OTCs chlorpheniramine
maleate and pseudoephedrine hydrochloride and prescription drug levetiracetam.
The earliest references favor use of active ingredient within the liquid composition
(print fluid), with use in the powder composition increasing over time. Forty
(40) excipients are shown. Among conventional tableting excipients, the earliest
in use for binder jetting include lactose, povidone, and colloidal silica serving
primarily as diluent, binder, and glidant, respectively. These each have been used
in binder jetting for at least two decades. Not surprisingly, these ingredients are
228 T. G. West and J. Yoo
Polycaprolactone (var)
Poly(lactide-co-glycolide)
Poly(l actic acid ) (various)
Polyanhydrides, P(FAD:SA)
Polyme thacrylates (E udragits)
Ethyl cellulose
Methyl cellulose
Hydroxypropyl cellulose
Hypromellose (HPMC)
Polyethylene oxide
Polyethylene glycol
PVCL-PVAc-PEG graft (Soluplus)
PVAc/PVP coproc (Kollidon SR)
PVAc/PVP copoly (Kollidon VA64)
Povidone
Sucrose
Lactose
Mannitol
Maltitol
Maltodextrin
Microcrystalline cellulose
Croscarmellose sodium
Pregelatinized starch
Sodium starch glycolate
Magnesium stearate
Stearic acid
Calcium sulfate
Dicalcium phosphate
Tricalcium phosphate
Colloidal sili ca
Buffer(s) / pH -modifier(s)
Antioxidant
Triethyl citrate
2-Pyrrolidone
Glycerin
Polysorbate (various)
Sodium lauryl sulfate
Sweetener (various)
Citric Acid
Flavors (Various)
Dyes or markers
5-Fluorouracil
Diclofenac sodium
Ethinyl estradiol
Chlo rpheniramin e maleate
Pseudoephedrine hydrochloride
Isosorbide mononitrate
9-Nitrocamptothecin
Captopril
Acetaminophen (Paracetamol)
Levofloxacin
Isoniazid
Rifampicin
Warfarin sodium
Levetiracetam
Amitriptyline hydrochloride
Indomethacin
Pyridoxine hydrochloride
Hydroxychloroquine sulfate
Ritonavir
Favipiravir
Caffeine
Quinapril hydrochloride
Clotri mazole
Ketoprofen
Ibuprofen
Timi ng of
Usage
Referenc e
B
P
P
P
2022 Wang et al. 2022
L
P
P
P
P
P
P
2022 Kreft et al. 2022
P
P
P
B
P
L
L
P
P
2022 Kozakiewicz-Latala et al. 2022
P
P
P
P
P
2022 van den Heuvel et al. 2022
P
O
O
O
O
2022 Lu et al. 2022
P
P
P
P
P
P
2021 van den Heuvel et al. 2021
P
P
P
L
L
2021 Antic et al. 2021
L
P
P
P
L
P
P
L
P
L
2021 Hong et al. 2021
L
P
P
P
L
L
P
P
P
2021 Wang et al. 2021
B
P
L
P
2021 Chang et al. 2021
L
L
L
B
P
P
P
P
2020 Chang et al. 2020
P
P
P
L
2020 Sen et al. 2020
P
P
P
P
2019 Infanger et al. 2019
O
O
P
O
2019 Shi et al. 2019
P
P
P
P
P
P
2018 Tian et al. 2018
L
P
P
P
L
L
L
L
L
P
2015 West and Bradbury 2019
P
L
L
L
L
2014 Wu et al. 2014
P
L
L
2009 Wu et al. 2009
B
P
P
P
B
2009 Yu et al. 2009c
B
P
P
P
L
P
2009 Yu et al. 2009b
B
P
P
P
L
P
2009 Yu et al. 2009a
B
L
2007 Huang et al. 2007
L
B
P
P
L
P
L
L
P
2007 Yu et al. 2007
P
P
L
L
L
L
2006 Wang et al. 2006
B
P
P
P
L
L
L
L
2003 Lee et al. 2003
B
P
L
P
P
P
P
L
L
L
2002 Rowe et al. 2002
P
P
L
2001 Lin et al. 2001
L
L
P
P
L
L
L
2000 Katstra et al. 2000
B
L
P
P
L
L
2000 Rowe et al. 2000
B
P
P
P
L
2000 Wang 2000
B
P
L
L
1998 Yoo et al. 2002, Ex 6.4
P
P
O
L
1997 Monkhouse et al. 1997
P
P
O
1996 Wu et al. 1996
Polycaprolactone (var)
Poly(l actide-co-gl ycolide)
Poly(l actic acid ) (various)
Polyanhydrides, P(FAD:SA)
Polymethacrylates (Eudragits)
Ethyl cellulose
Methyl cellulose
Hydroxypropyl cellulose
Hypromellose (HPMC)
Polyethylene oxide
Polyethylene glycol
PVCL-PVAc-PEG graft (Soluplus)
PVAc/PVP coproc (Kollidon SR)
PVAc/PVP copoly (Kollidon VA64)
Povidone
Sucrose
Lactose
Mannitol
Maltitol
Maltodextrin
Microcrystalline cellulose
Croscarmellose sodium
Pregelatinized starch
Sodium starch glycolate
Magnesium stearate
Stearic acid
Calcium sulfate
Dicalcium phosphate
Tricalcium phosphate
Colloidal sili ca
Buffer(s) / pH -modifier(s)
Antioxidant
Triethyl citrate
2-Pyrrolidone
Glycerin
Polysorbate (various)
Sodium lauryl sulfate
Sweetener (various)
Citric Acid
Flavors (Various)
Dyes or markers
5-Fluorouracil
Diclofenac sodium
Ethinyl estradiol
Chlo rpheniramin e maleate
Pseudoephedrine hydrochloride
Isosorbide mononitrate
9-Nitrocamptothecin
Captopril
Acetaminophen (Paracetamol)
Levofloxacin
Isoniazid
Rifampicin
Warfarin sodium
Levetiracetam
Amitriptyline hydrochloride
Indomethacin
Pyridoxine hydrochloride
Hydroxychloroquine sulfate
Ritonavir
Favipiravir
Caffeine
Quinapril hydrochloride
Clotri mazole
Ketoprofen
Ibuprofen
Timi ng of
Usage
Referenc e
B
P
P
P
2022 Wang et al. 2022
L
P
P
P
P
P
P
2022 Kreft et al. 2022
P
P
P
B
P
L
L
P
P
2022 Kozakiewicz-Latala et al. 2022
P
P
P
P
P
2022 van den Heuvel et al. 2022
P
O
O
O
O
2022 Lu et al. 2022
P
P
P
P
P
P
2021 van den Heuvel et al. 2021
P
P
P
L
L
2021 Antic et al. 2021
L
P
P
P
L
P
P
L
P
L
2021 Hong et al. 2021
L
P
P
P
L
L
P
P
P
2021 Wang et al. 2021
B
P
L
P
2021 Chang et al. 2021
L
L
L
B
P
P
P
P
2020 Chang et al. 2020
P
P
P
L
2020 Sen et al. 2020
P
P
P
P
2019 Infanger et al. 2019
O
O
P
O
2019 Shi et al. 2019
P
P
P
P
P
P
2018 Tian et al. 2018
L
P
P
P
L
L
L
L
L
P
2015 West and Bradbury 2019
P
L
L
L
L
2014 Wu et al. 2014
P
L
L
2009 Wu et al. 2009
B
P
P
P
B
2009 Yu et al. 2009c
B
P
P
P
L
P
2009 Yu et al. 2009b
B
P
P
P
L
P
2009 Yu et al. 2009a
B
L
2007 Huang et al. 2007
L
B
P
P
L
P
L
L
P
2007 Yu et al. 2007
P
P
L
L
L
L
2006 Wang et al. 2006
B
P
P
P
L
L
L
L
2003 Lee et al. 2003
B
P
L
P
P
P
P
L
L
L
2002 Rowe et al. 2002
P
P
L
2001 Lin et al. 2001
L
L
P
P
L
L
L
2000 Katstra et al. 2000
B
L
P
P
L
L
2000 Rowe et al. 2000
B
P
P
P
L
2000 Wang 2000
B
P
L
L
1998 Yoo et al. 2002, Ex 6.4
P
P
O
L
1997 Monkhouse et al. 1997
P
P
O
1996 Wu et al. 1996
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Fig. 6.10 Listing of nonvolatile excipients and APIs studied over time in selected binder jetting
references. Active ingredients are shown in red text. Letter codes denote method of incorporation:
P = Powder, L = Liquid, B = Both Powder and Liquid, O = Other
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