Journal of Drug Delivery Science and Technology 46 (2018) 148–155

Contents lists available at ScienceDirect

Journal of Drug Delivery Science and Technology

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

Formulation strategies for solid oral dosage form using 3D printing T

technology: A mini-review
Pinak Khatria,b,∗, Mansi K. Shahc, Namrata Vorad
a
Product Development, G&W PA Laboratories, 650 Cathill Road, Sellersville, PA, USA
b
Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ, 08854–8020,
USA
c
Department of Obstetrics & Gynecology, University of Texas Medical Branch, 301 University Boulevard, 77555-1062, Galveston, TX, USA
d
Formulation Development - Pharmaceutical Development Services, Capsugel – now a Lonza Company, 4910 Savarese Circle, Tampa, FL, 33624, USA

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

Keywords: 3D printing: a layer-by-layer process to produce drug products has gained a lot of attention in recent years
3D printing especially after its first FDA approval due to several advantages offered as an effort for an improved pharma-
Drug delivery cotherapy. This technology is indeed an old and widely used in other industries; however due to various reg-
3D printing manufacturing methods ulations and complex application, it is yet to flourish in the pharmaceutical industry. Despite this fact, numerous
3D drug product
dosage forms have been prepared and reported in the literature using this technology. This review highlights the
3D pharmaceuticals
various formulation strategies available at the disposal of the formulation scientists to manufacture solid oral
dosage form with desired drug release profile. Also, it provides a basic understanding of the various 3D printing
manufacturing techniques available to manufacture solid oral dosage forms. We have also attempted to sum-
marize the most important practical consideration while formulating the pharmaceutical drug products using
this technology.

1. Introduction comprehensive review on the 3D printing technologies for drug de-

livery [4]. While there have been many reviews on this technology
The concept of 3D system was developed in 1986 by Charles Hull in [5–7] detailing the manufacturing techniques and application of each
California as an effort to improve the plastic fabrication process. With technique to create pharmaceuticals, this review focuses specifically on
the establishment of 3D system, they developed the very first 3D printer the capability of 3D printing technology to manufacture the entire
“Stereolithography Apparatus” and first commercial printer SLA-250, gamut of currently available oral solid dosage forms and to assess if it
which appear to be the beginning of new technology era, 3D printing can replace the conventional method of manufacturing or not.
[1]. Followed by his work, several other researchers have contributed
towards development and utilization of this technique. However, the 2. 3D printing techniques
very first apparatus “3D printer” was patent by Michael Cima and
Emanuel Sachs, professors from MIT in 1993 [2]. Few years later, the A drug product is manufactured layer by layer using a 3D printer. A
pharmaceutical application of 3D printing technology was realized [3] schematic representation of the 3D printing process has been re-
but there has been a lull since then; however, with the approval of the presented in Fig. 1. As depicted in this figure, the main three steps in-
first pharmaceutical product (SPRITAM®) manufactured by 3D printing volved in creating a drug product are-designing the drug product in the
technology, there is a rejuvenated interest in this exciting field of drug computer, slicing the design (i.e. translate the 3D model into multiple
product manufacturing, which has shown potential to revolutionize the individual layers) and eventually printing the drug product. A CADD
pharmaceutical manufacturing, especially for solid oral dosage form. In (Computer Aided Design and Draft) software is utilized to create a
addition, efforts are being put together to make personalization of drug design of the drug product. This design is then sliced to input the de-
delivery systems and complex controlled drug delivery systems as well. sired processing parameters like the extrusion and platform tempera-
3D printing has already shown promising results in implants, various ture, speed of printing, infill percentage, etc., using software. Once the
types of tablets, microneedles for transdermal routes as compared to the design is sliced, it can be executed on the 3D printer to produce the drug
conventional dosage forms. Readers are referred to the article that has product. Based on the printing technique employed, filaments or inks

∗
Corresponding author. G&W PA Laboratories, 650 Cathill Road, Sellersville, PA, 18960, USA.
E-mail address: [email protected] (P. Khatri).

https://doi.org/10.1016/j.jddst.2018.05.009
Received 20 December 2017; Received in revised form 26 March 2018; Accepted 6 May 2018
Available online 07 May 2018
1773-2247/ © 2018 Elsevier B.V. All rights reserved.
P. Khatri et al. Journal of Drug Delivery Science and Technology 46 (2018) 148–155

Fig. 1. Schematic representation of 3D printing process.

can be produced using appropriate choice of excipients. The quality the drug product of the desired shape and volume. Fig. 2 exhibits the
target product profile (QTPP) can be achieved by varying the for- ink-jet based 3D printing process, where formulations of drug or binder
mulation and process variables. In general the methods follow some is sprayed in small droplets on the powder bed. These droplets are
common steps such as raw material processing which often involves sprayed at precise speeds, motions and sizes [6]. Typically, the ink-jet
drug along with the other excipients. The second step involves the based 3D printing can be divided into two types: continuous inkjet
printing followed by other unit operations such as drying, polishing, printing (CIJ) and drop-on-demand (DoD) inkjet printing [5]. As the
packaging etc. depending upon the desired QTPP. Hence, the selection names suggest, a continuous flow of the ink is provided often by the
of method is essentially crucial to achieve the optimum desired 3D drug piezoelectric crystals during the process. On the other hand, in DoD, it
product. Here, we have discussed the main three methods and some of is either created by thermal or piezo process only as needed. Both the
the variations often reported in literature. techniques involve the printer head and require control of the drop
formation. In the DoD technique, if the drop is allowed to deposit on the
powder bed it is known as drop-on-powder deposition. However, if the
2.1. Ink-jet based 3D printing droplets itself are allowed to deposit on each other to form a bed, it is
known as drop-on drop deposition [8,9]. Table 1 summarizes the DoD
In this method, drug is dissolved in a suitable solvent to form a printing techniques.
solution which can be mixed with other excipients for immediate re-
lease or sustained release and a polymeric gel to form a homogenous
paste. This prepared paste is then fed into the 3D printer for creating

Fig. 2. Inkjet printing process.

(Adapted with permission from Norman et al. [6])

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Table 1
Ink-jet based 3D printing techniques.
Technique Drop-on-drop deposition Drop-on-powder

Process Solid layer or bed is produced by droplets depositing on each other Droplets are deposited onto the powder bed
Factors affecting the technique Droplet size, binding, cooling, their interaction and solidification, Powder properties such as particle size, density and powder- binder
droplet size etc. wettability and reactivity
Licensed application – TheriForm™
Major Advantage High drug loading controlled delivery, various shape and size can be achieved
Limitations Difficult to implement Low drug loading

2.1.1. Powder-based 3D printing

Similar to the above mentioned ink-jet based printing technique, in
this method the ink-jet printers sprays the raw materials in a liquid state
onto a powder bed in the form of small droplets [6,10]. The major
advantage of this method is that the drug can either be present as a
liquid state or can be a part of powder bed. Schematic representation of
this technique is presented in Fig. 3. As shown in the figure, materials
are jetted from the jet head that solidify drop by drop. The formulation
is designed for jetting followed by rapid solidification. The shape of the
final product is highly dependent on the path, impact and surface
wetting of the droplets falling on the tray [6]. This method offers the
advantage of processing the liquid drug or the excipients. In addition,
the drug or a binder can be jetted either as a solution or suspension at a
desired speed, motion and even a particle size (microns to nanometer
size) onto a powder bed [5,11].
Similar to this method, powder bed fusion technique requires
heating in order to obtain melting and fusion later on. The heat is often
Fig. 3. Material Jetting printing process.
(Adapted with permission from Norman et al. [6]) applied by the laser. Although a bit complex, it is a useful technique for
the heat processing materials [12].

Fig. 4. Fused filament fabrication printing process.

(Adapted from open source website http://reprap.org/wiki/File:FFF.png)

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2.2. Nozzle-based deposition systems release kinetics by adjusting the concentration of the drug in either
layer of this dosage form. Also, two different drugs can be incorporated
The above mentioned inkjet methods often produces a rough, irre- in a dosage form.
gular and highly porous surface as the binder solution is dropped on a
powder bed. As an effort to resolve the issues associated with inkjet 3. Dosage forms produced using 3D printing techniques
methods, nozzle based methods can be used. In this method, the solid
components are mixed with the binder followed by the 3D printing Similar to the conventional manufacturing technique, 3D printing
allowing the direct writing. The nozzle based system is controlled by techniques can be harnessed to produce a various types of dosage forms
the computer assisted program to produce layer-by-layer 3D pattern in from immediate release tablets to osmotic drug delivery systems. Fig. 6
which the ink is deposited from the nozzle. Generally, depending upon can be referred for a flow chart which summarizes how 3D printing can
the material handling process, the methods can be divided into two: be used for various printing tablets previously manufactured by con-
Process involving melting (hot melt) the materials and process without ventional manufacturing processes. Some recent attempts at developing
the melting (pressure-assisted microsyringes (PAM)). various oral dosage forms using 3D printing techniques have been
compiled in Table 3.
2.3. Fused filament 3D printing
3.1. Immediate release tablets
Here the polymer filament is dipped in the drug solution so that the
drug partitions into the filament. Now the filament is printed into ta- An immediate release tablet can be prepared by preparing a fila-
blets using the Fused Deposition Modeling (FDM) technique. Fig. 4 ment of drug and a hydrophilic polymer with or without plasticizers.
shows a pictorial representation of fused filament 3D printing process. Hydrophilic polymer can be chosen from the traditionally used poly-
The filament from the filament spool passes through a geared system to mers like povidone, hydroxypropylmethylcellulose, hydro-
a heated block for extrusion. The processing parameters that affects xypropylcellulose or recent graft polymers like Soluplus®. Such fila-
FDM based 3D printing includes rate of extrusion, nozzle temperature, ments are fed in a FDM based 3D printer to produce an immediate
infill % extrusion [13]. Table 2 compares Fused Deposition Modeling release tablet. Okwuosa et al. prepared immediate release tablets of
and Pressure-Assisted Microsyringes (PAM). Goyanes et al. loaded theophylline and dypridamole using PVP as polymer, triethylcitrate
polyvinyl alcohol (PVA) filament with fluorescein from its ethanolic (TEC) as plasticizer and talc as filler at ratio of 10, 50, 12.5, and 27.5 %
solution followed by its fabricating into a tablet. The final drug loading wt. More than 90% of the drug was shown to dissolve in 30 min for both
of 0.28 ± 0.02% w/w was obtained with this technique [14]. Skowyra the drugs with 10% loading, demonstrating the utility of 3D printing in
et al. prepared an extended release tablet of prednisolone by loading formulating an immediate release tablet [18].
prednisolone onto PVA with a drug loading of approximately 1.29% w/
w by incubating in a saturated solution of prednisolone in methanol. 3.2. Orodispersible films
Drug content from 2 to 10 mg was obtained with dose accuracy range of
88.7–107%. The in-vitro release of the drug was shown to extend up to Jamróz et al. prepared orodispersible films of aripiprazole using
24 h [15]. Another variant of this technique is incorporation of two polyvinyl alcohol as polymer, using FDM based 3D printing technique.
nozzles that accommodates a filament each. A recent study was per- The disintegration time was found to be 43.00 ± 1.00 s compared to
formed by Li et al. where Glipizide was loaded at different concentra- 27.50 ± 4.23 s for placebo tablets. Compared to casted films 3D
tions into polyvinyl alcohol (PVA) filaments using hot melt extrusion printed films showed improved dissolution as a result of the conversion
process to create two filaments with different drug concentrations, of aripiprazole to amorphous form and high surface area of the printed
which were then 3D printed using a dual-nozzle 3D printer [16]. The films; however mechanical properties of the casted films were slightly
delivery system was a Tablet-in-Tablet system named as DuoTablet, better due to their continuous structure [19].
where the inner and outer tablet was created by different filaments
leading to different release kinetics. Fig. 5 exhibits a section of this 3D 3.3. Floating drug delivery system (FDDS)
printed DuoTablet. Fig. 5 also exhibits the comparison of release pro-
files obtained using DuoTablets with different concentration of glipizide Chai et al. demonstrated the utility of FDM based 3D printing to
in outer, inner or both layers. DuoTablets were formulated with 2.18% develop a FDDS [20]. In FDM 3D printing, shells and infill are the key
glipizide in the outer layer and 4.76% glipizide in the core; 2.18% parameters which define the outline shape and inner support structure
glipizide in the outer layer and blank core; and blank outer layer and of an object. At least one shell is needed to print an object, and addi-
4.76% glipizide in the core. The release profile of the DuoTablet was tional shells will add body's strength and weight but consume more
found to fit Korsmeyer-Peppas release kinetics. In these systems, it was printing time and materials. Similarly, infill percentage is another
observed that the drug incorporated in the internal layer was released parameter, which could be adjusted from 0% to 100%, generating the
only after the external layer was completely dissolved. Moreover, al- object from completely hollow structure to fully solid filled structure
most 90% of the drug in the external layer was dissolved in the first 2 h. [20]. By keeping the structure hollow, the overall density can be de-
The lag time before the release of the drug from the internal layer was creased that imparts buoyancy. In this study the optimized tablet design
attributed to the thickness, uniformity as well as polymer composition with density of 0.77 g/cm3, which had 2 shells and 0% infill, had the
of the external layer [16]. Thus it is feasible to modulate the drug capability floated for more than 10 h in dissolution batch, whereas

Table 2
Fused deposition modeling and pressure-assisted microsyringes (PAM).
Techniques Fuse Deposition Modeling (FDM) Pressure-Assisted Microsyringes (PAM)

Material processing Involves melting Does not involve melting, hence can be processed at room temperature
Type of materials Thermoplastic polymers Extrusion of semi-liquid materials from a syringe
Factors affecting the process Temperature, density, various extruder factors, polymer to drug Various rheological properties of the material
ratio
Limitations Suitable only for thermostable drugs Requires solvents and therefore issue of residual solvent, prolong drying
step

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Fig. 5. DuoTablet developed using 3D printing by Li et al. [17].

Commercially available Dry Blending

filament Mix API and excipients (filler, plasticizers)

Drug deposition Hot Melt Extrusion Wet mixing Powder bed layering
Drug deposition in filament Preparation of drug Preparation of paste of Preparation of paste of
by dipping in drug solution containing ilament from the blend from the blend

3D Printing 3D Printing 3D Printing

Introduce filament(s) in to the Introduce paste(s) in to the Spray binder liquid (may contain
FDM printer to print tablets extrusion based 3D printer drug) using Inkjet based printing
technique

Fig. 6. Flowchart 3D printing using various techniques.

Table 3 commercially available polyvinyl alcohol (PVA) filaments. The drug

Summary of various Dosage forms prepared by 3D Printing Technique. loading of the filament was found to be 0.06% w/w and 0.25% w/w for
Dosage form 3D printing technique Reference
5-ASA and 4-ASA, respectively. Dissolution of tablets containing 5-ASA
in modified bicarbonate buffer (pH 6.8) controlled by an Auto pH
Immediate release tablet FDM [18] System™ showed that tablets with 90% infill showed 100% release over
Orodispersible films FDM [19] 4 h time period. Decrease in the % infill accelerated the drug release. It
Floating drug delivery system FDM [20]
Monolithic Sustained release FDM [21]
was observed that 50% of 4-ASA degraded during preparation of tablet
tablets due to high extrusion temperature (210 °C) for PVA filament. Therefore,
Pulsatile drug release tablets FDM [22] this method might not be suitable for thermolabile drugs [21]. Alter-
Biphasic release tablets Extrusion based 3D printer [17] nate polymers with lower extrusion temperature may help in reducing
Multi-active solid dosage Extrusion based 3D printer [23]
drug degradation due to temperature.
forms
Fast disintegrating tablet Powder-based 3D printing [24]
Zero order release tablets TheriForm™(Inkjet based 3D [25,26] 3.5. Pulsatile drug release tablets
printing technique)
Enteric release tablets FDM [27]
Tablets with polymeric FDM [28] ChronoCaps® are pulsatile delivery systems based on capsular de-
nanocapsules sign. Capsules of varying thickness are prepared, with injection molding
technique, using hydrophilic polymers that yields varying degree of
time lag [29]. Such capsular devices can also be prepared using FDM
tablets prepared with shells more than 3 or infill percentage more than based 3D printing of HPC filaments [22]. Melochhi et al. studied the
20% had densities above 0.9 g/cm3 which caused them to sink in less behavior of such capsular devices prepared by 3D printing and injection
than 1 h [20]. The release rate was sustained for 12 h which was not molding [22]. It was observed that the 3D printed devices showed a lag
significantly affected by the number of shells or the infill percentage phase before liberation of the drug. Moreover, the morphological
[20]. changes were comparable with the system produced using injection
molding. This study shows that the 3D printing can be used alter-
3.4. Monolithic sustained release tablets natively with injection molding technique.

Sustained release tablets of 5-aminosalicylic acid, were fabricated 3.6. Biphasic release tablets
by using drug loaded polyvinyl alcohol (PVA) filaments. The filaments
were prepared by loading drug from its ethanolic solution on Khaled et al. prepared bi-layered tablets of guaifenesin using 3D

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printing technique to compare against commercially available bi-layer et al. [25]. The dosage form had a cubic design with multi-chambered
tablet brand-Mucinex®. The prepared bi-layered tablet consisted of an cubic core containing drug. The substrate was a mixture of Kollidon SR
immediate release and a sustained release layer. Immediate release and HPMC. An aqueous binder containing 50% (by weight) of PEH was
layer was printed using a paste prepared from Immediate Release (IR) used to fabricate the core region to form an immediate release matrix
paste, which contained Guifenasin powder, hypromellose® (HPMC containing 7.5 mg of active while ethanolic binder containing 15%
2910) as a binder along with microcrystalline cellulose (MCC) triethyl citrate was used for the fabrication of the shell region, which
(Pharmacel® 102) and sodium starch glycolate (SSG) (Primojel®) as forms the release-controlling matrix. The release rates were adjusted by
disintegrants. Sustained release layer was printed using Sustained modulating the Kollidon SR-HPMC ratio. The drug released through the
Release (SR) paste that contained hydroxypropyl methylcellulose diffusional pathways formed by the hydration of HPMC in the shell
(HPMC 2208) (Methocel™ K100M Premium) and poly(acrylic acid) matrix. Being a hydrophilic polymer, increase in HPMC ratio in the
(PAA) (Carbopol® 974P NF). Tablets were manufactured using 3D Kollidon SR-HPMC mixture exhibited increase in drug release rate. Due
printer (Fab@Home) with two printing heads. Formulation containing to its diffusional drug release mechanism, the dissolution rates were
14% w/w of HPMC 2208 as hydrophilic polymer along with 2% w/w as independent of changes in pH of the dissolution medium, paddle stir-
binder showed dissolution profile that was a faster than, but not sig- ring rate, and the presence/absence of a sinker. Also, the near zero-
nificantly different than, that of Mucinex®. Increase in HPMC 2208 order release properties remained unchanged for a dosage form con-
showed decrease in the dissolution due to the formation of thicker gel taining single chamber or multiple chamber of drug encapsulated
barrier on hydration that decreases the drug release [17]. Although the within a gelatin capsule. The formulations demonstrated stability for at
printed tablets had half the hardness compared to the commercial least1 month's exposure to 25 °C/60% RH or 40 °C/75% RH environ-
product, it could be handled well without compromising its integrity. ment under open container condition. Furthermore, a level A IVIVC
Moreover, it showed comparable friability [17]. correlation was possible with the formulations prepared by different
Kollidon SR-HPMC ratio [26].
3.7. Multi-active solid dosage forms

Shaban et al. designed a tablet containing nifedipine, captopril and 3.11. Nanocapsule based formulation
glipizide with separate controlled release profiles using room tem-
perature extrusion-based 3D printing [23]. Additionally, the same re- Beck et al. loaded 3D printed tablets with polymeric nanocapsules of
search group has reported the polypill containing 5 drugs in a single deflazacort with a particle size of 138 nm. Here the 3D printed tablets
tablet with immediate release of aspirin and hydrochlorothiazide and were prepared using the commonly used fused deposition modeling
sustained release of atenolol, pravastatin, ramipril using extrusion (FDM). Filaments of poly(ε-caprolactone) (PCL) and Eudragit® RL100
process [30]. (EUD) were used with or without mannitol, a channeling agent. The
tablets were then soaked in to a specified amount of suspension of
3.8. Fast-disintegrating tablets polymeric nanoparticles (2 ml per device) and dried at 30 °C for 24 h. It
was found that up to 0.62% drug loading was achieved by soaking the
Yu et al. designed a fast-disintegrating tablet by incorporating loose tablet for 24 h. The study showed that up to 24 h, soaking time im-
powder in the core region surrounded by printed binder region. Hollow proves drug loading [28].
core region for depositing the loose powder was created by printing
binder solutions in three phases printing: solid circular region to form a
base, several layers of rings to form a cavity and finally solid circular 4. Practical considerations while formulating tablets using 3D
region to cover. The disintegration time of such was shown to be mere printing technology
21.8 s with a hardness of 54.5 N/cm2; however friability was 0.92%
[24]. Contrary to conventional tablet manufacturing technology, which
involves many unit operations like granulation, drying, milling, com-
3.9. Enteric release tablets pression and coating, which in turn has many critical processing
parameters like granulation time, drying time, mill speed, compression
Goyanes et al. prepared enteric release tablets of paracetamol using force etc. to mention few. Tablet manufacturing via 3D printing process
enteric polymers like HPMCAS (Hydroxy Propyl Methyl Cellulose involves less unit operations and hence less critical processing para-
Acetate Succinate). Filaments of drug and enteric polymer were pre- meters. This aids the formulator since only formulation variables need
pared using hot melt extrusion. These filaments were used to manu- to be altered without considering any process-related influence. Since
facture tablets using single filament fused deposition modeling (FDM) the formulation involves drug, polymer with or without plasticizer, the
based 3D printing. Up to 50% drug loading was achieved while main- formulation variables are less. The major process variables are the
taining the enteric protection [27]. This approach can be evaluated as printing speed, the % infill, nozzle temperature, bed temperature and
an alternative option to conventional enteric coating process. This can printing pattern. The drug release can be easily modified by altering the
be advantageous in terms of environmental and safety concerns, com- shape (and hence the surface area) of the dosage form. Goyanes et al.
pared to conventional coating process involving organic solvent. demonstrated that geometrical shape of the dosage form affects drug
release. The release rate for cube, pyramid, cylinder, sphere and torus
3.10. Zero order release tablets shapes was evaluated. The results indicated erosion-mediated release
that depends on the ratio of surface area to volume instead of just
Zero order-release tablets could be produced by fabricating a release surface area with pyramid shape showing fastest release, while sphere
rate regulating shell around an immediate release core. The release rate and cylinder showing slowest release. The drug was found to be mo-
regulating shell can be composed of water soluble and insoluble poly- lecularly distributed with about 4% w/w loading. Therefore, this ap-
mers that are generally used for sustained release membrane coating of proach of modulating the geometry design can be used to tailor the
tablets or pellets. The release rate is controlled by the hydrophilic drug release using 3D printing [31]. Some machine related variables
fraction of the shell, which regulates the diffusional pathway for the like nozzle size also affects the morphology of the dosage form. As
drug. Wang et al. fabricated a near zero-order controlled-release compared to the conventional manufacturing technology, 3D printing
pseudoephedrine hydrochloride (PEH) formulations using 3- technology can be easily adapted to suit the current needs of pharma-
Dimensional Printing (3-DP™) technology [26] that is described by Lee ceutical industry.

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5. 3D printing over conventional manufacturing both the approaches.

The advantage of 3D printing technology for oral solid dosage form Conflicts of interest
includes individualized treatment and precise control of drug release.
However, few drawbacks of this technique that has gathered attention None.
is the lack of quality control procedures for the dosage forms printed at
hospitals or pharmacy, which can affect the in vivo performance of the References
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