Special Feature

Three-dimensional drug printing:

A structured review
Iulia Ursan, Ligia Chiu, and Andrea Pierce

Received November 11, 2012, and in re-

Abstract vised form February 1, 2013. Accepted for
publication February 6, 2013.

Objectives: To summarize the published literature on existing three-dimen-
sional (3D) printing (3DP) technologies for pharmaceutical manufacturing,
describe the limitations of the 3DP process, and highlight the potential of
these technologies in pharmacy practice.
Iulia D. Ursan, BA, is a student pharmacist;
Ligia Chiu, BS, is a student pharmacist;
and Andrea Pierce, BS, is a student phar-
macist, College of Pharmacy, University of
Illinois at Chicago.

Correspondence: Iulia D. Ursan, BA, Col-

Data sources: A structured search of PubMed and Embase was performed lege of Pharmacy, University of Illinois at
to identify articles published between January 1, 1990, and August 31, 2012. Chicago, M/C 874, 833 S. Wood St., Chi-
Search terms included drug printing, drug 3D printing, and drug three-dimen- cago, IL 60612. Fax: 312-996-3272. E-mail:
iursan2@uic.edu
sional printing.
Disclosure: The authors declare no con-
Study selection: Original research articles describing 3DP related to drug flicts of interest or financial interests in any
manufacturing were included. product or service mentioned in this article,
including grants, employment, gifts, stock
holdings, or honoraria.
Data extraction: Ink formulation, printing substrate, printing technol-
ogy, drugs printed, and results of each study. Acknowledgments: To Glen T. Schumock,
Center for Pharmacoepidemiology and
Data synthesis: 21 of 511 identified references were included in the review. Pharmacoeconomic Research, University
of Illinois at Chicago, for assisting with this
Inkjet and powder-based printing were the primary printing technologies structured review.
used for drug development and fabrication. Eleven articles described a
powder delivery system, and 10 identified inkjet printing. These printing
technologies are currently being used in the pharmaceutical manufactur-
ing process with the promise to transform pharmacy practice. Advantages
include precise control of droplet size, high reproducibility, complex drug
release profiles, and personalized medication therapy.

Conclusion: Individualized medications fabricated through 3DP may of-

fer an important benefit to patients. Printable dosage forms on paper may
be easier to deliver to the patient than powder-based printed forms. In ad-
dition, medications that have narrow therapeutic indices or have a higher
likelihood to be influenced by genetic polymorphisms may be the first to be
printed via this technology.
Keywords: 3D drug printing, pharmaceutical innovation, drug manufac-
turing, personalized medicine
J Am Pharm Assoc. 2013;53:136144.
doi: 10.1331/JAPhA.2013.12217

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A s future pharmacists in a technology-driven gener-
ation, we cannot help but ask the question, What
technology will drive pharmaceutical manufacturing
or even pharmacy dispensing in the future? Although
some might argue vending machines or other auto-
mated dispensing systems are the future, we believe an
equally promising future direction is the three-dimen-
sional (3D) drug printer.
3D printing (3DP) is a relatively new technology that
was first described in the early 1990s.1 In its most basic
setup, 3DP uses computer-aided drafting technology
and programming to produce a 3D object by layering
material (e.g., ink) onto a substrate. The material is first
ejected from a printer head onto an xy plane to create
the foundation of the object. The printer then moves
along the z-axis, and a liquid binder is ejected onto the
base of the object to a certain thickness. This process is
repeated following the computer-aided drafting in-
structions until the object is built layer by layer. After
treatment to remove the unbound substrate, the object
is complete.
Since the process was first described, 3DP has been
used in many fields such as architecture, medicine, and
At a Glance
Synopsis: Three-dimensional (3D) printing (3DP)
technologies allow for the creation of highly re-
producible pharmaceutical dosage forms with
precise control of droplet size and complex drug
release profiles. 3DP technology may offer an im-
portant benefit to patients who need medications
that have narrow therapeutic indices or a higher
predilection to be influenced by genetic polymor-
phisms. This review of the literature identified
inkjet printing and powder-based printing as the
primary printing technologies used for drug de-
velopment and fabrication.
Analysis: 3DP technologies may transform pharmacy
practice by allowing medications to be truly individual-
ized and tailored specifically to each patient, although
technical and regulatory hurdles remain. At least some
3D printed drug products do not have proper hardness
and binding of materials to justify using a printer, as
the ink formulation components must be able to self-
bind but not bind to other printer elements, which could
interfere with the timing of drug release. Also, meeting
the regulatory requirements of the Food and Drug Ad-
ministration could be a hurdle to be cleared before large-
scale use of 3D printed products could be realized. In
addition, different manufacturing regulations and state
board requirements could impose obstacles to the adop-
tion of the drug printers in practice. An imperative dif-
ference must be established to distinguish drug printers
as manufacturing or compounding technologies.
Journal of the American Pharmacists Association
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3d drug printing Special Feature
even pharmaceutical manufacturing.2 A variety of 3DP
technologies have been used to produce novel dosage
forms, which are among the most renowned and distinct
product outcomes.2,3 To our knowledge, no comprehen-
sive review of the use of this technology in the area of
pharmaceutical manufacturing has been conducted.
Objectives
We sought to summarize the published literature on ex-
isting 3DP technologies for pharmaceuticals, describe
the limitations of the 3DP process, and highlight the po-
tential of these technologies in pharmacy practice.
Methods
A structured search of PubMed and Embase identified
articles published between January 1, 1990, and August
31, 2012 (Figure 1). Search terms included drug printing,
drug 3D printing, and drug three-dimensional printing.
Original research articles describing 3DP related to drug
manufacturing were included. Editorials, opinion piec-
es, reviews, and articles not focused on 3D drug print-
ing were excluded. Working separately, two reviewers
examined each abstract to determine whether it was eli-
gible for full-text review. A third reviewer resolved the
discrepancies about article inclusion. Article abstracts
were screened, and those not excluded were subjected
to full-text review. 3DP technologies were classified
based on the self-reported technology design identified
by the original author(s).
Results
Of 533 citations identified, 21 studies met our inclu-
sion criteria. Abstracted information provided details
about the objective(s) of the study; the ink formula-
tion, printing substrate, printing technology, and drugs
printed; and the results (Table 1). Drug development
and fabrication printing technologies were categorized
into one of two types of 3DP: inkjet printing (n = 10) and
powder-based printing (n = 11). Both inkjet and pow-
der-based printing follow the basic setup of a 3D printer
but differ in the materials forming the solid object. We
categorized the studies according to the substrate used;
however, studies can be categorized using alternative
criteria.
Objectives and topics
We found a variety of the objectives and topics in the
original publications, ranging from producing mi-
crocapsules to creating hyaluronan-based synthetic
extracellular matrices to provide biomaterials.4,5 The
most common topics included encapsulation technolo-
gies, orally disintegrating tablets, printed antibiotic
micropatterns, printable dosage forms on porous sub-
strates, printed mesoporous bioactive glass scaffolds,
nanosuspensions, and multilayered drug delivery de-
vices.425 The publications also covered a wide range of
j apha.org MAR /APR 2013 | 53:2 | JAPhA 137
 Special Feature 3d drug printing
Publications identified from PubMed and Embase
(published between January 1, 1990, and August 31, 2012)
511 citations identified and screened
44 citations
21 citations included
Figure 1. Structured search of literature on 3DP technologies
Abbreviation used: 3D, three dimensional; 3DP, 3D printing.
drug agents, such as steroidal anti-inflammatory drugs,
acetaminophen, vancomycin, ofloxacin, tetracycline,
dexamethasone, paclitaxel, folic acid, and others.5,7,9,10,15
These final products were created using inkjet printing
or powder-based printing.
Inkjet printing
Home inkjet printers work by forming small ink drop-
lets on paper. In the same fashion, drug inkjet printers
form small liquid droplets and deposit them onto a
substrate. Inkjet printers prepare the ink formulation,
which consists of binders and medications, and spray
the ink droplets at precise velocity, motion, and size
onto a nonpowder substrate. Investigators ten Cate et
al.4 improved this technology by spraying the ink drop-
lets onto a liquid film that encapsulates the uniform
ink droplet. Prestwich5 formed microparticles by com-
bining inkjet printing with this unique encapsulating
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Excluded (abstract review, n = 467)
Review (n = 30)
Editorials or opinions (n = 7)
Not focused on 3D drug printing
(n = 430)
Excluded (full-text review, n = 23)
Not an original study describing
3DP related to drug
manufacturing
technique. These matrices may be used for delivery of
small hydrophobic molecules, growth factors, antibod-
ies, microparticles, and nanoparticles. These technolo-
gies have further been used to produce pharmaceutical
dosage forms on porous substrates (e.g., paper) for drug
implants with fabricated micropatterns that have eradi-
cated Staphylococcus epidermidis bacteria.68
Powder-based printing
The powder substrate differentiates inkjet and powder-
based 3DP. The inkjet printer head sprays the ink onto
the powder, which is laid as a foundation. This ink acts
as a binder and/or active ingredient. When it contacts
the powder, it hardens and creates a solid. The ink-
jet head continues to spray the liquid onto the powder
through subsequent layers until a solid forms. After it
is dry, the solid object is removed from the surrounding
unprinted loose powder substrate.
Journal of the American Pharmacists Association
 Table 1 continued
Table 1. 3DP: Summary of studies meeting inclusion criteria
Article Objective(s)
ten Cate et al., To produce novel encapsulation
20104 technology for the preparation of
coreshell microparticles
Prestwich, To create a hyaluronan-based
20115 synthetic extracellular matrix that
provides highly reproducible, manu-
facturable, approvable, and afford-
able biomaterials
Gu et al., To characterize the morphology
20126 of inkjet-printed micropatterns as
a function of ink formulations and
printing parameters, to measure
antibiotic release rates from the
Journal of the American Pharmacists Association
micropatterns as a function of the
composite compositions, and to
evaluate the in vitro efficacy of the
micropatterns in killing Staphylo-
coccus epidermidis bacteria and
promoting osteoblast development
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Sandler et al., To produce printable pharmaceutical
20117 dosage forms on porous substrates
j apha.org
such as paper
Wu et al., Used 3DP technology to fabricate a
20098 programmed release multidrug im-
plant for bone tuberculosis therapy.
Gbureck et To investigate the adsorption and
al., 20079 desorption kinetics of different
MAR /APR 2013 | 53:2 |
antibiotics to microporous bioc-
eramics fabricated by a novel low-
temperature 3D power direct printing
process
JAPhA 139
Ink formulation
Linseed oil, carrageenan (3
w%) dissolved in demate-
rialized water for the shell
material, sodium alginate (3
w%), and CaCl2 (5 w%) in
dematerialized water
Endothelial cells encap-
sulated within a synthetic
extracellular matrix
Dimethyl sulfoxide, poly(d,l-
lactic-co-glycolic), biphasic
calcium phosphate nanopar-
ticles; used to accelerate
osteoblast cell differentiation
Ink solutions containing the
drug substances were dis-
solved in propylene glycol
purified water (30:70, v%).
Rifampicin and isoniazid
were dissolved in methanol
and distilled water, respec-
tively, at a concentration of
150 mg/mL. Acetone was
added at a rate of 20:80 v/v.
The printing liquid was
a mixture of 0.5 mmol/L
Ca(H2PO4)2 in 10% phos-
phoric acid.
Printing substrate Technology Drugs Results
NA Inkjet printing NA Water-in-lipid, water-in-water, and lipid-in-water
based microcapsules were produced. The encapsulation
process and greater loading capacity may improve drug
delivery systems.
NA Inkjet printing Steroidal anti- The steroids release over the course of days to weeks. An
inflammatory inverse correlation between the hydrophobicity of steroid
drugs (small and the rate of release was observed. These matrices may
hydrophobic be used for delivery of growth factors, small molecules,
molecules) antibodies, microparticles, and nanoparticles.
Polished titanium Inkjet printing Rifampicin Rifampicin release is influenced by the nanocomposite
alloy substrates morphology. The smaller rifampicin nanoparticles exhibit
a more steady release because their dissolution is expect-
ed to be dictated by the degradation kinetics of the matrix.
Both planktonic bacteria and biofil colonies were found
in the rifampicin-free control changers but were absent in
the chambers with rifampicin-containing patterns.
Uncoated paper, Inkjet printing Acetaminophen, Penetration of the substances into the porous paper struc-
coated paper, and anhydrous tures enables controlling not only the deposition but also
polyethylene tere- theophylline, the crystallization of the drug substances.
phthalate film and caffeine
Poly(d,l-lactic-acid) Desktop 3DP Isoniazid and The drug release profile indicated that the drug implant
machine: pow- rifampicin was observed to have a distinct programmed or controlled
der delivery drug release property. The antibiotics were released
system orderly in a certain sequence as we ranged them in the
order of isoniazidrifampicinisoniazidrifampicin from
the periphery to the center, which was just like a pulsed
drug release.
Hydroxyapatite, Desktop 3DP Vancomycin, This study demonstrated the potential to combine a novel
3d drug printing Special
brushite, and monetite machine: pow- ofloxacin, and 3D bioceramic powder printing process with adsorption
der delivery tetracycline of antibiotics to create a delivery system. Drug release for
system all structures was found to follow an exponential kinetic
with a quantitative drug release after approximately 2
days, whereas the hydroxyapatite samples were found to
release the drug comparatively slower than the brushite
Feature
and monetite matrices.
 Table 1 continued
Wu et al., To demonstrate that 3D printed
201110 mesoporous bioactive glass scaf-
folds may be excellent candidate for
bone regeneration
Yu et al., To describe a fast-disintegrating
200911 tablet that contains loose powders
on the inner region fabricated by
3DP technology
140 JAPhA | 5 3 :2 | M AR/AP R 2013
Yu et al., To produce complex tablets with
200712 zero-order drug release charac-
teristics fabricated by using 3DP
processes
ja p h a .org
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Rowe et al., To fabricate more complicated oral
200013 dosage forms using the 3DP pro-
cess: immediate release, breakaway,
enteric dual pulsatory, and dual
pulsatory
Katstra et al., To confirm the ability to modulate
200014 release properties of devices by
changing the printing parameters
and to verify the precise dosage con-
trol and spatial positioning inherent
to the process
Journal of the American Pharmacists Association
The injectable mesoporous
bioactive glass paste was
prepared by mixing 3 g glass
powder with 3.3 g aqueous
PVA solution (15 w%).
Mixed powder contained
acetaminophen, lactose,
polyvinyl pyrrolidone, K30,
mannitol, and colloidal sili-
con dioxide.
Drug premixed with excipient
powders and held together
by binder solution containing
release retardation materials:
hydroxypropyl methylcellu-
lose, ethyl cellulose, Eudragit
RS 100, stearic acid, and
sodium lauryl sulfate
Formulation of binder solu-
tions and active solutions
differed for each release
mechanism.
Binders: 20 w/w% Eudragit
E-100 and ethanol, active
30 w/w% chlorpheniramine
maleate/water; Eudragit
RLPO 20 w/w%/acetone,
active 30 w/w% chlorphe-
niramine maleate solution;
Pharmatose DCL spray dried
lactase in powder bed, binder
22% polyvinyl pyrrolidone
and 0.1% Tween 20.
3D printed mesopo- Desktop 3DP Dexamethasone Novel multifunctional mesoporous bioactive glass
rous bioactive glass machine: pow- scaffolds with a hierarchical pore architecture and well-
scaffolds were used der delivery ordered mesopores were successfully prepared using
for cell culture. system the method of 3DP combined with PVA as a binder. 3DP
method produces a more uniform and continuous pore
structure.
Binder liquid methy- Desktop 3DP Acetaminophen Scanning electron microscope images show printed
Special Feature
lene blue (0.05% w/v) machine: pow- regions were bound together; particle size was reduced
and polyvinyl pyrrol- der delivery or not distinguishable. In vitro dissolution tests showed
idone K30 (5.0% w/v) system 97.7% acetaminophen was released in initial 2 min.
in 75% (v/v) ethanol
in water
Powder bed (ethyl Desktop 3DP Acetaminophen Matrix tablets showed material gradients in the radial
cellulose) machine: pow- direction and had drug-free release barrier layers on both
der delivery bases. The ethyl cellulose tablets showed acceptable
3d drug printing
system mechanical and pharmacotechnical properties. Erosion
and dissolution studies showed 98% of drug released
linearly in 12 h.
Microcrystalline cel- Desktop 3DP Chlorphenira- Devices in this study demonstrated the ability to mix two
lulose powder or 30 machine: pow- mine maleate different release mechanisms, erosion and diffusion, in
wt% Avicel PH301, 30 der delivery and diclofenac two halves of a single device. Pulsatory devices were
wt% Pharmatose DCL system fabricated to release two pulses in the intestine or one
100 spray dried lac- pulse in the stomach and a second in the intestine.
tose, 40 wt% Eudragrit
L100
Cellulose powder Desktop 3DP Chlorphenira- Active delivery studies with fluorescein indicated that
PH301 machine: pow- mine maleate 3DP is capable of accurately constructing dosage forms
der delivery with active content as low as 1.0 1012 moles per tablet.
system Hardness and friability testing indicated that samples
fabricated with this technique are comparable with other
standard products.
 Table 1 continued
Lee et al., To demonstrate that a piezoelectric
201215 inkjet printing system would provide
a new approach for large-scale
manufacturing of drug carriers with a
desired geometry
Scoutaris et To produce a formulation capable of
al., 201116 controlling the release of a drug
Pardeike et To demonstrate the advantages of
al., 201117 formulating poorly soluble drugs as
nanosuspensions and their use in
an inkjet-type printing technique to
produce personalized medicine
Journal of the American Pharmacists Association
Buanz et al., To evaluate the use of thermal inkjet-
201118 ting as a method for dosing drugs
onto oral films
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j apha.org
Wang et al., To develop formulations capable
200619 of controlling releases of highly
water-soluble compounds at prede-
termined rates following zero-order
or near-zero-order kinetics using
3DP technology
Genina et al., To fabricate drug delivery systems
201220 with accurate doses and tailored
drug release
MAR /APR 2013 | 53:2 |
JAPhA 141
Huang et al., To use 3DP technology to prepare
200721 a drug implant that displays both
pulsatile and steady-state release
Poly(lactic-co-glycolic acid)
inks
Various ratios of felodipine
and polyvinyl pyrrolidone in
an ethanoldimethyl sulfox-
ide mixture (95:5, v%)
10% folic acid nanosuspen-
sions stabilized with Tween
20
First series: salbutamol
sulphate (0.5% w/v) with
glycerin (1, 2, 3, 5, 10, 20,
40, 50, and 60% v/v); second
series: glycerin (10% v/v),
with salbutamol sulphate
(0.5, 1, 1.5, 2, 2.5, and 3%
w/v)
Drug carriers: Kollidon SR
and hydroxypropylmethyl
cellulose; shell: aqueous
pseudoephedrine HCl and
ethanolic triethyl citrate
binder
Propranolol ink: 50 mg/
mL propranolol powder in
propylene glycol:water mix-
ture (30:70, v%); riboflavin
ink: 31.5 mg/mL powder
with glycerol:ethanol: water
(10:10:80, v%)
Binders: ethanol and acetone
(20:80, v/v); polymer phase;
poly l-lactic acid
NA Inkjet printing Paclitaxel Paclitaxel-loaded microparticles with different geometries
exhibited different drug release rates mainly due to differ-
ent surface areas and geometries.
Hydrophobic substrate Inkjet printing Felodipine The deposition of felodipine and polyvinyl pyrrolidone
to form felodipinepolyvinyl pyrrolidone spots was
achieved using single or multiple drops. Drug release rate
was related to the loading, with loadings in excess of 33%
by weight reducing drug release.
NA Inkjet printing Folic acid The printing of 10% folic acid nanosuspension could be
successfully demonstrated. The particle size of folic acid
nanosuspension prepared via high-pressure homogeni-
zation was highly reproducible. Nanosuspensions may
be a new approach for the formulation of poorly soluble
drugs.
Oral film made of Inkjet printing Salbutamol The measured dose was in agreement with the theoretical
potato starch sulphate dose when doses were deposited in a single pass under
the print head. Although with multiple passes the mea-
sured dose was always significantly less than the theoreti-
cal dose, the losses were predictable.
Powder bed Desktop 3DP Pseudoephed- Release rate was shown to increase correspondingly with
machine: pow- rine HCl the fraction of hydroxypropylmethyl cellulose contained
der delivery in the polymer blend; dosage forms were insensitive to
system changes in pH of the dissolution medium and paddle
stirring rate.
Three model paper Combined con- Riboflavin so- Combining inkjet and flexographic printing was success-
substrates were stud- ventional inkjet dium phosphate fully applied to produce drug delivery systems with high
ied: A (alkyl ketene printing tech- and propranolol dose precision and controlled drug release.
3d drug printing Special
dimer-sized uncoated nology with hydrochloride
wood-free paper), B flexographic
(triple-coated inkjet printing
paper), and C (double-
coated sheet-fed offset
Feature
paper).
NA Desktop 3DP Levofloxacin The implants prepared by 3DP process achieved a distinct
machine: pow- bimodal or pulsed release profile from a single implant,
der delivery showing its advantage compared with implants created by
system conventional technology.
 Special Feature 3d drug printing

Powder-based 3DP technique is used to build 3D

total mass loss during friability tests. Printed regions were

ethyl cellulose concentrations, and central aperture diam-

and fine hardness but unsatisfactory friability with 3.55%

vitro tests. Nearly all of the drug (98.5%) was released in

well bound; tablets disintegrated and wetted rapidly in in
Devices showed acceptable pharmotechnical properties
bone scaffolding.6,9,10 This new advancement in bone

two-stage release profile with distinctly different release

drug delivery devices with different diameters, heights,

The drug release profiles from the structures showed a

In vitro dissolution experiments showed that the 3DP

reconstruction happens in vivo. The scaffold holds the
cells together and mimics the natural bone extracellular
matrix. Powder-based 3DP allows unlimited geometries

eters demonstrated linear release profiles.

of the scaffolds and precision to create high-resolution

rates and minimal initial burst release.

desired models. Although our search did not focus on
3D printed scaffolds, printing of medications onto bone
reconstructions have been tested. In the future, it may be
2 min in dissolution tests.

possible to print antibiotics into these implant scaffolds

and influence their release profile. Controlling powder-
based 3DP parameters has been used to formulate orally
disintegrating acetaminophen tablets and oral dosage
forms of chlorpheniramine maleate with a complex re-
lease profile.1114

Ink formulations and printing substrates

Dexamethasone
Acetaminophen

Acetaminophen

The ink formulations covered a wide range of com-

pounds, including poly(lactic-co-glycolic acid) inks,
Abbreviations used: 3D, three-dimensional; 3DP, 3D printing; DCL, directly compressible lactose; NA, not applicable; PVA, polyvinyl alcohol; v, volume; w, weight.

ethanol-dimethyl sulfoxide, surfactants (e.g.,Tween 20),

Kollidon SR, glycerin, cellulose, propylene glycol, meth-
anol, acetone, and others.425 The composition of these
machine: pow-

machine: pow-
Inkjet printing

ink formulations could be valuable for a compounding

Desktop 3DP

Desktop 3DP
der delivery

der delivery

pharmacy at which the inks need to be reconstituted.

system

system

The majority of publications (n = 15) included a

printing substrate, while 7 articles did not report a sub-
strate. Among the articles with a printing substrate, the
lene blue (0.05% w/v)

idone K30 (5.0% w/v)

Binder liquid: methy-

and polyvinyl pyrrol-

in 75% (v/v) ethanol

most common were different types of cellulose, coated

or uncoated paper, microporous bioceramics, glass scaf-
folds, metal alloys, and potato starch films.614,16,1820,22
in water

Advantages and disadvantages

NA

NA

3DP allows precise control of droplet size, dosage

strength, complex drug release profiles, and multidos-
[poly(lactic-co-glycolic acid]
and colloidal silicon dioxide

ethanol and acetaminophen

pyrrolidone, K30, mannitol,
Mixed powder: acetamino-

ing.1520 Creating different release profiles is one of the

Binders: ethyl cellulose in
phen, lactose, polyvinyl

Biodegradable polymer

and water-soluble PVA

most researched uses of 3DP. An amount of chlorphe-

niramine maleate as small as 1012 moles was repeatedly
printed onto a cellulose powder substrate to demon-
strate that a specified printed quantity of drug can be
in ethanol

designed to be released at a specified time.14 This study

also showed the potential of improved accuracy for very
small doses compared with conventional manufactur-
release-retardant material for provid-
spatial distribution of drug within the

ing. This advantage was further evidenced in tubercu-

To demonstrate the ability to control

To develop novel doughnut-shaped

with local variations of the drug and

delivery devices with special inner-

the drug release profile through the

multilayered drug delivery devices

To design fast-disintegrating drug

losis medicine design. A multilayered bone implant was

constructed with distinct release profiles that allowed
ing linear release profiles

alternate release of rifampicin and isoniazid to mimic a

structure characteristics

printed 3D structures

pulse release mechanism.8 In another study, dexametha-

sone was used in a two-stage release profile,10 and in a
third study, both pulsatile and steady-state levofloxacin
release mechanisms were used in a nonconventional
drug implant.21
Table 1 continued

The ability to create limitless dosage forms (e.g.,

orally disintegrating tablets, delayed-release capsules)
Rattanakit et

challenges conventional dosage forms even further.

al., 201224

Yu et al.,
Yu et al.,

Acetaminophen, anhydrous theophylline, and caffeine

200922

200925

have been formulated using 3DP on a porous paper

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substrate.7 Acetaminophen also has been designed as
an orally disintegrating tablet with a unique inner struc-
ture.22
The 3D drug printing has drawbacks and disadvan-
tages, as does any revolutionary technology still in de-
velopment. For example, precise ink viscosity must be
achieved for proper flow with inkjet printing.23 Other
disadvantages include mechanical properties of the for-
mulations being printed. At least some 3D printed drug
products do not have proper hardness and binding of
materials to justify using a printer, as the ink formula-
tion components must be able to self-bind but not bind to
other printer elements.11 Binding to other elements may
interfere with the timing of the drug release. Parameters
such as speed and rate of printing must be taken into ac-
count and may not be suitable for all drug candidates.
A need exists for proper postprinting processes that will
not interact or counterinteract with the finished printed
process.
Discussion
These technologies may transform pharmacy practice
by allowing medications to be truly individualized and
tailored specifically to each patient, although technical
and regulatory hurdles remain.1925 Pharmacists could
use patients characteristics (e.g., age, race, elimination,
metabolism) and pharmacogenetic profile to predict
a specific medication dose. The medication then could
be dispensed by an automated system that incorporates
3DP technology.7 The dose then could be adjusted by
changing printer parameters based on the patients clini-
cal response.
A compounding pharmacy could take full advan-
tage of the benefits of 3DP technology because patients
already are familiar with individualized medication.
However, eventually, 3DP technology could trickle
down to ambulatory settings such as independent and
chain community pharmacies. If most common medi-
cations become available in ink form or the ink may be
compounded in the pharmacy, then patients may be
able to shrink their medication burden considerably to
one polypill per day, which would improve patient ad-
herence substantially.26 This is one step further than the
specialized community setting and even the compound-
ing setting, as it will encompass a much broader spec-
trum of medications and patients. Additional studies
of the design and engineering of the printer would be
needed to make 3DP of medications profitable and ben-
eficial in a high workload environment.
Further, 3DP technologies may replace current ad-
ditive technologies and decrease the overall cost of
manufacturing because they may reduce the use of un-
necessary resources. For example, a tablet weighing 10
mg may be condensed to a 1-mg tablet. Printable dosage
forms on paper may be easier to deliver to patients than
powder-based printed forms. The drug printer can be a
Journal of the American Pharmacists Association
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3d drug printing Special Feature
cost-effective option compared with other technologies.
Meeting the regulatory requirements of the Food
and Drug Administration could be a hurdle to be
cleared before large-scale use of 3D printed products
could be realized. In addition, different manufacturing
regulations and state board requirements could impose
obstacles to the adoption of the drug printers in practice.
An imperative difference must be established to distin-
guish drug printers as manufacturing or compounding
technologies. Large randomized controlled trials take
time and funding, which could pose a barrier to imple-
mentation of 3D printed dosage forms. However, we
feel this investment of time and funding is worth the ef-
fort because of the promise of this new technology and
its potential applications in pharmacy practice.
Limitations
The studies identified for this review may not represent
a comprehensive survey of the literature; however, we
used a structured approach to our literature search, and
our strategy could easily be replicated. The search also
was limited to articles that used either a specific drug
in the printing techniques or certain encapsulation pro-
cesses, possibly excluding other studies that may only
address matrices, drug delivery devices, or systems
(e.g., reactionware matrices, scaffolds excluding active
drugs). Our search was limited to English-language
studies, possibly limiting the breadth of the pertinent lit-
erature identified. However, some of the studies includ-
ed in this review come from international pharmaceuti-
cal journals describing research from different countries.
Conclusion
Our structured review summarizes the available pub-
lished literature on existing 3DP technologies for phar-
maceuticals. From the literature, we identified inkjet
printing and powder-based printing as the primary
printing technologies used for drug development and
fabrication. Advantages of the 3D printers to create
pharmaceutical dosage forms include precise control of
droplet size and complex drug release profiles. Further
study and use of 3DP technology may offer an impor-
tant benefit to patients who need medications that have
narrow therapeutic indices or a higher predilection to
be influenced by genetic polymorphisms. Personaliz-
ing these medications and therefore decreasing the risk
of adverse reactions should be the driving force behind
any technological innovation in pharmacy practice.
References
1. Sachs EM, Cima MJ, Cornie J. Three-dimensional printing: rapid
tooling and prototypes directly from a CAD model. CIRP Ann Manuf
Technol. 1990;39(1):2014.
2. Yu DG, Zhu LM, Branford-White CJ, Yang XL. Three-dimensional
printing in pharmaceutics: promises and problems. J Pharm Sci.
2008;97(9):366690.
j apha.org MAR /APR 2013 | 53:2 | JAPhA 143
 Special Feature 3d drug printing
3. Sethia S, Squillante E. Solid dispersions: revival with greater pos-
sibilities and applications in oral drug delivery. Crit Rev Ther Drug
Carrier Syst. 2003;20(2-3):21547.
4. ten Cate AT, Pieterse G, Eversdijk J, et al. Novel encapsulation tech-
nology for the preparation of core-shell microparticles. J Control
Release. 2010;148(1):e89.
5. Prestwich GD. Hyaluronic acid-based clinical biomaterials derived
for cell and molecule delivery in regenerative medicine. J Control
Release. 2011;155(2):1939.
6. Gu Y, Chen X, Lee JH, et al. Inkjet printed antibiotic- and calcium-
eluting bioresorbable nanocomposite micropatterns for orthopedic
implants. Acta Biomater. 2012;8(1):42431.
7. Sandler N, Mttnen A, Ihalainen P, et al. Inkjet printing of drug sub-
stances and use of porous substrates: towards individualized dos-
ing. J Pharm Sci. 2011;100(8):338695.
8. Wu W, Zheng Q, Guo X, et al. A programmed release multi-drug im-
plant fabricated by three-dimensional printing technology for bone
tuberculosis therapy. Biomed Mater. 2009 Dec;4(6):065005.
9. Gbureck U, Vorndran E, Mller FA, Barralet JE. Low temperature di-
rect 3D printed bioceramics and biocomposites as drug release ma-
trices. J Control Release. 2007;122(2):17380.
10. Wu C, Luo Y, Cuniberti G, et al. Three-dimensional printing of hi-
erarchical and tough mesoporous bioactive glass scaffolds with a
controllable pore architecture, excellent mechanical strength and
mineralization ability. Acta Biomater. 2011;7(6):264450.
11. Yu DG, Branford-White C, Yang YC, et al. A novel fast disintegrat-
ing tablet fabricated by three-dimensional printing. Drug Dev Ind
Pharm. 2009;35(12):15306.
12. Yu DG, Yang XL, Huang WD, et al. Tablets with material gradi-
ents fabricated by three-dimensional printing. J Pharm Sci.
2007;96(9):244656.
13. Rowe CW, Katstra WE, Palazzolo RD, et al. Multimechanism oral
dosage forms fabricated by three dimensional printing. J Control
Release. 2000;66(1):117.
14. Katstra WE, Palazzolo RD, Rowe CW, et al. Oral dosage forms
fabricated by three dimensional printing. J Control Release.
2000;66(1):19.
144 JAPhA | 5 3 :2 | M AR/AP R 2013 ja p h a .org
Downloaded From: http://www.japha.org/ by a University of Utah User on 05/05/2013
15. Lee BK, Yun YH, Choi JS, et al. Fabrication of drug-loaded polymer
microparticles with arbitrary geometries using a piezoelectric inkjet
printing system. Int J Pharm. 2012;427(2):30510.
16. Scoutaris N, Alexander MR, Gellert PR, Roberts CJ. Inkjet print-
ing as a novel medicine formulation technique. J Control Release.
2011;156(2):17985.
17. Pardeike J, Strohmeier DM, Schrdl N, et al. Nanosuspensions as
advanced printing ink for accurate dosing of poorly soluble drugs in
personalized medicines. Int J Pharm. 2011;420(1):93100.
18. Buanz AB, Saunders MH, Basit AW, Gaisford S. Preparation of per-
sonalized-dose salbutamol sulphate oral films with thermal ink-jet
printing. Pharm Res. 2011;28(10):238692.
19. Wang CC, Tejwani Motwani MR, Roach WJ, et al. Development of
near zero-order release dosage forms using three-dimensional
printing (3-DP) technology. Drug Dev Ind Pharm. 2006;32(3):367
76.
20. Genina N, Fors D, Vakili H, et al. Tailoring controlled-release oral dos-
age forms by combining inkjet and flexographic printing techniques.
Eur J Pharm Sci. 2012;47(3):61523.
21. Huang W, Zheng Q, Sun W, et al. Levofloxacin implants with pre-
defined microstructure fabricated by three-dimensional printing
technique. Int J Pharm. 2007;339(1-2):338.
22. Yu DG, Shen XX, Branford-White C, et al. Novel oral fast-disin-
tegrating drug delivery devices with predefined inner structure
fabricated by Three-Dimensional Printing. J Pharm Pharmacol.
2009;61(3):3239.
23. Katstra WE. Fabrication of complex oral drug delivery forms by three
dimensional printing [doctoral dissertation]. Cambridge, MA: Mas-
sachusetts Institute of Technology; 2001.
24. Rattanakit P, Moulton SE, Santiago KS, et al. Extrusion printed poly-
mer structures: a facile and versatile approach to tailored drug deliv-
ery platforms. Int J Pharm. 2012;422(1-2):25463.
25. Yu DG, Branford-White C, Ma ZH, et al. Novel drug delivery devices
for providing linear release profiles fabricated by 3DP. Int J Pharm.
2009;370(1-2):1606.
26. Saini SD, Schoenfeld P, Kaulback K, Dubinsky MC. Effect of medi-
cation dosing frequency on adherence in chronic diseases. Am J
Manag Care. 2009;15(6):e2233.
Journal of the American Pharmacists Association