Drug Development and Industrial Pharmacy

ISSN: 0363-9045 (Print) 1520-5762 (Online) Journal homepage: http://www.tandfonline.com/loi/iddi20

3D Printing technologies for drug delivery: a

review

Leena Kumari Prasad & Hugh Smyth

To cite this article: Leena Kumari Prasad & Hugh Smyth (2016) 3D Printing technologies for
drug delivery: a review, Drug Development and Industrial Pharmacy, 42:7, 1019-1031, DOI:
10.3109/03639045.2015.1120743

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 DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY, 2016
VOL. 42, NO. 7, 1019–1031
http://dx.doi.org/10.3109/03639045.2015.1120743

REVIEW ARTICLE

3D Printing technologies for drug delivery: a review

Leena Kumari Prasad and Hugh Smyth
Division of Pharmaceutics, College of Pharmacy, University of Texas at Austin, Austin, TX, USA

ABSTRACT ARTICLE HISTORY

With the FDA approval of the first 3D printed tablet, SpritamÕ , there is now precedence set for the utilization Received 31 August 2015
of 3D printing for the preparation of drug delivery systems. The capabilities for dispensing low volumes with Revised 10 November 2015
accuracy, precise spatial control and layer-by-layer assembly allow for the preparation of complex Accepted 12 November 2015
compositions and geometries. The high degree of flexibility and control with 3D printing enables the Published online
preparation of dosage forms with multiple active pharmaceutical ingredients with complex and tailored 14 December 2015
release profiles. A unique opportunity for this technology for the preparation of personalized doses to KEYWORDS
address individual patient needs. This review will highlight the 3D printing technologies being utilized for 3D printing; drug delivery;
Downloaded by [McMaster University] at 13:28 28 November 2017

the fabrication of drug delivery systems, as well as the formulation and processing parameters for fused deposition modeling;
consideration. This article will also summarize the range of dosage forms that have been prepared using inkjet powder bed printing;
these technologies, specifically over the last 10 years. particle printing; persona-
lized dosage forms; tablets

Introduction History
Three-dimensional (3D) printing is a form of additive manufacturing, Charles Hull is considered the pioneer of 3D printing, as he
wherein a structure is built by depositing or binding materials in developed, patented and commercialized the first apparatus for the
successive layers to produce a 3D object1. Additive manufacturing is 3D printing of objects in the mid 1980s10–12, as well as developed
considered a subset of rapid prototyping, which encompasses the STL file format that interfaced with existing CAD software. Hull’s
techniques to quickly fabricate models and prototypes; however, it is technique, stereolithography (SL), consists of a laser that moves
now being considered a scalable manufacturing process2. The use of across the surface of a liquid resin, curing the resin, before the stage
3D printing and other additive manufacturing techniques in is again submerged to allow for the curing of another layer; this
engineering through biomedical applications has been steadily process is repeated layer by layer until the desired geometry is
growing over the last 30 years3. The application of these printed.
technologies into the field of drug delivery has been investigated During this time, parallel work was on-going at the University of
and more recently realized with the FDA approval of the 3D printed Texas at Austin (UT Austin), Massachusetts Institute of Technology
orodispersible tablet, SpritamÕ (levetiracetam), further supporting (MIT), Stratasys, Ltd. and other companies to develop other additive
the capabilities of 3D printing to manufacture complex and manufacturing techniques. The same year that Hull filed a patent for
customized dosage forms4–6. his stereolithography apparatus, a researcher and his advisor from
The benefits of using additive manufacturing techniques for UT Austin filed a patent for selective laser sintering, a process
dosage form design include the ability to accurately control the whereby a laser beam is scanned over a powder bed to sinter or fuse
spatial distribution of an active pharmaceutical ingredient (API) the powder; the powder bed is then lowered, fresh powder is spread
within a dosage form, produce complex geometries, deposit very and the process is repeated to produce a solid object13. Professors at
small amounts of API, reduce waste and allow for rapid fabrication of MIT were credited with first using the term ‘‘3D printer’’ with their
varying compositions to allow for screening activities or preparation invention of a layering technique using a standard inkjet print head
of individualized dose strengths5–8. Business incentives associated to deposit ‘‘ink’’ or a binder solution onto a powder bed to bind
with printing pharmaceuticals include moving away from tradition- powder, again repeating this process layer-by-layer to produce a
ally complex, slow and expensive supply chains, reducing manu- desired geometry. The un-bonded or loose powder, which acts as a
facturing and inventory waste, as well as allowing for more support during processing, is then removed. The structure can be
individualized dosage forms (i.e. varying dose strengths) without further treated, for example with heat, to enforce the bonding14. This
the need for a high volume manufacture9. process is generally referred to as 3D printing. In this review, this
The purpose of this review is to highlight the 3D printing technique will be referred to as 3D powder bed or powder bed inkjet
techniques being developed for the fabrication of drug delivery printing.
systems, as well as the formulation and processing considerations In 1989, Scott Crump, co-founder of Stratasys, Ltd., filed a patent
for each. This review will also summarize the range of dosage forms on fused deposition modeling (FDM). This technique fabricates
that have been prepared using these methods, specifically over the an object by depositing layers of solidifying material until the
last 10 years, 2006–present. desired shape is formed. Material such as self-hardening waxes,

CONTACT Leena Kumari Prasad [email protected] Division of Pharmaceutics, College of Pharmacy, University of Texas at Austin, 2409 University Avenue,
Stop A1920, Austin, TX 78712, USA

ß 2015 Informa UK Limited, trading as Taylor & Francis Group

 1020 L. K. PRASAD AND H. SMYTH

Figure 2. Schematic of DOD printing with (a) thermal and (b) piezoelectric
actuation. Reprinted with permission from Derby19.

the resistor. Although the short duration and small contact area
makes thermal degradation of the ink a low risk, it is something to
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be considered. Additionally, the thermal print heads require the use

of a high vapor pressure or volatile solvent, which may limit its
pharmaceutical application7.
Piezoelectric print heads utilize a piezoelectric element, such as
Figure 1. Schematic representation of CJ printing. Reprinted with permission from crystal or ceramic that produces a mechanical movement when a
Derby19. voltage is applied, as shown in Figure 2(b). The deformation of the
element creates a pressure wave that ejects the fluid from the
nozzle20. Piezoelectric printing has been shown to allow for more
thermoplastic resins and molten metals can be used for this
control of droplet formation and does not operate by heat
process15. In 1996, inventors at Helisys, now Cubic Technologies,
generation, making it more desirable for use in drug
developed a laminated object manufacturing technique consisting
development4,21.
of the shaping (usually by lasers) and stacking of sheets of defined
3D powder bed printing is the deposition of a liquid or ‘‘ink’’ onto
materials, with adjacent layers bonded by adhesives or welding16.
a powder bed to bind the powder. The powder bed is then lowered,
a new powder layer is spread, and the process repeated to bind
3D printing technologies for drug delivery powder layer-by-layer to produce the final geometry, as shown in
Figure 3.
3D inkjet printing and FDM techniques have found their way into
drug product research and development. The implementation of
Formulation and process parameters for consideration
these technologies in dosage form design has spurred the fabrica-
tion of novel, multifunctional and customizable dosage forms. 3D inkjet printing can be separated into three parts: (1) droplet
formation, (2) droplet impact and spreading and (3) drying or
solidification. Note that the majority of DOD printing conducted for
3D inkjet and 3D powder bed printing preparation of pharmaceutical dosage forms utilizes piezoelectric
Inkjet printing is based on the Lord Rayleigh’s instability theory actuation, as thermal actuation requires the use of high vapor
developed in 1878, which explains the breaking of a liquid stream or pressure or volatile materials. Droplet formation is a complex
jet into droplets17. This concept was used to develop continuous jet process, which is influenced by fluid viscosity, density and surface
(CJ) and drop on demand (DOD) printing, both of which are used in tension, among other factors. Many dimensionless values have been
developed to predict fluid behavior, including Reynolds (Re), Weber
traditional desktop printing18. CJ printing utilizes a pressurized flow
(We), and Ohnesorge (Oh) numbers, shown in Equation (1),
to produce a continuous stream of droplets. The droplets are
Equation (2), and Equation (3), respectively. The inverse of the Oh
charged upon exiting the nozzle and directed by electrostatic plates
number, Z ¼ 1/Oh, as a function of Re number was used to define
to the substrate or to waste to be recirculated, as shown in Figure 1.
areas for stable drop generation and We number was used to
DOD is considered more precise and less wasteful in that it can
determine areas where energy was sufficient to eject a drop from
produce droplet volumes as low as 1–100 pL at very high speeds,
the nozzle19,22,23, as represented in Figure 4. Generally speaking, Z
but only as needed. The two most common types of actuation with
values of 1–10 are classified as printable fluids23. Hon et al.
DOD printing are thermal (sometimes called bubble) and piezo-
summarized some of the performance and fluid properties used
electric. Micro-electro-mechanical systems, electrostatic and other
with typical commercial inkjet systems, which is shown in Table 124.
methods of droplet actuation are available or under investigation
Reynolds (Re) number
but will not be discussed here.
A thermal print head utilizes a resister that upon receipt of a
Re ¼ ð1Þ
electrical pulses rapidly heats and forms a vapor bubble in the ink 
reservoir, as shown in Figure 2(a). This bubble then forces ink out of Weber (We) number
the print head; the bubble then collapses, producing a negative
pressure that draws ink from the reservoir to refill the chamber.  2 a
We ¼ ð2Þ
Thermal inkjet printing can produce high local temperatures near 
 DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY 1021

Figure 3. Schematic of 3D powder bed printing of a tablet. Reprinted with permission from Katstra et al.8.

satellite drop formation was seen with Z values as low as 6.57;

however, these drops were able to merge with the primary droplet
prior to deposition. This study also showed that satellite drops from
fluids with Z values of up to 13.68 were able merge with the primary
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drop prior to deposition, concluding that fluids with Z514 were

able to deposit as single droplets26. Note that theses valuations of
printable fluids are based on the assumption of Newtonian flow.
However, due to the increased interest in 3D printing in biomedical
and pharmaceutical manufacturing, numerous studies have been
conducted to evaluate the ‘‘printability’’ of polymer solutions and
other liquids with complex rheology27–30.
When using a suspension as the ink, particle size, suspension
stability and effect on fluid rheology must be considered. Pardeike
et al. showed successful printing of a folic acid nanosuspension
(d505500 nm)31, inline with previously reported printing of nano-
suspensions32–34. However, in a study by Gu et al., 100 nm biphasic
calcium phosphate (BCP) suspended in the ink formulation resulted
in clogging of the nozzle; this was attributed to agglomeration of
the BCP particles during printing35. Generally, it is recommended
that the suspension mean particle size be two orders of magnitude
Figure 4. Diagram of stable drop generation as a function of Re, We and Oh smaller than the nozzle diameter (typical nozzle diameters are 20–
numbers. Reprinted with permission from Mckinley and Renardy23.
50 mm)36.
The distance from nozzle to substrate is known as the standoff
distance. This distance is usually minimized to decrease the effects
Table 1. Summary of performance and fluid properties of commercially available of environmental airflow on droplet trajectory; however, this value
CJ and DOD printers.
should also be sufficient to allow proper droplet formation.
Parameters CIJ DOD Typically, a standoff distance of 2–3 mm is used with piezoelectric
Drop velocity (m/s) 10–20 5–10 actuation. When droplets are impacted onto a smooth, nonporous
Drop diameter (mM) 10–150, typically 120 10–150, typically 50 substrate, droplet spreading is primarily a function of droplet
Drop volume (pL) 0.5–2000 0.5–2000 volume and equilibrium contact angle19. When deposited onto a
Fluid viscosity (mPa s) 2–10 10–100
Reynolds No. (Re) 100–1000 2–50
porous substrate, such as paper or a powder bed, the spreading
Weber No. (We) 500–1500 50–150 behavior is additionally influenced by fluid infiltration into the
Ohnesorge No. (Oh) 0.03–0.2 0.1–1 porous substrate. Furthermore, the infiltration is influenced by the
Reprinted with permission from Hon et al.24.
particle size or porosity of the substrate37.
The drying or solidification process also influences the properties
of the final printed dosage form. Most often, drying occurs via
solvent evaporation and thus the rate of evaporation is a function of
Ohnesorge (Oh) number
the solvent system selected. This solvent evaporation can be used
 strategically, such as using a polymer–API–solvent system as
Oh ¼ pffiffiffiffiffiffiffiffi , ð3Þ
a printing ink to prepare an amorphous solid dispersion upon droplet
drying38,39. This provides not only the ability to produce enabling
where , , a, , and  are the velocity, density, characteristic length formulations for poorly soluble compounds, but also the means to
(usually droplet diameter), dynamic viscosity and surface tension, prepare very low dose strengths with the small volume capabilities
respectively. of the inkjet print head. However, the recrystallization of an API form
With low-viscosity fluids, usually resulting in a Z410, a phenom- the print fluid can lead to changes in mechanical properties of the
enon known as satellite drop formation occurs such that smaller dosage form, as well as changes in release behavior; therefore,
droplets are created from the drop tail25,26, as shown in Figure 5. physical stability of printed API should be studied. For example,
The deposition of these satellite drops leads to low-resolution Meléndez et al. showed that the use of an ethanol, water, glycerol
printing and reduced deposition accuracy. Jang et al. showed that solvent system converted prednisolone from Form I to Form III
 1022 L. K. PRASAD AND H. SMYTH

Figure 5. Photographs of proper droplet formation (left) and the improper droplet formation resulting in satellite droplets (right). Reprinted with permission from Jang
et al.26.

after printing40, further emphasizing the need for an appropriate

solvent system selection.
With 3D powder bed printing, the binder concentration may be
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critical to the strength of the final structure. Patirupanusara et al.

investigated the impact of binder concentration of maltodextrin and
polyvinyl alcohol (PVA) as binders for a polymethyl methacrylate
structure41. With this system, at least 10% binder was needed in the
powder bed for successful fabrication. Increase in binder concen-
tration led to decreased porosity and increased strength; however,
at over 40%, deformation in the structure shape was seen.
Patirupanusara described the mechanism of binding as dissolution
of binder in the printed liquid, followed by infiltration into the
powder bed, and finally solidification upon drying. Alternatively, one
could print with binder in the ink solution, as the spraying of wetted
binder can lead to more efficient migration in the powder bed and
potentially enhanced mechanical properties42–44. In this case, one
should evaluate fluid properties of the ink, as polymer solutions can
have complex rheology. Particle size of the powder bed also effects
binder distribution and ultimately the final structure porosity and
strength. Typical layer thickness during powder be inkjet printing
can be 50–200 mm, therefore, average particle size is recommended
to be 50–150 mm45.
Other processing parameters that should be considered include
nozzle diameter, droplet spacing, print head speed, and droplet
Figure 6. Schematic of fused filament modeling (FDM) printer. Reprinted with
frequency and velocity, which can be controlled by the amplitude of permission from Gross et al.18.
the piezoelectric actuation pulse.

utilized for the preparation of tissue scaffolds, its use in the

Fused deposition modeling preparation in pharmaceutical dosage forms has not yet been
Thermoplastic polymers such as polylactic acid (PLA), PVA, and reported in the literature. More recently, the term FDM has
acrylonitrile butadiene styrene are used with the FDM process. Some expanded to include the deposition of anything that can flow
widely used polymers are commercially available as preprocessed through a nozzle or syringe and harden or be hardened to produce
filaments and coiled to allow for easy feed into FDM printing a final structure50,51.
systems, as shown in Figure 6. This process is also referred to as
fused filament modeling. As the filament is fed via the rollers, the
Formulation and process parameters for consideration
filament is heated by heating elements/liquefier into a molten state
to allow for extrusion through the nozzle tip. Upon deposition, the FDM fabricates 3D objects by (1) extruding molten material, (2)
material cools or is cooled and solidifies. depositing them in a layer-by-layer fashion to produce a desired
For added flexibility, a hot melt extruder (HME) can be geometry followed by (3) solidification, usually by cooling of the
incorporated upstream from the printer nozzle46,47. This configur- molten material back to its solid form. FDM is similar to HME in that
ation allows for the preparation of custom formulations, including it the feed material must be extruded through a die or nozzle, thus
amorphous solid dispersions, to be used as the printing material. the feed material must have the appropriate rheological properties
Alternatively, precision extrusion deposition (PED) has been devel- to facilitate processing. These rheological properties are influenced
oped to incorporate a mini extruder just prior to the nozzle, by the nozzle diameter, pressure drop and feed rate, as well as the
allowing for powder/granule feed versus the prefabricated filaments thermal properties of the feed, such as specific heat capacity,
used with standard FDM equipment48,49. While PED has been thermal conductivity, density and glass transition temperature. Aho
 DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY 1023

et al. summarize the various rheological measurement techniques and other attributes that can affect drug release kinetics. These
for the characterization of polymers for use with HME or FDM printed implants have been shown to significantly reduce or
processing52. eliminate burst effect and produce more controlled zero-order
PLA is a biodegradable polymer, with significant application in release than conventional implant fabrication techniques, such as
the manufacture of implants and injectable microspheres53. With a compression or injection molding67–69.
melting point of 150–160  C with reported melt viscosities of less Over the last 10 years, 3D printing has been utilized for the
than 1000 Pas at temperatures above 200  C and 5100 Pas with the fabrication of implantable dosage forms, as well as the treatment of
application of shear stress at elevated temperatures54,55, PLA is implantable devices. In 2007, Huang et al. fabricated monolithic
considered a appropriate polymer for processing by FDM56. PVA is a implants of levofloxacin (LVX) for comparison with implants with
water-soluble polymer, often used in oral dosage forms as a binder, compression, as well as implants with complex architecture for
control release agent or polymer carrier for amorphous solid pulsed and bimodal release70. The printed implants showed more
dispersions53. Although PVA has a higher melting point of 200  C, porous infrastructure than those prepared by compression; thus, the
its melt viscosity has been reported at around 1000 Pas or lower at drug release from the printed implant showed faster and slightly
temperatures above 190  C57,58. Both PLA and PVA filaments are higher burst release than the compressed dosage form18. The
commercially available as feed for the FDM process and have implants printed with an inner drug reservoir and inner and outer
application in pharmaceutical dosage form design. Studies have drug layers were able to show pulsed and bimodal drug release,
been done to impregnate these filaments with API59,60 or to re- respectively. The implants were shown to reach burst or pulse
process the filaments by extrusion to incorporate API47 to create release up to 400 mg and reach a steady state of 120 mg or less for up
drug loaded filaments for use with FDM. With processing tempera- to 90 days70. This group later utilized the bimodal implant
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tures around 200  C for the PLA and PVA, the thermal stability of an configuration for the delivery of two drugs, LVX and rifampicin
API must also be considered. As with HME, the use of plasticizers can (RFP)71, with immediate release (IR) of LVX on day 1 and delayed
aid in reducing melt viscosity of a polymer to decrease processing release of the inner reservoir of RFP on day 8, with sustained release
temperatures, as needed. Other materials are being investigated for of both APIs through 6 weeks, showing the ability to prepare a
use with the FDM process; however, these materials may or may not combination produce with multimechanism release behavior.
be suitable for pharmaceutical use61–64. Medical implants and devices, such as stents and catheters, are
Processing parameters for FDM include nozzle diameter, feed treated with active solutions or suspensions for local drug delivery,
rate, block and nozzle temperatures, head speed and envelope usually by coating or spray-coating techniques72,73; however, 3D
temperature. These parameters should be optimized for a given printing offers increased efficiency, spatial and volume control for
feed material such that there is accurate deposition, but also the treatment process. Tarcha et al. showed the ability to deposit
sufficient bond formation to impart strength into the fabricated drug solutions onto stents using CJ print heads for a low dose
structure. Bond formation between two filaments is driven by coating with high accuracy and repeatability on various stent
surface contact, coalescence or neck growth, and potentially configurations and with improved coating efficiency over standard
molecular diffusion and polymer chain entanglement. Sun et al. coating methods74. Gu et al. utilized a piezoelectric print head to
found that the cooling profile of the deposited material greatly deposit micropatterns of RFP containing PLGA dots, 50 mm droplet
affects bond formation and strength65. The cooling profile is a diameter, onto an orthopedic implant to prevent biofilm formation
function of the thermal conductivity of the extruded material, but is from bacterial adherence to the implant35. These studies showed full
greatly influenced by the surrounding environment, including the release and biofilm prevention over 24 h, showing feasibility of drug
envelope temperature and convective conditions during fabrication. delivery with minimal obstruction of the implant surface. Gupta
These environmental conditions can be adjusted to enable et al. evaluated printing of drug-loaded capsules onto a hydropho-
deposited material to stay at or above glass transition temperatures bic surface that were further functionalized with a polymeric coating
for longer duration, allowing for greater bond formation, reduction containing gold nanorods75. Using a laser trigger, the gold nanorods
of voids and a corresponding increase in bond and overall structure absorbed the energy leading to local heat generation and rupture of
strength. the PLGA capsule shell to release the encapsulated drug – in this
study fluorescent dextran was used to show proof-of-concept.
Alternatively, drug delivery devices can be fabricated using 3D
3D printing of drug delivery systems
printing techniques. Sandler et al. were able to incorporate an anti-
This section will highlight the range of dosage forms prepared using microbial agent, nitrofurantoin (NF), into PLA to produce filaments
3D printing technologies, specifically highlighting studies con- by hot melt extrusion and subsequently use those filaments to feed
ducted over the last 10 years, 2006–present. a 3D printer to fabricate a model drug eluting device, such as a
catheter47. The drug loaded PLA device showed better inhibition of
biofilm formation (85%) than the coated device (24%), most
3D printing or treatment of implants probably due to the slower release of NF from the polymer matrix.
Shortly after patenting and publishing on 3D powder bed inkjet A summary of the 3D printing for the treatment or fabrication of
printing14,66, researchers at MIT fabricated biodegradable implants drug delivery implants over the last 10 years is shown in Table 2.
to show proof of concept of their technology to produce drug
delivery devices67. Wu et al. used polyethylene oxide as the polymer 3D printing of tablets
matrix and polycaprolactone (PCL) as a rate limiting component and
prepared various systems with methylene blue and alizarin yellow Early work with 3D printing of tablet dosage forms was conducted
dyes as surrogates for API. These studies showed the ability for using 3D powder bed printing5,8,80. Katstra et al. highlighted the
accurate placement of small volume droplets of dye solution and ability to achieve appreciably low drug deposition, measuring 1012
microstructural control, such as wall thickness, as a function of moles or 0.34 ng per droplet, using a 10.6 mg/mL active solution. He
binder deposition and print speed. This technique showed potential also conducted physical characterization of the resulting tablets
for more control over the geometry, surface area, spatial deposition showing the ability to obtain comparable hardness and friability to
 1024 L. K. PRASAD AND H. SMYTH

Table 2. Summary of studies for the fabrication of implants using 3D printing (2006–present).
Dosage form API 3D technique (equipment) Summary Ref.(s)
76
Implant, CR Dye (surrogate) FDM (FDM 3000, Stratasys) Prepared prototype drug delivery devices using ABS with
a cylindrical geometry consisting of an API solution
reservoir (dye) at one end, with a porous matrix at the
other. Showed ability to control drug diffusion by
controlling matrix porosity.
74
Coated stent Fenofibrate, Inkjet (developmental version of Showed high coating efficiency using CJ for coating of
Zotarolimus JetLab II, Microfab Tech.) stents, with the ability to deposit low dose, 100 mg,
with precision (SD of 0.6 mg). Drug release was
comparable to stents produced by spray coating.
70,71
Implant, CR RFP, LVX Powder bed inkjet (Fochif Co.) Implant geometries designed for sustained and/or
delayed release of LVX from PLA matrix, as well as
combinations with delayed and sustained release of
RFP. Combination implants confirmed multimechan-
ism release using in vivo rabbit model.
35
Coated orthopedic RFP, BCP (bioceramic) Inkjet (Dimatix Materials Printer, Piezoelectric print head was used to deposit 50 mm
implant Fujifilm Dimatix) microparticles RFP encapsulated in PLGA onto implant.
Addition of dispersed BCP resulted in nozzle clogging
and splashing, due to BCP agglomeration.
77
Implant, SR Dexamethasone-21- Custom Dex21P in varying molecular weight PVA solutions were
phosphate diso- printed onto PLGA film either rolled or sandwiched
dium salt (Dex21P) between another PLGA layer, with the latter technique
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showing reduced burst and longer release (4100

days).
47
General device NF FDM (Up! Plus, PP3DP) HME was employed to create drug loaded 1.7–1.8 mm
(i.e. catheter) diameter PLA filaments for use with FDM printer.
Printed implant showed better inhibition of biofilm
formation (85%) than the coated device (24%), due to
the slower release of NF from the matrix.
78
General device Gentamicin sulfate FDM (Makerbot ReplicatorÕ 2X) PLA pellets were coated with silicone oil and drug prior to
(GS), methotrexate HME to create drug loaded filaments. Extrusion was
(MTX) conducted at 175 and 160  C for GS and MTX filaments
and were shown to have activity postextrusion.
Printing of GS discs was conducted at 4200  C, but
retained antibacterial activity.
75
Functionalized coating Dye, fluorescent dex- Custom (based on Fisnar Two-component system was printed on hydrophobic
tran (surrogates) F5200N) surface: aqueous drug-containing core and PLGA gold
nanorod-containing shell. The type of gold nanorod
utilized could be programmed such that a given laser
wavelength triggered the rupture of the shell and
therefore, release of the drug from the core.
79
Implant NF, hydroxyapatite FDM (Makerbot ReplicatorÕ 2) HME was employed to create drug loaded 1.6 mm
(bioceramic) diameter PLA filaments for use with FDM printer.
Surface roughness of printed disk and drug release
rate increased with increased drug loading.

compressed dosage forms by increasing polymer/binder concen- a doughnut shape, as shown in Figure 783. This shape had been
trations8; however, 3D inkjet printing generally produces more previously shown to produce zero-order release by controlling
porous and therefore more friable tablets that those prepared by surface area during erosion84,85; however, manufacturing these
compression81. The increased porosity with 3D inkjet printing has tablet geometries required complex compression processes. Yu
been attributed to incomplete interaction with the printed binder et al. made a structure with the top and bottom layers comprised
solution, leading to areas of ‘‘unbound’’ particles18. Aprecia ethylcellulose (EC) to produce impermeable layers; the inner core
Pharmaceuticals took advantage of this increased porosity to was prepared using an active blend of acetaminophen (APAP) with
create orodispersible tablets that rapidly dissolve (10 s) with very the binder used for the outer surface (shown in gray in Figure 7)
small amounts of water (15 mL or less)82. Their patented ZipDoseÕ consisting of 2% EC to create a slower release rate from the outer
technology is adapted from the powder bed printing technology surface. 3D inkjet printing allowed for the fabrication of very thin,
developed at MIT and boasts the ability to support drug loading up but functional barrier layers on the top and bottom, as well as an
to 1000 mg. This technology led to the development and approval EC-containing outer surface. Theoretically, this geometry allows for
of SpritamÕ (levetiracetam) for the treatment of epilepsy, particu- the decrease in the surface area due to the outward releasing
larly in pediatric and geriatric patient populations that have portion and the increase in the surface area of the inward releasing
difficulty swallowing tablets. The rapid dissolution allows for rapid portion to be more synchronized to produce a zero-order release.
onset of action with Tmax achieved in as little as 9 min82. Zero-order release was seen for the printed tablet with the release
Rowe et al. emphasized the ability of 3D fabrication to produce rate varying with the thickness of the rate-controlling membrane
complex dosage forms by producing tablets with IR and extended and tablet height. Moreover, no burst release was seen, as can be
release (ER) components, delayed release, pulsatory drug release, the issue with many sustained release formulations.
inclusion of multiple APIs, and breakaway tablets that generate Most recently, prefabricated PVA filaments have been utilized as
smaller fixed geometries with tailored erosion rates5. Using this drug carriers for the fabrication of tablet by FDM59,60,86. Goyanes
flexibility for the printing of geometries that are not readily et al. were the first to evaluate the use of FDM with the
prepared through tablet compression, Yu et al. prepared tablets in incorporation of fluorescein into commercially available PVA
 DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY 1025

Figure 7. Doughnut-shaped tablet for zero-order release. Reprinted with permission from Yu et al.83.
Downloaded by [McMaster University] at 13:28 28 November 2017

Figure 8. Schematic of infill percentage with FDM of tablets Budmen et al.87.

filaments and the printing of tablets of different infill percentages. crystalline. This study showed not only the ability to prepare highly
After a shell is printed, the infill percent determines the amount of tailored FDC dosage forms, but also the ability to use an amorphous
material packed into that shell; 0% infill would result in a hollow solid dispersion as feed filament – a valuable tool given the number
shell and 100% infill would lead to a completely solid geometry, as of poorly soluble compounds currently in the market and under
shown in Figure 887. The tablets showed a slower release with development89–91.
increase in infill percentage, showing a more ER profile60. Goyanes To increase the range of polymers that can be used with FDM,
et al. then incubated PVA filaments in a solvent solution of Pietrzak et al. evaluated the use of methacrylic polymers, Eudragit
aminosalicylates; aqueous solutions cannot be used, as PVA is water- RL, RS and E, and cellulosic polymer HPC to extrude theophylline
soluble. The solubility of the API in solvent affected the resulting loaded filaments92. To facilitate processing at lower temperatures,
drug entrapment, with 5-ASA (0.092 mg/mL ethanol solubility) and up to 7.5% triethyl citrate was added as a plasticizer.
4-ASA (47.99 mg/mL ethanol solubility) producing 0.06% and 0.25% Thermogravimetric analysis showed that although the physical
drug loading, respectively. Additionally, the 4-ASA was shown to be mixtures showed a degradation event at 170  C, the upper end of
less thermally stable at the high processing temperatures used for the reported temperatures used for FDM, the drug content of the
FDM (210  C), showing 50% loss of potency in the final tablet86. final printed tablet was 91–95% of theoretical. FDM can require
Skowyra et al. used the same process but with prednisolone, which temperatures of 20–50  C greater than those required for HME,
shows greater thermal stability, and successfully manufactured a albeit for shorter duration; however, the impact of this thermal
range of tablet dose strengths with 88.7–107% of the target potency stress during both thermal processes may contribute to degradation
achieved. of the polymer and/or API and must be considered.
As stated earlier, the incorporation of HME upstream allows for Khaled et al. have recently conducted studies to produce FDC
added flexibility for the composition of the filaments used for FDM. products with up to five different APIs with varying drug release
Goyanes et al. prepared drug loaded PVA filaments with each APAP mechanisms – from IR to first-order and zero-order SR93,94. However,
and caffeine (CAF) using HME88. These filaments were then used for instead of FDM by heating and layering thermoplastic filaments,
FDM to prepare fixed dose combination (FDC) tablets containing Khaled produces pastes of varying drug-containing formulations to
both drugs in a multilayer and tablet-in-tablet configuration. The extrude at room temperature. Although, this removes the require-
multilayered tablets showed simultaneous release of both drugs, ment for high temperature thermal processing, it introduces the
while the tablet-in-tablet geometry showed a delayed release of the need for solvents and a secondary drying step to remove solvents
inner component by 50 minutes when the outer layer was APAP and and set the final dosage form.
135 min with the outer layer was CAF. The APAP was rendered A summary of the 3D printing for the fabrication of tablets over
amorphous during the HME process, while the CAF remained the last 10 years is shown in Table 3.
 1026 L. K. PRASAD AND H. SMYTH

Table 3. Summary of studies for the fabrication of tablets using 3D printing (2006–present).
Dosage form API 3D technique (equipment) Summary Ref.(s)
95
Tablet, ER Acetaminophen Powder bed inkjet (Fochif Co.) Fabricated tablets using radial gradients of different
rate controlling excipients and impermeable EC
top and bottom to produce near zero-order
release.
96
Tablet, ER Pseudoephedrine HCl Powder bed inkjet (TheriFormä/ Water-soluble drug release modulated by outer rate
3-DPä machine) limiting shell material. In vitro tests showed no
sensitivity to pH and hydrodynamics. In vivo results
showed Level A IVIVC for near zero-order release.
97–99
ODT Acetaminophen Powder bed inkjet (Fochif Co.) Fabricated ODT tablets with bound outer shell and
free powder fill will disintegration under 30 s and
acceptable mechanical properties (51% friability)
82
ODT Levetiracetam Powder bed inkjet (Custom) Prepared rapidly dissolving (510 s) ODT that requires
little water (515 mL) with up to 1000 mg drug
loading of water soluble API. Higher printer fluid
saturation used on outer edges and top and
bottom to increase hardness of overall ODT.
83
Tablet, ER Acetaminophen Powder bed inkjet (Fochif Co.) Fabricated doughnut-shaped tablets with imperme-
able top and bottom to produce zero-order release
from sides.
81
Tablet, IR/ER bilayer Guaifenesin FDM (Fab@home) Pastes of IR and ER formulations extruded into bilayer
tablets; lower hardness, friability and slightly faster
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release profiles were seen when compared to the

commercial tablet.
93
Tablet, SR Captropril (CAP), Nifedipine FDM (RegenHU 3D Printer) Pastes of individual formulations for each drug
(NIF), Glipizide (GLI) prepared for extrusion at room temperature;
pastes prepared with acetone–DMSO (3:1) or
water. Zero-order release seen with CAP due to
osmotic drug release mechanism, while NIF and
GLI showed first-order SR from hydrophilic matrix.
94
Tablet, IR/SR Pravastatin, atenolol, ramipril, FDM (RegenHU 3D Printer) Preparation of paste similar to above study. IR release
aspirin, profiles obtained for aspirin and hydrochlorothia-
hydrochlorothiazide zide, while the remainder showed SR release over
720 h.
60
Tablet Fluorescein FDM (Makerbot ReplicatorÕ 2) 0.29% drug load impregnated by incubation with PVA
filaments. Tablets made with 0–100% infill showed
slower release with more infill (less porosity).
86
Tablet, MR 5-ASA, 4-ASA FDM (Makerbot ReplicatorÕ 2) Only 0.06% drug load achieved for 5-ASA with
incubation due to poor solvent solubility. 4-ASA
was significantly degraded (50%) during process-
ing due to high temperatures (210  C). Very strong
tablets, with 0% friability, manufactured.
59
Tablet, ER Prednisolone (2–10 mg) FDM (Makerbot ReplicatorÕ 2X) Drug impregnated by incubation with PVA filaments
at 1.9% drug load; 88.7–107% theoretical dose
strength achieved. API was mostly amorphous in
final tablet.
100
Tablet Acetaminophen FDM (Makerbot ReplicatorÕ 2X) Study evaluated the effect of surface area, surface
area to volume ratio, and tablet weight on
dissolution of varying geometries. Higher surface
area to volume ratios exhibited faster release rates.
Constant weights showed less variability in release
indicating erosion-mediated release from PVA
matrix.
101
Tablet, MR (Capsule) Acetaminophen FDM (Makerbot ReplicatorÕ 2) Utilized HME to prepare HPC filaments that were then
fed to FDM to prepare hollow capsule shell. Wall
thickness of 700 mm was tested against compar-
able dimensions of a capsule prepared using
injection molding. The standard FDM 0.4 mm tip
was replaced with a 0.2-mm tip to enable
deposition for thin walls. Delayed release of
encapsulated APAP was seen with both FDM and
IM capsules with 70 min to 10% drug release,
followed by 10 min for 100% release.
88
Tablet, IR and MR Acetaminophen, CAF FDM (Makerbot ReplicatorÕ 2X) Utilized HME to produce drug loaded PVA filaments of
each drug; filaments were then used to prepare
FDC with a multilayered tablet for simultaneous
release and tablet-in-tablet (DuoCaplet) for
delayed release. One hundred percent infill
produced tablets with high hardness (4hardness
tester measurement range) and 0% friability.
Tablet design was comparable to a Size 4 capsule
showing ability to produce more rounded features
for ease of swallowing. APAP and PVA produced
amorphous solid dispersion during HME.
 DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY 1027
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Figure 9. Micrograph of (a) array of and (b) single miconazole-loaded microneedle. Reprinted with permission from Boehm et al.108.

3D printing of transdermal delivery systems Alternative applications of printing technologies

Transdermal delivery systems can be advantageous to avoid first- One of the more unique potentials of the use of 3D printing
pass metabolism and/or pH mediated degradation or to allow for techniques in pharmaceuticals is the ability to prepare dosage forms
ease of administration for patients with chronic illnesses, such as at the point of care. Most drug product manufacturing processes
diabetes. The layer-by-layer 3D printing techniques could readily include multiple unit operations, such as blending, compression
be utilized for the preparation of multilayered transdermal and/or coating, and produce large volumes of drug product at
patches of films; however, 3D technology offers a unique predetermined dose strengths. These products must display chem-
advantage for the printing of drug-loaded microneedles for ical and physical stability through manufacturing, packaging and
transdermal delivery. Microneedles are generally less than 500 mm storage for months to, preferably, years. The ability to print dosage
in height and are meant to penetrate the stratum corneum forms at the point of care would allow for flexible and individualized
(10–15 mm) to deliver active agents102. These needles should be dose strengths without the prerequisite of a long shelf-life (years),
sufficiently strong to penetrate the epidermis, but not too strong thus increasing the therapeutic options available to
as to cause pain or irritation; insertion forces have been measured patients31,38,109,110. In addition to printing conventional dosage
between 0.1 and 3.0 N and clinical studies have shown little to no forms, i.e. tablets, individualized dosage forms can be prepared by
pain reported with the use of 150 mm microneedles against a 26- printing active solution or suspension onto edible substrate, such as
gauge needle control103,104. Additionally, biodegradable polymers paper or other oral film, as shown in Figure 10, or onto a tablet39,111.
are preferred for the fabrication of these needles in the case that The ability for rapid, accurate and low volume delivery using
a tip breaks off and is impregnated in the skin. The size, shape inkjets can also be used in a supportive role for drug development
and number of microneedles make them a complex geometry to to screen drug candidates112–114, polymorphs40 and formulations38,
construct and/or coat but ideal for the capabilities of 3D printing as well for high throughput assays115. Scoutaris et al. demonstrated
technologies. the use of an inkjet printer to screen different drug loads for a
Boehm et al. utilized two additive manufacturing processes felodipine-PVP amorphous solid dispersion formulation38, using
to prepare drug-loaded microneedles. SL was used to prepare ATR-IR, thermal analysis and confocal Raman microscopy to
microneedles of poly(methyl vinyl ether-alt-maleic anhydride), a characterize the homogeneity and crystalline nature of the printed
biodegradable polymer, and inkjet printing was used to coat dispersions. The results from this small-scale screening were
the needles with quantum dot as a model active agent105. consistent with previous studies of felodipine-PVP amorphous
These microneedles were shown to have good mechanical solid dispersions supporting the use of inkjet printing for formula-
strength for transdermal administration and Boehm et al. later tion screening.
applied the stereolitrography and inkjet techniques to produce Inkjet technology is also an attractive technique for the prepar-
microneedles with antimicrobial properties106, coated with ation of monodisperse particles. Drop on demand print heads can
amphotericin B107 and loaded with miconazole108. The micro- be used to dispense polymer-API solutions into a solvent extraction
needles coated with quantum dot and amphotericin B solutions media or crosslinking solution to prepare uniform drug encapsu-
showed some changes to the microneedle surface and geom- lated microspheres116, allowing for more particle size control than
etry, attributed to the wetting of microneedle surface by the standard manufacturing methods, such as double emulsion solvent
printing ink. The studies with the miconazole show less of an evaporation or spray drying117,118. Microspheres, and specifically
effect on the structure of the microneedle, as the deposition biodegradable microspheres, have been of great interest as drug
was concentrated at the top of the needle versus coating the delivery systems, as they can be designed for particle size, shape,
surface of the needle, as shown in Figure 9; a characteristic porosity and degradation rate to enable a high degree of control in
that would be difficult to obtain using conventional dip coating the drug release rate and duration118–120. Particle engineering has
techniques. also been an intense area of research for the development of
 1028 L. K. PRASAD AND H. SMYTH

manufacturing of customized, complex and innovate dosage

forms. Their use in the screening, development and manufacturing
of drug delivery systems will only increase as there is more
understanding of and need for tailored drug release profiles and
personalized dose strengths to better address complex dosing
regimens and heterogeneous patient populations.

Declaration of interest
The authors declare no conflict of interest.

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