European Journal of Pharmaceutics and Biopharmaceutics 131 (2018) 44–47

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European Journal of Pharmaceutics and Biopharmaceutics

journal homepage: www.elsevier.com/locate/ejpb

Technical note

3D printing of tablets containing amorphous aripiprazole by filaments co- T

extrusion
⁎
Witold Jamróza, , Mateusz Kureka, Anna Czecha, Joanna Szafranieca,b, Karolina Gawlakb,
Renata Jachowicza
a
Chair and Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna str., 30-688
Krakow, Poland
b
Department of Physical Chemistry and Electrochemistry, Faculty of Chemistry, Jagiellonian University, 2 Gronostajowa str., 30-387 Krakow, Poland

A R T I C LE I N FO A B S T R A C T

Keywords: Three-dimensional printing is one of the fastest developing technology within pharmaceutical field. With many
3D printing advantages this method can be found as a new dosage form manufacturing technique, however low printing
Hot melt extrusion efficiency stays as one of the major limitations. Therefore, the preparation of filaments as a feedstock and
Amorphization printing of the final dosage forms in pharmacies may by the direction of development for this method. Thus,
Aripiprazole
simple dosage and dissolution profile modification seems to be essential. This can be done in simple way by
Tablet
addition drug-free filament during printing process. In this work the influence of dual co-extrusion process on
the properties of 3D-printed tablets with aripiprazole was evaluated. A ZMorph® 3D printer equipped with
DualPro extruder was employed to produce tablets made from Kollicoat® IR aripiprazole-loaded filament and
commercially available PLA filament used to modify the release profile. Optical and polarized light microscopy
were utilized to evaluate structure of printed objects and X-ray diffraction studies were performed to determine
crystallinity of aripiprazole within filament and tablets. Fast dissolution of aripiprazole resulted from its
amorphization while prolonged drug release was a result of co-extrusion with PLA filament. Importantly, the
drug remained crystalline within the filament and phase transition into disordered system appeared during
printing of tablets. Given the high stability of crystalline materials such feature is especially beneficial for long-
term storage of feedstock filament.

1. Introduction
Three-dimensional printing (3DP) is a group of rapid prototyping
techniques that are believed to be the most revolutionary in current
pharmaceutical applications. The great interest of additive manu-
facturing is manifested by the first 3D-printed drug - Spritam® that
received U. S. Food & Drug Administration approval in 2015. The
technique that is very promising for solid dosage form preparation is
Fused Deposition Modelling (FDM) which is classified as a solid ex-
trusion-based 3D printing method [1]. This approach uses the filament
that is prepared by hot-melt extrusion from thermoplastic polymers
such as poly(vinyl alcohol) (PVA), poly(lactic acid) (PLA), cellulose or
acrylic acid derivatives and active pharmaceutical ingredient (API) [2].
The filament is melted in the nozzle and subsequently deposited to
create the three-dimensional object layer by layer. The type of used
polymer, the geometry of the printed object, drug loading and possible
amorphization of API may affect its dissolution characteristics as shown
by Pietrzak et al. who reported that the amount of dissolved theo-
phylline changes with the size of the printed tablet [3–5]. This problem
can be solved using the co-extrusion with the drug-free filament made
from the same polymer what results in the formation of dosage forms
characterized by the same size and dissolution behavior but different
content of an active substance. To achieve this goal it is necessary to use
print head that allows co-extrusion from two filaments at the same
time. Due to the fact that both filaments are heated simultaneously in
one print head and extruded through one nozzle without mixing,
polymers utilized in this technology have to be characterized by similar
melting temperatures and rheological properties. This approach opens
new opportunities in dosage forms development, however it has to be
carefully investigated in terms of material mixing, potential interac-
tions and release mechanism. While classical FDM provides easy mod-
ification of the internal structure of printed objects and spatial se-
paration of incompatible APIs in compartmentalized dosage form, it
requires the use of different filaments to obtain objects of the same

⁎
Corresponding author.
E-mail address: mfjamroz@cyf-kr.edu.pl (W. Jamróz).

https://doi.org/10.1016/j.ejpb.2018.07.017
Received 12 April 2018; Received in revised form 28 June 2018; Accepted 21 July 2018
Available online 23 July 2018
0939-6411/ © 2018 Elsevier B.V. All rights reserved.
W. Jamróz et al. European Journal of Pharmaceutics and Biopharmaceutics 131 (2018) 44–47

shape, size, infill ratio but various concentration of API [6]. The use of
co-extrusion technology allows to apply one drug-loaded filament as a
feedstock material and modify the printed object properties what lead
to the drug content or dissolution rate modifications in the printing
stage without the need of utilization of the new API-loaded filament. It
makes one filament can be easily implemented into the formation of
individualized product series.
The aim of this study is to evaluate the influence of dual co-extru-
sion of drug-loaded soluble filament and insoluble drug-free filament on
the properties of 3D-printed tablets with aripiprazole (ARP) being
practically insoluble antipsychotic drug assigned to BCS class II.
Performed studies confirmed that 3D printing led to drug amorphiza-
tion what positively affected the dissolution of aripiprazole while co-
extrusion with PLA resulted in its prolonged release.

2. Materials and methods

Aripiprazole (HyperChem, China) was used as a model drug.

Kollicoat® IR (BASF®, Germany) was used as matrix forming excipient
to prepare filaments. Commercially available PLA filament (1.75 mm in
diameter, 3DColor®, Poland), based on Ingeo™ Biopolymer 2003D
(Nature Works LLC, USA) was used as modifying agent.

2.1. Drug-loaded filament preparation

Aripiprazole and Kollicoat® IR were mixed and filament with ar-

ipiprazole was prepared with Noztek® Pro filament extruder (England)
at 150 °C.
2.2. Filament drug content determination
Six randomly taken filament samples were weighed and shaken in
100 mL Erlenmeyer flasks filled with 25 mL of water over 12 h in wa-
terbath (Memmert WNB 22, Germany) at 70 °C. After cooling, 50 mL of
ethanol was added and flasks were shaken for another 4 h at room
temperature. Drug content was assayed spectrophotometrically at
λ = 250 nm using UV-1800 spectrophotometer (Shimadzu, Japan).
2.3. Preparation of 3D-printed tablets
Tablet model (cylinder shape, 9 mm in diameter and either 1.8 mm
or 2.4 mm in height) was designed with Blender® software, transferred
to Voxelizer® slicing software and then printed with ZMorph® 2.0 SX
personal fabricator (Poland) equipped with two material DualPro ex-
truder (Fig. 1). The printing process was realized by two independently
working stepper motors which moved API-loaded and placebo filaments
into the single hot end where melting end extrusion by 0.4 mm nozzle
occurred. Process was conducted at 208–210 °C at 8–10 mm/s speed.
The plate temperature was 60 °C. The layer height was 0.2 mm, and
path width 0.4 mm. Two types of tablets were prepared: printed with
drug-loaded filament only (1:0) and composed of two types of fila-
ments, i.e. API filament: placebo filament in 4:1 wt ratio. Color (red:-
blue)1 placebo cylinder was printed to visualize and better understand
the mechanism of co-extrusion process.
2.4. Filament and tablets morphology
Tablets morphology were examined using stereoscopic microscope
MST 200 M (Poland) and polarized light microscope Hund Wetzlar
H600 (Germany). Digital images were captured by TPL MicroCam
5MPx (Poland). Digimatic Micrometer MDC-25SB (Mitutoyo, Japan)
was used to determine dimensions of the filament and tablets.
1
For interpretation of color in Figs. 1–3, the reader is referred to the web
version of this article.
Fig. 1. DualPro extruder (front).
2.5. X-ray diffraction (XRD)
The crystalline structure of the samples was analyzed using X-ray
diffractometer Rigaku Mini Flex II (Japan). Diffraction patterns were
collected from 3° to 70° with 5°/min step and a step size equal to 0.02.
Monochromatic Cu Kα radiation (λ = 1.5418 Å) at ambient tempera-
ture was used. The diffraction patterns were collected using a current of
15 mA and a voltage of 40 kV. The samples were measured as received.
2.6. Dissolution studies
Dissolution studies were performed in accordance to the pharmaco-
peial apparatus II (Hanson Research SR8 Plus, USA) in sink conditions
(900 mL of 0.1 mol/L HCl with KCl, pH = 1.2 at 37 °C). The paddle ro-
tation speed was 50 rpm. Samples were withdrawn at certain time in-
tervals, filtered and analyzed spectrophotometrically at λ = 250 nm
using a Shimadzu UV-1800 spectrophotometer (Japan). The tests were
carried out in triplicate and presented results represent average amounts
of dissolved drug with standard deviations (Mean +/- SD).
3. Result and discussion
The ARP-loaded filament was opaque and light yellow in color
(Fig. 2). The dimension of the filament was 1.4 mm and the drug con-
tent 13.68 ± 3.62%.
DualPro print head gives the opportunity for partial mixing and co-
extruding two materials at set temperature. The microscopic in-
vestigation of placebo prints revealed that the two types of filaments
were extruded side by side and mixing zone was limited. During
printing of cylindrical object the filaments paths were twisted and
changes in two color pattern were observed (Fig. 3).
The printed tablets were light yellow (Fig. 4a). Their height varied
between 1.80 and 1.85 mm (1:0) and 2.41–2.56 mm (4:1) while the
weight was 80–88 mg and 145–154 mg, respectively. Single layer of the
tablet was transparent and no crystals of ARP were observed in polar-
ized light (Fig. 4 b and c).
X-ray diffraction patterns confirmed amorphization of aripiprazole

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W. Jamróz et al. European Journal of Pharmaceutics and Biopharmaceutics 131 (2018) 44–47

Fig. 2. ARP-loaded filament.

Fig. 5. XRPD diffractogram of filament and 3DP tablets.

Fig. 3. Two color pattern of placebo cylinder.

in 3DP tablets as only a broad amorphous hallo was observed while

characteristic Braggs peaks were visible on the filament diffractogram.
This phenomena is a consequence of filament preparation in the tem-
perature not exceeded aripiprazole melting point, whereas 3D printing
process temperature was above drug melting point (Fig. 5). In our
previous study we showed that FDM method allows to produce or-
odispersible films containing amorphous aripiprazole characterized by
fast dissolution of the API [7].
The printed paths width were not even and observed gaps resulted
from differences in filaments diameter: 1.4 mm of ARP loaded filament
compared to 1.75 mm of placebo filament. It also influenced the drug
content homogeneity which was affected by co-extrusion process as
well. Dissolution data reveals that co-extrusion with insoluble PLA Fig. 6. Dissolution profiles of aripiprazole.
polymer can modify dissolution profile. After 6 h about 70% of ARP was
released from 4:1 formulation whereas over 90% of drug was released
filaments as over 95% of drug dissolved after 60 min [7]. The effect of
after 45 min from 1:0 formulation (Fig. 6). Similar results were ob-
improved dissolution was assigned to drug amorphization and in-
tained for orodispersible films printed from aripiprazole-loaded PVA
creased surface area.

Fig. 4. (a) 3D printed tablets (4:1) and (1:0); (b, c) visible and polarized light microscope images of tablets single layer.

46
W. Jamróz et al.
4. Conclusions
Performed studies confirmed that dual co-extrusion of aripiprazole-
Kollicoat® IR filament and drug-free PLA filament led to changes in the
dissolution characteristics from 3D-printed tablets. According to the
XRPD results, the molecular dispersion of aripiprazole in printlets was
attributed to the high temperature during the 3D printing process. The
amorphization of aripiprazole, as well as utilization of water soluble
polymer in the drug-loaded filament led to fast dissolution of API while
the co-extrusion with insoluble PLA filament resulted in prolonged drug
release from printlets. Importantly, the drug remained crystalline
within the filament and phase transition into molecularly disordered
system appeared during printing of tablets. The 3D printing based on
simultaneous co-extrusion of drug-free filament with drug-loaded one
as a feedstock material demonstrates a promising approach to become a
practicable preparation method of printlets with modified release. It
can be also implemented into the fabrication of tailor-made product
series.
Acknowledgements
The authors acknowledge Polish National Science Centre for the
47
European Journal of Pharmaceutics and Biopharmaceutics 131 (2018) 44–47
financial support (grant Symfonia 3 no 2015/16/W/NZ7/00404).
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