Journal of Pharmaceutical Sciences 107 (2018) 390-401

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Journal of Pharmaceutical Sciences

journal homepage: www.jpharmsci.org

Pharmaceutics, Drug Delivery and Pharmaceutical Technology

Formulation of 3D Printed Tablet for Rapid Drug Release by Fused

Deposition Modeling: Screening Polymers for Drug Release,
Drug-Polymer Miscibility and Printability
Nayan G. Solanki, Md Tahsin, Ankita V. Shah, Abu T.M. Serajuddin*
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, New York 11439

a r t i c l e i n f o a b s t r a c t

Article history: The primary aim of this study was to identify pharmaceutically acceptable amorphous polymers for
Received 16 August 2017 producing 3D printed tablets of a model drug, haloperidol, for rapid release by fused deposition
Revised 26 September 2017 modeling. Filaments for 3D printing were prepared by hot melt extrusion at 150
C with 10% and 20% w/w
Accepted 13 October 2017
of haloperidol using Kollidon® VA64, Kollicoat® IR, Affinsiol™15 cP, and HPMCAS either individually or as
Available online 21 October 2017
binary blends (Kollidon® VA64 þ Affinisol™ 15 cP, 1:1; Kollidon® VA64 þ HPMCAS, 1:1). Dissolution of
crushed extrudates was studied at pH 2 and 6.8, and formulations demonstrating rapid dissolution rates
Keywords:
3D printing were then analyzed for drug-polymer, polymer-polymer and drug-polymer-polymer miscibility by film
fused deposition modeling casting. Polymer-polymer (1:1) and drug-polymer-polymer (1:5:5 and 2:5:5) mixtures were found to be
FDM miscible. Tablets with 100% and 60% infill were printed using MakerBot printer at 210
C, and dissolution
drug-polymer miscibility
tests of tablets were conducted at pH 2 and 6.8. Extruded filaments of Kollidon® VA64-Affinisol™ 15 cP
rheology
amorphous solid dispersion mixtures were flexible and had optimum mechanical strength for 3D printing. Tablets containing 10%
tablets drug with 60% and 100% infill showed complete drug release at pH 2 in 45 and 120 min, respectively.
dissolution rate Relatively high dissolution rates were also observed at pH 6.8. The 1:1-mixture of Kollidon® VA64 and
Affinisol™15 cP was thus identified as a suitable polymer system for 3D printing and rapid drug release.
© 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Introduction Administration in 2015, the interest in pharmaceutical sector for 3D

Three-dimensional (3D) printing is a process of creating 3D
objects, where materials are deposited layer over layer using a
computer-driven process based on a digital model. In the
pharmaceutical field, it has the potential for delivering individu-
alized and on-demand medications to avoid variable effects and
adverse reactions during drug therapy.1-4 It also provides prospects
for formulating patient-centric fixed-dose combinations to reduce
multiple daily dosing and thus improve patient compliance.5
Various techniques for 3D printing, such as fused deposition
modeling (FDM), binder deposition, inkjet printing, material
jetting, powder bed fusion, photopolymerization, pen-based 3D
printing and molding, have been reported in the literature.1,6-9
Since the approval of the first orally disintegrating 3D printed
tablet, Spritam® (levetiracetam), by U.S. Food and Drug
This article contains supplementary material available from the authors by request
or via the Internet at https://doi.org/10.1016/j.xphs.2017.10.021.
* Correspondence to: Abu T. M. Serajuddin (Telephone: þ1 718 990 7822;
Fax: þ1 718 990-1877).
E-mail address: serajuda@stjohns.edu (A.T.M. Serajuddin).
printing has been growing very rapidly.10,11 However, Spritam® was
prepared by spraying the binder solution on successive layers of
powder (powder beds) to prepare a loose compact,12 and, as indi-
cated by Sadia et al.,13 the process requires specialized facilities and
is not amenable to small-scale and on-demand production of tab-
lets required for patient-tailored medications. In addition, tablets
produced are soft and porous, and there is potential wastage of
powders as some residues formed after printing have to be dis-
carded or reprocessed. Among various methods mentioned above,
FDM is possibly the most widely used and the low-cost method,
and it has been the subject of extensive research in both non-
pharmaceutical and pharmaceutical fields for additive
manufacturing, rapid prototyping, and drug delivery. In this
method, filaments of thermoplastic polymers are deposited layer-
by-layer at elevated temperature using a printer to prepare com-
plex geometries, presentation models, and visual aids.
For pharmaceutical application of FDM, especially for the
preparation of tablets, polymeric filaments with embedded drugs
are prepared by melt extrusion, and the filaments are then pushed
through the heated nozzle of a 3D printer by an automated gear
system. The molten material is deposited layer-by-layer into the

https://doi.org/10.1016/j.xphs.2017.10.021
0022-3549/© 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.
 N.G. Solanki et al. / Journal of Pharmaceutical Sciences 107 (2018) 390-401
desired shape.1,14 Recent publications on the FDM 3D printing,
however, indicate several limitations of the system that require
active investigation for wide scale application of the technology for
drug delivery.15,16
The first limitation has been the lack of suitable polymers for
successful development of FDM 3D printed tablets. Some of the
polymers that have been tested as carriers or matrices for drugs in
3D printing are poly(lactic acid),17-20 poly(vinyl alcohol),2,7,21-23
polyvinylpyrrolidone,24 methacrylate,5 hydroxypropyl cellulose,5
hydroxypropyl methylcellulose acetate succinate (HPMCAS),25
mixtures of polymers,26 acrylonitrile butadiene styrene,27
poly(ε-caprolactone),28 ethyl cellulose,29 and ethylvinyl acetate.30
Filaments with optimum mechanical properties, flexibility, and
melt viscosity to pass through the printer nozzle and thermal sta-
bility are required for successful 3D printing.9,31,32 However, most
of the polymers commonly used in the development of conven-
tional pharmaceutical dosage forms lack such attributes that could
make them suitable for 3D printing. The extruded filaments of
pharmaceutical grade polymers are either brittle that break in the
motor gear (plunger assembly) or soft that cannot be pushed by the
drive gear due to pliability of filaments, thus hindering FDM 3D
printing.26,33 For these reasons, filaments composed of
nonpharmaceutical grade polymers like poly(vinyl alcohol) and
poly(lactic acid) were studied in many of the reported studies,
where drug has been incorporated into the commercially available
filaments by solvent diffusion2 or cutting the filaments to small
pieces and mixing with the drug that was followed by extrusion to
get drug-loaded filaments for FDM 3D printing.22,34,35 Moreover,
many of these polymers are semicrystalline and exhibit high glass
transition temperature (Tg) and melt viscosity that hamper drug-
polymer miscibility and the formation of amorphous solid disper-
sion (ASD) in the filaments prepared by melt extrusion. Often,
additives and plasticizers are required to enable hot melt extrusion
(HME) and 3D printing with such polymers. In other studies, 3D
printing was enabled by incorporating large quantities of immis-
cible fillers, such as talc, lactose, microcrystalline cellulose, mag-
nesium stearate and tricalcium phosphate, and so forth with the
polymers in the preparation of filaments.24,25,36 For example, Sadia
et al.13 used these fillers at 50:50 ratio with Eudragit® EPO. In
another study, Pietrzak et al.5 used a very high melting drug,
theophylline (m.p. 273
C), at 50:50 ratios with Eudragit® RL, RS, or
E to prepare filaments and then 3D printing at temperatures below
the melting point of drug.4 Triethyl citrate, triacetin, PEG 400, and
Tween® 80, and so forth were also used as plasticizers in some of
the studies to increase the flexibility of filaments, flowability of
melt, and lower printing temperature.29,37-39 However, the addition
of fillers and plasticizers leads to the design of complex formula-
tions, adds to the weights of tablets, and increases the potential for
adverse stability of the pharmaceutical product. Many of the
polymers also require high printing temperatures where drugs,
polymers, or additives may degrade.21
The second major limitation of 3D printing is that the prepared
tablets exhibit slow and often incomplete drug release. This is
because the FDM 3D printed tablets do not disintegrate and the
drug remain embedded and trapped in the polymers. As a conse-
quence, such tablets appear to be more suitable for modified
release rather than immediate release of drugs.27,34 However, the
majority of the oral dosage forms currently available in the market
are immediate release tablets, and, in particular, immediate release
dosage forms are necessary for drugs requiring rapid onset of action
after oral administration.40 There are a few reports on FDM 3D
printing where the fabrication of immediate release tablets has
been explored.5,13,24 In their attempts to develop immediate release
tablets of theophylline and dipyridamole by FDM 3D printing,
391
Okwuosa et al.24 developed formulations containing large amounts
of talc as the crystalline filler, where the drugs also remained in the
crystalline form.24 In these formulations, the matrix structure and
the solubility of drugs governed the drug release from tablets. In
another study, Sadia et al.13 demonstrated immediate drug release
from FDM 3D printed tablets when such actives as captopril,
prednisolone, theophylline and 5-aminosalicylic acid, and the
excipient tricalcium phosphate were used at 50% of the tablet
weight as fillers. Also in this study, drugs in the filaments and
tablets remained mostly crystalline. Alhijjaj et al.37 prepared FDM
3D printed disc (0.6 mm thickness) containing felodipine using
Soluplus®, Eudragit® EPO and polyvinyl alcohol as polymeric matrix
and polyethylene glycol, Tween® 80 as plasticizer. Although the
drug release increased from the 3D printed discs, the drug
substance in the discs remained in crystalline form.37
In our opinion, the third major limitation of 3D printing is that,
in most of the reported studies, the miscibility of the drug and
additives with the polymers used was not evaluated. Since the
formulations usually contain several additive(s) or plasticizer(s), it
is especially important that the miscibility of drugs with polymers
in presence of such added materials is studied. As the majority of
drugs emerging from the discovery and development pipelines or
currently available in the market are poorly water-soluble and
many display pH-dependent solubility, the drug release from FDM
3D printed tablets would be solubility dependent and variable if
crystalline drugs are present in polymeric matrices. For such drugs,
it is desirable that they remain amorphous to form ASD in the
tablets so that the dissolution, dispersion, or erosion of tablets
control the drug release rather than the solubility of crystalline
drugs. However, to the best of our knowledge, no systematic studies
on the use of ASD in 3D printed tablets have been reported in the
literature. Since the preparation of filaments by melt extrusion and
the 3D printing by FDM require high temperature, it is possible that
the drug may fully or partially convert to the amorphous form.
However, unless the miscibility of the drug with the polymer used
is established, the drug may crystallize out in tablets during shelf
life, resulting in physical stability issues and variability in drug
release.41
For successful preparation of 3D printed tablets containing ASD
by FDM, polymers have to be pharmaceutical grade, the drug
should be miscible with the polymer, the extruded filaments should
be flexible to be used in the FDM 3D printer, and the printing
should not require very high temperature. Moreover, it is preferable
that the tablets should release drugs as fast as possible and the
amounts of nonmelting fillers used to enhance drug release should
be avoided or reduced. The present study was undertaken to
identify pharmaceutically acceptable polymers that may be used
for producing 3D printed tablets, where the drug would remain
amorphous and the drug release would be relatively rapid. Halo-
peridol, which has a relatively low therapeutic dose in the range of
5 to 20 mg,42 was used as the model drug. It is a weakly basic and
poorly water-soluble drug with pKa of ~8.0 and the intrinsic free
base solubility of ~1 mg/mL that exhibits pH-dependent solubil-
ity.43,44 Different polymers and their mixtures were screened for
drug release, extrudability, and printability. To keep the formula-
tions relatively simple, no fillers or additives were used. The
step-by-step processes used in the study are as follows: (a) prepare
ASDs of haloperidol with different pharmaceutical grade polymers
using HME, (b) evaluate drug release from crushed extrudates to
identify polymers exhibiting immediate drug release, (c) determine
drug-polymer, polymer-polymer, and drug-polymer-polymer
miscibility, (d) print tablets by FDM using drug-loaded filaments
with selected polymers or polymer blends, and (e) evaluate drug
release from FDM 3D printed tablets.
392 N.G. Solanki et al. / Journal of Pharmaceutical Sciences 107 (2018) 390-401
Materials and Methods
Materials
Polyvinylpyrrolidone-vinyl acetate copolymer (Kollidon® VA64)
and polyvinyl alcohol-polyethylene glycol graft copolymer (Kolli-
coat® IR) were donated by BASF Corp. (Tarrytown, NY). Hydrox-
ypropyl methylcellulose HME 15 cP (HPMC HME 15 cP; Affinisol™
15 cP) and hydroxypropyl methylcellulose acetate succinate
(HPMCAS MG; Aqoat® AS-MG) were received as gifts from,
respectively, DOW Chemical Co. (Midland, MI) and Shin-Estu
Chemical (Totowa, NJ). Haloperidol was purchased from VWR
(Radnor, PA). All materials were used as received.
Rheology
Rheology of polymers, mixtures of polymers, and mixtures of
haloperidol with one or more polymers was studied to determine
melt viscosity and processing parameters as the functions of tem-
perature for HME and 3D printing. The experiments were per-
formed by a Discovery hybrid rheometer-2 (TA Instruments,
Wilmington, DE) with an oven heating assembly using 25-mm
parallel plate geometry according to the general procedure
described by Gupta et al.45 A 500-mg slug of each mixture was
prepared using a Carver press at 5000 lb of compression pressure
and the dwell time of 5 s. The rheometer was calibrated for zero gap
at the starting temperature of analysis (190
C) before analyzing
samples by the temperature sweep method. The temperature
sweep was conducted from 190
C to 130
C at the ramp rate of
5
C/min, oscillation strain of 0.5%, and angular frequency at 0.1

radian/s to determine viscosity of samples.
Hot Melt Extrusion
Physical blends of different ingredients were prepared using the
Turbula® mixer. Melt extrusion of the mixtures was then conducted
using the Process 11 co-rotating twin screw extruder (Thermo
Scientific, Bridgewater, NJ) at the barrel temperature of 150
C,
which is above the glass transition temperature (Tg) of polymer
used and close to the melting point of haloperidol (152
C). Screw
configuration of 3 kneading zones containing forward kneading
elements and series of conveying elements was used to prepare
filaments. In the first kneading zone, near the feeding zone, there
were 7 kneading elements with offset angle of 30
, which were
then followed by 7 kneading elements with offset angle of 60
. In
the second kneading zone, there were 6 kneading elements with
offset angle of 60
, and, in the third kneading zone, 4 kneading
elements with offset angle of 60
, followed by 7 kneading elements
with offset angle of 90
were used. Feed rate and screw speed
during melt extrusion were kept constant at, respectively, 2 g/min
and 200 RPM. The die temperature and diameter were, respec-
tively, 170
C and 1.55 mm. Conveyor belt was used to obtain longer
filaments that could later be used for 3D printing.
Printing of Tablets
A MakerBot Replicator 2 desktop 3D printer (MakerBot, Brooklyn,
NY) equipped with a single nozzle of 0.40 mm diameter was used to
print tablets. The tablet was designed online on https://www.
tinkercad.com/ and the .stl file was then downloaded for printing
tablets. Tablets were printed with 100% and 60% infill densities and
hexagonal infill pattern. For tablets with 100% infill, the diameter and
the thickness were, respectively, 10 and 2 mm. For both infills, the
tablet weights were kept same to maintain the amount of the drug
constant. Since this required larger tablets for 60% infill, it was
accomplished by increasing the diameter of tablets while retaining
the thickness (2 mm) constant. The printing was performed at 210
C
on the build plate at room temperature. The following printer set-
tings were used to print the tablets: first layer printing speed, 10
mm/s; infill printing speed, 45 mm/s; traveling speed 150 mm/s;
infill layer height of 0.10 mm; and shell thickness, 0.10 mm. The time
required to print each tablet was 150 s.
Miscibility Study
The drug-polymer, polymer-polymer, and drug-polymer-
polymer miscibility testing was performed by the film-casting
method described previously.41,46 For this purpose, 500 mg of
each haloperidol-Kollidon® VA64 (1:9, 2:8 and 3:7), haloperidol-
Affinisol™ 15 cP (1:9, 2:8 and 3:7), Kollidon® VA64-Affinisol™ 15 cP
(1:1) binary mixtures, and haloperidol-Kollidon® VA64-Affinisol™
15 cP ternary mixtures (1:5:5 and 2:5:5) were dissolved in 3 mL of
methanol-dichloromethane (1:1) mixture and shaken for 1 h in a
closed scintillation vial using wrist action shaker. One milliliter of
each solution was then poured on a glass plate, and the 200-
microns film was casted using a film applicator. The films were
air dried and then analyzed on days 1, 15, and 30 for any phase
separation or the presence crystals (crystallization) using differ-
ential scanning calorimetry (DSC), powder X-ray diffraction
(PXRD), and polarized light microscopy (PLM). For analysis on days
15 and 30, the films were subjected to 40
C and 75% RH to accel-
erate phase separation and crystallization, if any.
Differential Scanning Calorimetry
DSC analysis of the films was performed to detect the number of
phases, including any drug crystallization, in the films. A Q200
modulated DSC analyzer (TA Instruments) was used to analyze the
films. Physical mixtures of the materials used in the films were also
analyzed as references. About 5 mg of each sample was weighed
and crimped in a Tzero pan with hermetic lid, equilibrated at 5
C,
and then heated to 200
C at 5
C/min with the modulation of ±1.0
C
every min. The recorded data were analyzed using Universal
Analyzer 2000 (TA Instruments), where reversible heat flow in the
modulated DSC scan was used to find melting endotherm for drug,
if any.
Powder X-Ray Diffraction
A Shimadzu XRD-6000 Diffractometer (Shimadzu, Kyoto, Japan)
equipped with Ni filter and monochromatic Cu-Ka radiation source
was used to record PXRD diffraction patterns for the determination
of the presence of crystals in films and extrudates. The diffrac-
tometer was operated with a copper anode tube at the generator
voltage and the current of 40 kV and 30 mA, respectively. The 2q
scanning was used from 10
to 50
at the rate of 2
/min. The
samples were analyzed for any characteristic peaks of haloperidol.
Thermogravimetric Analysis
Thermogravimetric (TG) analysis of drug, drug-polymer-
polymer physical mixture and crushed extrudates was performed
to evaluate their thermal stability using a thermogravimetric
analyzer, TGA Q50 (TA Instruments). Before analysis, the ther-
mogravimetric analyzer was equilibrated for 30 min at room tem-
perature under nitrogen purge. For analysis, 5 mg of sample was
weighed into a tared platinum pan followed by heating up to 300
C
at 10
C/min.
 N.G. Solanki et al. / Journal of Pharmaceutical Sciences 107 (2018) 390-401
Polarized Light Microscopy
Casted films were examined microscopically using Nikon
Eclipse 50i Microscope (Nikon Inc., Tokyo, Japan) using 10 cross
polarized lens. Polarized light and birefringent images of the films
were recorded using a Nikon digital single-lens reflex camera
attached to the microscope, which were then analyzed qualitatively
for any crystallization of drug from the polymeric matrix.
In Vitro Dissolution
Dissolution of crushed extrudates and 3D printed tablets
containing 12-mg equivalent of haloperidol was studied in 250 mL of
United States Pharmacopeia hydrochloric acid (pH 2) buffer and
phosphate buffer (pH 6.8) at 37 ± 0.5
C using the United States Phar-
macopeia dissolution apparatus II (Distek Inc., North Brunswick
Township, NJ) at 50 RPM. The crushed extrudates for dissolution
testing were prepared by milling filaments using a Scienceware®
micro-mill and then passing the powders through a sieve no. 30 (600
micron) and retaining on sieve no. 70 (212 micron). Sinkers were used
since the tablets were floating in dissolution media. Aliquots of
dissolution media, 3 mL each, were withdrawn periodically for
determining the extent of drug release. At the end of experiments at 50
RPM at both pH conditions, the paddle speed was increased to 250
RPM to determine whether any additional drug would be released at
higher agitation. Aliquots were filtered using the polypropylene sy-
ringe filter (VWR, Radnor, PA) with 0.45 micron pore size, and filtrates
were diluted with the high-performance liquid chromatography
(HPLC) mobile phase before the HPLC analysis according to the method
described in the next section. Unfiltered aliquots were also analyzed to
determine whether there is any difference in drug concentrations
between filtered and unfiltered samples that would indicate the
possibility of drug precipitation during dissolution testing.
Drug Analysis
Haloperidol concentrations in aliquots of dissolution media and
in tablets were analyzed using the Waters HPLC equipment and the
Waters XBridge C8 Column (3.5 mm, 150 mm  4.6 mm), according
to the method described previously.47 Briefly, the mobile phase
consisting of the 60:40 v/v mixture of methanol and 0.05-M
monobasic potassium phosphate (adjusted to pH 2.5 to 3 using
phosphoric acid) and the flow rate of 0.75 mL/min were used to
analyze the drug at wavelength of 247 nm. The mobile phase was
also used to dissolve or dilute samples. In addition, the 3D printed
tablets were analyzed for weight, diameter, and thickness.
Results and Discussion
Screening Polymers for Drug Release and 3D Printing Ability
As mentioned earlier, the primary objective of the study was to
identify polymeric systems for 3D printing where the drug remains
as ASD, the filaments produced by melt extrusion are suitable for
printing, and the printed tablets have relatively rapid dissolution
rate. The ASD would make the formulation matrix-controlled rather
than being controlled by the solubility of the crystalline drug. Thus, it
would increase dissolution rate and bioavailability of poorly water-
soluble drugs. It may also make the drug release less pH-dependent
in case of acidic and basic drugs where the solubility varies with pH.
Kollidon® VA64, which is a water-soluble polyvinylpyrrolidone-
vinyl acetate copolymer, is commonly used to prepare solid
dispersion for immediate drug release.48 It was, therefore, tested as
393
a polymeric carrier for 3D printing. However, filaments prepared
using Kollidon® VA64 itself and its mixture with 10% w/w halo-
peridol were brittle and collapsed in the 3D printer when pushed
by a drive gear. For successful FDM 3D printing, the filaments
should be robust enough to withstand the pressure exerted by the
drive gear during printing to push into the printer nozzle, and the
melt should have optimal viscosity to pass through the printer
nozzle.33,49 Therefore, to modulate the mechanical properties of
extruded filaments and enable printing, 2 cellulosic fibrous poly-
mers (HPMCAS MG and Affinisol™ 15 cP) were mixed individually
with Kollidon® VA64 for the preparation of filaments. Although
HPMCAS is an enteric polymer that dissolves in aqueous media due
to ionization at around pH 5.4 and higher and thus provides
delayed drug release,25 it was used in the present investigation to
determine whether its 1:1 mixture with the highly water-soluble
Kollidon® VA64 could possibly provide rapid drug release.
Another hydrophilic polymer, Kollicoat® IR, was also studied in
conjunction with Kollidon® VA64. Kollicoat® IR is chemically
polyvinyl alcohol-polyethylene glycol graft copolymer, and since it
contains partial polyethylene glycol backbone and polyvinyl
alcohol, the filaments produced by itself or its mixture with Kolli-
don® VA64 could be suitable for 3D printing. The filaments were
tested in the 3D printer for their suitability for use. It was observed
that all filaments produced by HPMCAS MG, Affinisol™ 15 cP, and
Kollicoat® IR by themselves or their 1:1 w/w mixtures with Kolli-
don® VA64 exhibited optimum mechanical properties for 3D
printing. Filaments were then prepared by incorporating 10% w/w
haloperidol with these polymers or their mixtures, and the drug
release from crushed filaments and printed tablets was studied. The
presence of drug did not adversely affect the printability of the
filaments. All polymers used in the study are water-soluble,
although by itself HPMCAS MG is soluble at only pH >5.4.
Crushed extrudates were used for initial screening of drug-
polymer or drug-polymer-polymer mixtures for drug release. It
was hypothesized that if rapid drug release can be obtained from
crushed extrudates, it may also be possible to get relatively rapid
drug release from the 3D printed tablets. The crushed extrudates
that required relatively longer time for the drug release were not
selected to print tablets.
Figure 1 gives the drug release profiles at pH 2 and 6.8 from the
crushed extrudates containing 10% w/w haloperidol and 90% w/w
individual polymers or their mixtures (1:1 w/w). The drug release
from the crushed extrudates containing only Kollidon® VA64 as the
polymeric matrix was faster than that of other polymers and
polymer-polymer mixtures. The complete drug release from Kolli-
don® VA64 was achieved within 15 min at both pH conditions. In
contrast, the drug release from Affinisol™ 15 cP was the slowest at
both pHs, where the drug release at pH 6.8 was even slower than
that at pH 2. Moreover, the drug release from Affinisol™ 15 cP at
both pH conditions was incomplete. While Kollicoat® IR showed
almost complete drug release at pH 2 in <60 min, it exhibited slow
and incomplete drug release at pH 6.8. Since HPMCAS MG is a
polymer used for enteric coating that dissolves pH >5.4 and would
not dissolve at pH 2, it was expected that the polymer would
provide pH-dependent drug release. Therefore, the drug release
from extrudates having this polymer was not studied. Although
filaments of Affinisol™ 15 cP and Kollicoat® IR had flexibility and
mechanical strength suitable for 3D printing, the results of these
studies with crushed extrudates showed that they may not release
drug rapidly and uniformly throughout the gastrointestinal pH
range and thus may not be suitable for formulating 3D printed
tablets for rapid drug release. HPMCAS MG would also not be
suitable for the development of such tablets because of its expected
394 N.G. Solanki et al. / Journal of Pharmaceutical Sciences 107 (2018) 390-401
Figure 1. Drug release from crushed extrudates of drug-polymer or drug-polymer-
polymer mixture containing 10% w/w haloperidol at (a) pH 2 and (b) 6.8. The
symbols used for dissolution profiles in (b) are the same as those in (a). Each point
refers to mean ± SD (n ¼ 3).
pH-dependent dissolution. On the other hand, Kollidon® VA64
released drug rapidly at both gastric and intestinal pH conditions;
however, its filaments did not have optimal mechanical properties
for FDM 3D printing. For these reasons, our attempts shifted next to
evaluating drug release from mixtures of Kollidon® VA64 with
other polymers to modify mechanical property of filaments for
FDM 3D printing.
Affinisol™ 15 cP and HPMCAS MG were added to Kollidon® VA64
to improve its mechanical properties for 3D printing. Preliminary
studies showed that the filaments of mixed polymers containing
10% haloperidol can easily be printed into tablets. Drug release
profiles from crushed extrudates containing 10% haloperidol and
1:1 w/w mixtures of Kollidon® VA64 and HPMCAS MG or Affinisol™
15 cP are also shown in Figure 1. Although HPMCAS MG is an enteric
coating polymer, the drug release was observed at both pH 2 and
6.8 from the extrudates of its mixture with Kollidon® VA64. How-
ever, the release rates were rather slow as it took >120 min for
>80% drug release from crushed extrudates at both pH conditions.
On the other hand, drug release from the mixture of Kollidon®
VA64 and Affinisol™ 15 cP exhibited rapid and complete drug
release irrespective of pH. Furthermore, the drug-loaded filaments
of this mixture showed good flexibility and mechanical strength for
3D printing. Based on drug release, the 1:1 w/w mixture of Kolli-
don® VA64 and Affinisol™ 15 cP was selected in the present study
for 3D printing and drug release from 3D printed tablets.
Drug-Polymer, Polymer-Polymer, and Drug-Polymer-Polymer
Miscibility
As mentioned earlier, one of the objectives of the present
investigation was to develop 3D printed tablets where the drug
would remain molecularly dispersed in polymers to form ASD. This
would enhance dissolution rate of poorly water-soluble drugs.
When haloperidol was extruded at 150
C with different polymers,
it formed ASDs. However, it is essential that the drug remained
physically stable and did not crystallize out on storage for pro-
longed periods of time. Since a combination of 2 polymers, Kolli-
don® VA64 and Affinisol™ 15 cP, were used for 3D printing, the
miscibility of haloperidol with the polymers individually and with
the mixtures was tested. It was also important to establish that the
2 polymers are miscible with each other. A film-casting method
previously developed in our laboratory41,46 was used to evaluate
drug-polymer, polymer-polymer, and drug-polymer-polymer
miscibility, and the results are presented below:
Haloperidol-Kollidon® VA64 and Haloperidol-Affinisol™ 15 cP
Miscibility
The miscibility testing of haloperidol-Kollidon® VA64 and
haloperidol-Affinisol™ 15 cP mixtures with 1:9, 2:8, and 3:7 w/w
ratios was conducted by analyzing the casted films using DSC,
PXRD, and PLM on Day 1 (freshly prepared films) and after expo-
sure to 40
C/75% RH for 30 days (Day 30). As shown in Figure 2,
haloperidol-Kollidon® VA64 mixtures were miscible up to 2:8 w/w
for 30 days as no DSC endotherms or PXRD patterns of the films due
to the possible crystallization of drug at this ratio was observed
initially and after storage for 30 days under accelerated stability
testing conditions (Figs. 2a and 2b, respectively). The PLM also did
not reveal the presence of any crystals. At the 3:7 w/w ratio, the DSC
and PXRD patterns as well as PLM revealed drug crystallization,
indicating that haloperidol was not completely miscible with Kol-
lidon® VA64 at this ratio. However, the endotherm for the crys-
tallization of haloperidol from the freshly prepared 3:7 w/w
haloperidol-Kollidon® VA64 film was observed at 130
C instead of
152
C, which is the melting temperature of the pure haloperidol.
The depression in melting point may be attributed to the partial
dissolution of the drug in the polymer melt.50
For haloperidol-Affinisol™ 15 cP mixtures, the DSC, PXRD, and
PLM analyses of films with 1:9, 2:8 and 3:7 w/w of haloperidol to
Affinisol™ 15 cP ratios were conducted, which showed that the drug
was miscible at 1:9 and 2:8 w/w ratios on Day 1 (Figs. 2c and 2d).
When the films were exposed to 40
C/75% RH for 30 days, the
crystallization of haloperidol was observed for 2:8 w/w drug to
polymer ratio. Thus, haloperidol was found to be miscible with
Affinisol™ 15 cP only at 1:9 w/w ratio.
Kollidon® VA64-Affinisol™ 15 cP Miscibility
Before testing the miscibility of haloperidol with the mixture of
Kollidon® VA64 and Affinisol™ 15 cP, it was important to establish
that the 2 polymers were also miscible between themselves. If any
phase separation occurs when the drug is added to the polymer
mixture, this would rule out the possibility of any polymer-polymer
immiscibility to be the cause of such phase separation. To evaluate
the polymer-polymer miscibility, films of the 1:1 w/w Kollidon®
VA64-Affinisol™ 15 cP mixture was analyzed by DSC initially and
after exposure to 40
C/75% RH for 30 days. Single Tg for the mixture
between Tg values of 2 individual polymers would infer that the
blend is miscible.51,52 As shown in Figure 3a, the Tg of the freshly
prepared film of the mixture was 106
C, which is in between the Tg
values of Affinisol™ 15 cP (98
C) and Kollidon® VA64 (108
C).53
After aging at 40
C/75% RH for 15 and 30 days, there was still
 N.G. Solanki et al. / Journal of Pharmaceutical Sciences 107 (2018) 390-401 395

Figure 2. DSC scans and PXRD patterns of haloperidol-Kollidon® VA64 binary mixtures are given in (a) and (b), respectively. Similarly, DSC scans and PXRD patterns of haloperidol-
Affinisol™ 15 cP binary mixtures are shown in (c and d), respectively. Results for both freshly prepared films (Day 1) and after exposure to 40
C/75% RH for 30 days (Day 30) are
depicted.

single Tg of the mixture (~105
C), thus confirming the mixture to be
miscible.
Haloperidol-Kollidon® VA64-Affinisol™ 15 cP Miscibility
The films of 1:5:5 (9.1% drug) and 2:5:5 (16.6% drug) w/w
haloperidol-Kollidon® VA64-Affinisol™ 15 cP mixtures were
analyzed periodically by DSC, PXRD, and microscopy. The results
of DSC and PXRD analyses on days 1 and 30 are given in Figure 3.
There was no characteristic endotherm peak for haloperidol in
the DSC scans and, in addition, only single Tg values for both
mixtures were observed, confirming that the ternary mixtures
were miscible and produced only one phase. Polarized light
microscopic images also indicated that no crystallization of the
drug occurred (data not shown). Although the drug-polymer-
396 N.G. Solanki et al. / Journal of Pharmaceutical Sciences 107 (2018) 390-401

Figure 3. (a) DSC scans and (b) PXRD patterns of Kollidon® VA64-Affinisol™ 15 cP binary mixture and haloperidol-Kollidon® VA64-Affinisol™ 15 cP ternary mixtures of freshly
prepared films (Day 1) and after exposure to 40
C/75% RH for 30 days (Day 30).

polymer miscibility testing was established in detail for the 2:5:5 extrudate showed similar TG scans since they would be in the
w/w ratio (16.6% drug), one of the mixtures used for 3D printing molten state, and the drug and polymers would be similarly
contained 20% drug (2:4:4 w/w), which was also found to be intermixed with each other at high temperature. However, even
miscible. considering that only 10% haloperidol was present in the compo-
sitions, the absence of any weight loss from them up to 250
C is
Thermogravimetric Analysis noteworthy. It appears that haloperidol or its possible thermal
decomposition products did not evaporate out when they were
Previously, Gupta et al.53 reported ~1% weight loss by both present in molten mixtures with polymers. To ascertain whether
Affinisol™ 15 cP and Kollidon® VA64 during TG analyses up to 100
C
due to the removal of unbound moisture. In case of Affinisol™ 15 cP,
there was some additional weight loss gradually between 100
C to
220
C (~0.6%) due to the loss of weakly bound water, whereas
Kollidon® VA64 showed the minimal weight loss in this tempera-
ture range. Rapid weight losses that may be attributed to possible
thermal decomposition of the polymers were observed only above
240
C. Thus, both polymers were apparently stable at the melt
extrusion temperature of 150
C and the 3D printing temperature of
210
C. In the present investigation, TG analyses of haloperidol itself,
its physical mixture with Kollidon® VA64 and Affinisol™ 15 cP
containing 10% drug and 45% each of the 2 polymers (10:45:45 w/
w) and the crushed extrudate with similar composition as that of
the physical mixture were conducted to determine any weight loss
at melt extrusion and 3D printing temperatures. The results are
given in Figure 4, where haloperidol by itself exhibited minimal
weight loss when heated up to 200
C and, above 200
C, the weight
loss of haloperidol was rapid that may be attributed to its subli-
mation, thermal decomposition or both. To further investigate the
weight loss from haloperidol at the printing temperature of 210
C,
the isothermal TG analysis at this temperature was conducted over
a period of 10 min, which showed a zero-order weight loss at the
rate of 0.852 percent/min (r2 ¼ 0.9999) (data not shown). In Figure 4. TG analyses of haloperidol and haloperidol-Kollidon® VA64-Affinisol™ 15 cP
(10:45:45) ternary physical mixture and crushed extrudates. The initial weights of the
contrast, the physical mixture and the crushed extrudate did not physical mixture and the crushed extrudate were set at 100%. In the overlay in figure,
exhibit any significant weight loss during TG analysis up to at least the scans are shown separately for better clarity. The weight loss for each sample is
250
C. It is not surprising that the physical mixture and the crushed proportional.
 N.G. Solanki et al. / Journal of Pharmaceutical Sciences 107 (2018) 390-401 397

Figure 5. Temperature sweep analysis of Kollidon® VA64, Affinisol™ 15 cP, binary mixtures of haloperidol-Kollidon® VA64, haloperidol-Affinisol™ 15 cP, Kollidon® VA64-Affinisol™
15 cP, and ternary mixture of haloperidol-Kollidon® VA64-Affinisol™ 15 cP at angular frequency of 0.1 rad/s and oscillation strain of 0.5% from 190
C to 130
C. Each data point
represents the mean of 2 determinations.

there was any possible thermal degradation of haloperidol at 210
C,
HPLC analyses were conducted for the drug-polymers physical
mixtures (10% haloperidol), the extrudate prepared at 150
C and
the extrudate heated to 210
C. In all 3 cases, the recovery of halo-
peridol was close to 100% and within 1% of each other, and there
were no extraneous HPLC peaks due to possible degradation of the
drug. The HPLC chromatograms of the samples are shown in
Figure 1 in the Supplementary Material, indicating that there were
no any extraneous peaks due to the presence of any possible
degradation products. Based on the above results and considering
that the filaments would be exposed to 210
C only for a few sec-
onds during 3D printing, it was concluded that there was no ther-
mal degradation of haloperidol and the weight loss (evaporation), if
any, would be minimal.

Figure 6. Photographs of FDM 3D printed tablets, where 1 and 2 are, respectively, haloperidol-Kollidon® VA64-Affinisol™ 15 cP (10:45:45) tablets at 100% and 60% infill, whereas 3
and 4 are, respectively, haloperidol-Kollidon® VA64-Affinisol™ 15 cP (20:40:40) tablets at 100% and 60% infill. Both diameter and thickness of each tablet is shown (a and b,
respectively).
398 N.G. Solanki et al. / Journal of Pharmaceutical Sciences 107 (2018) 390-401

Table 1
Tablet Weight, Dimensions, and Drug Content After 3D Printing of Haloperidol-Kollidon® VA64-Affinisol™ 15 cP Tablets (Mean ± SD, n ¼ 3)

Drug (%) Infill (%) Tablet weight (mg) Diameter (mm) Thickness (mm) Drug Content After Drug Content
3D Printing (%) After HME (%)a

10 100 115 ± 5.3 9.5 ± 0.1 2.31 ± 0.01 96.7 ± 0.8 96.9 ± 0.8
60 117 ± 5.5 12.5 ± 0.1 2.84 ± 0.04 95.2 ± 2.0
20 100 64.8 ± 3.4 7.5 ± 0.17 1.50 ± 0.08 97.4 ± 1.0 98.1 ± 1.1
60 62.1 ± 4.8 9.0 ± 0.12 1.42 ± 0.04 97.5 ± 0.8
a
Drug analyses of HME filaments are also given.

Rheology printing tablets using haloperidol-Kollidon® VA64-Affinisol™ 15 cP

mixtures.
Viscosity of polymers decreases with the increase in tempera-
ture and shear rate. In HME, materials are passed through rotating
twin screws at elevated temperature, where they are also subjected Characterization of 3D Printed Tablets
to high shear rates. Both of these factors influence melting, flow,
and deformation behavior of materials during melt extrusion. It has The photographs of FDM 3D printed tablets are given in Figure 6.
been reported earlier that the complex viscosity should preferably The tablets containing 20% w/w haloperidol were somewhat darker
be between 1000 to 10,000 Pa s at angular frequency of 0.1 rad/s for in color than that with 10% w/w drug. The more intense yellow
optimal HME operation.45 Accordingly, the extrusion temperature color with 20% w/w tablets may be attributed to the higher drug
should be set such that the complex viscosity falls within this range. concentration. Tablets with 100% infill also appeared to have denser
It was also reported that certain polymers, such as Affinisol™ 15 cP, color than that with 60% infill. The filaments containing drug-
can undergo shear thinning during the extrusion process, which polymer are yellow, and the same intensity of color was also
further reduces melt viscosity and facilitates melt extrusion at observed in the printed tablet. Although filaments and tablets were
lower temperature.53 prepared at, respectively, 150
C and 210
C, which indicate that the
The viscosity also plays a major role in determining optimal formation of color was not dependent on temperature. Even if there
processing conditions for FDM 3D printing, where the filament
previously prepared by HME is pushed through the heated nozzle
as even thinner filaments for deposition into layers to form the
desired shape. The viscosity, however, has to be much lower than
that for melt extrusion for efficient printing and, at the same time, it
should not be so low that it flows as liquids or very soft filaments
from the printing nozzle. Often, higher temperature for FDM 3D
printing is required than HME as very limited shear rate is associ-
ated with 3D printing. Therefore, the optimal viscosity is attained
by increasing the temperature for 3D printing.54 There are,
however, no reports in the literature what should be the optimal
viscosity range for FDM 3D printing.
Figure 5 shows the complex viscosity of individual polymers,
polymer-polymer binary mixture, drug-polymer binary mixtures,
and drug-polymer-polymer ternary mixtures as a function of
temperature at an angular frequency of 0.1 rad/s. Kollidon® VA64
showed the lowest complex viscosity, whereas Affinisol™ 15 cP
showed highest complex viscosity at all temperatures. When Kol-
lidon® VA64 was mixed with Affinisol™ 15 cP at 1:1 w/w ratio, there
was no considerable decrease in the viscosity of Affinisol™ 15 cP,
and there was also no decrease in viscosity when 10% haloperidol
was added to Affinisol™ 15 cP. In contrast, the presence of drug
greatly decreased the viscosity of Kollidon® VA64. However, as
mentioned earlier, Kollidon® VA64 was not suitable for FDM 3D
printing as it formed brittle filaments after melt extrusion. For this
reason, the effect of the presence of 10% and 20% haloperidol on the
viscosity of Kollidon® VA64-Affinisol™ 15 cP mixture was investi-
gated. There was a major decrease in viscosity as a function of
temperature in 10:45:45 and 20:40:40 w/w mixtures of haloper-
idol-Kollidon® VA64-Affinisol™ 15 cP as compared to that of the 1:1
w/w Kollidon® VA64-Affinisol™ 15 cP mixture. These results show
the plasticizing effect of haloperidol. Although the viscosity of
drug-polymer-polymer mixtures indicated the melt extrudable
temperature range to be 160
C to 180
C, it was possible to extrude
the mixtures at 150
C due to the shear thinning effect of Affinisol™
15 cP at the high shear rate provided by the melt extruder.52 For the
Figure 7. In vitro drug release profiles at (a) pH 2 and (b) pH 6.8 from physical
identification of the 3D printing temperature, attempts were made mixtures, crushed extrudates, and 3D printed tablets (100% and 60% infill) containing
to print tablets at higher temperatures in the range of 190
C to 10:45:45 w/w haloperidol-Kollidon® VA64-Affinisol™ 15 cP mixtures (10% w/w
220
C, and it was observed that 210
C was most suitable for haloperidol). Each point refers to mean ± SD (n ¼ 3).
 N.G. Solanki et al. / Journal of Pharmaceutical Sciences 107 (2018) 390-401
was any minute degradation responsible for the color, it was not
detectable by HPLC analysis. As given in Table 1, weights and
dimensions of the tablets were within the narrow ranges. The drug
contents of tablets and extrudates were at least 96% of the theo-
retical amounts, and there were no indications of drug degradation
in the HPLC analysis. It was, therefore, concluded that there was
good thermal stability of drug during extrusion and printing.
In Vitro Dissolution of FDM Printed Haloperidol Tablets
Haloperidol-Kollidon® VA64-Afifnisol™ 15 cP (10:45:45) Mixture
Dissolution profiles of haloperidol-Kollidon® VA64-Affinisol™
15 cP containing physical mixtures, crushed extrudates, and FDM
printed tablets with 100% and 60% infill at pH 2 and 6.8 are given in
Figure 7. The concentration of haloperidol was 10% w/w. At pH 2
(Fig. 7a), both the physical mixture and the crushed extrudate
exhibited fast dissolution rates with >90% drug dissolving in
15 min. The dissolution rates from the 3D printed tablets were
relatively slower. Tablets with 60% infill showed drug release of
~90% within 45 min, whereas tablets with 100% infill showed 85%
drug release in 2 h and complete drug release when the paddle
speed was increased to 250 RPM.
The drug release rate from the 3D printed tablets with 60% infill
was also relatively high at pH 6.8 (Fig. 7b), where ~70% and ~80%
drug release was observed in 60 and 120 min, respectively. With
100% infill, it took about 3 h for complete drug release (>80%). For
Figure 8. In vitro drug release profiles at (a) pH 2 and (b) pH 6.8 from physical mix-
tures, crushed extrudates, and 3D printed tablets (100% and 60% infill) containing
20:40:40 w/w haloperidol-Kollidon® VA64-Affinisol™ 15 cP mixtures (20% w/w halo-
peridol). Each point refers to mean ± SD (n ¼ 3).
399
comparison, the drug release from crushed extrudates and physical
mixtures at pH 6.8 are also shown in Figure 7b. Although the
crushed extrudate gave the highest dissolution rate among all
samples, the physical mixture showed incomplete drug release that
could be due to low solubility of haloperidol at pH 6.8.44 When
Figures 7a and 7b are compared, the dissolution rates of all
formulations at pH 2 were higher than that at pH 6.8, which, again,
could be due to the higher solubility of haloperidol at pH 2. The
faster drug release from 60% infill tablets may be attributed to its
higher porosity as compared to 100% infill tablets. Furthermore,
tablets with 60% infill disintegrated into fragments during the
dissolution test, thus exposing larger surface area, whereas tablets
with 100% infill did not disintegrate and dissolved by erosion only.
This could be another reason for the faster dissolution rate of tab-
lets with 60% infill.
Haloperidol-Kollidon® VA64-Affinisol™ 15 cP (20:40:40) Mixture
Figure 8 shows the in vitro drug release profiles from the
physical mixture, the crushed extrudate, and 3D printed tablets
containing 20% w/w haloperidol at pH 2 (8A) and 6.8 (8B). In all
cases, the drug release from formulations containing 20% w/w
haloperidol was slower than those with 10% w/w haloperidol
(Figs. 7a and 7b). At pH 2, extents of drug release from 60% and
100% infill tablets were, respectively, ~75% and ~90% in 1 and 2 h. At
pH 6.8, approximately similar drug release was observed in 2 and
3 h, respectively. The higher drug release from tablets with 60%
infill than those with 100% infill may be attributed to the porosity of
the tablets.
Overall, the dissolution studies in the present investigation
indicate that FDM 3D printed tablets with relatively rapid release of
haloperidol could be obtained when the 1:1 w/w mixture of Kol-
lidon® VA64 and Affinisol™ 15 cP was used as the polymeric matrix.
Despite extreme difference in the solubility of haloperidol at pH 2
and 6.8 (>2 mg/mL vs. ~ 60 mg/mL), complete drug release from the
3D printed tablets could be obtained at both pH conditions. The
drug release rate could be modulated by formulation and design of
tablets (i.e., changing infill density). At 10% drug concentration in
the tablet, complete drug release in 45 min was obtained from
tablets with 60% infill. Also in most other cases, complete drug
release could be obtained in 1 to 2 h. Such tablets may thus be
suitable for immediate release dosage forms of drugs. Since the
drug was dispersed molecularly in the polymeric matrix, the
influence of pH-dependent drug solubility on drug release could
also be minimized.
Conclusions
A systematic study was conducted for identifying pharmaceu-
tically acceptable polymers for the formulation of 3D printed tab-
lets by FDM that would provide relatively rapid drug release.
Filaments of drug-polymer mixtures prepared by HME were used
for 3D printing into tablets. Polyvinylpyrrolidone-vinyl acetate
copolymer (Kollidon® VA64), polyvinyl alcohol-polyethylene glycol
graft copolymer (Kollicoat® IR), hydroxypropyl methylcellulose
HME 15 cP (HPMC HME 15 cP; Affinisol™ 15 cP), and hydroxypropyl
methylcellulose acetate succinate (HPMCAS MG; Aqoat® AS-MG)
were used as the polymers. Haloperidol, a basic drug with
pH-dependent solubility in aqueous media, was used as the model
drug. The drug release from crushed filaments (extrudates) was
studied to screen polymers for drug release with the expectation
that if the drug release from the crushed filaments is rapid, it may
also be relatively rapid from the printed tablets. The dissolution
testing at pH 2 and 6.8 showed that, among all the polymers used,
Kollidon® VA64 provided the fastest drug release from crushed
filaments. However, Kollidon® VA64 filaments were not suitable for
400 N.G. Solanki et al. / Journal of Pharmaceutical Sciences 107 (2018) 390-401
3D printing as they were brittle and collapsed when pushed
through the drive gear. After further testing, it was demonstrated
that the use of 1:1 w/w blend of 2 pharmaceutically acceptable
polymers, Kollidon® VA64 and Affinisol™ 15 cP, provided optimum
mechanical strength for 3D printing. They were miscible between
themselves, and the polymer blend was also miscible with 10% and
20% w/w haloperidol. To achieve immediate drug release from the
FDM 3D printed tablets, 100% and 60% infill tablets were prepared
and drug release from the tablets was studied. Complete drug
release from the porous tablets (60% infill) was achieved in 45 min,
which was significantly faster as compared to non-porous tablets
(100% infill). The procedure adapted in the present study may be
used for the development of FDM 3D printed tablets as immediate
release dosage forms.
Acknowledgments
The authors thank Mr. Jaydip Vasoya and Dr. Suhas Gumaste for
technical assistance and helpful discussions.
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