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3D printing for drug manufacturing: A perspective on the future of pharmaceuticals

viscous nature of hydrogels allows for extrusion-based on the scale of microns to hundreds of microns [48] . For
or inkjet-based printing. Finally, various forms of smart all particle sizes, the laser sintering causes the forma-
materials are described for drug delivery applications. tion of necks between the particles; these necks, or
link ages, remain small compared to the size of the
3.1 Materials for Powder-Based Printing particles themselves. This neck formation process is
Materials used for powder-based printing methods due to the surface heating of adjacent powder particles,
must meet certain criteria for printability. With respect and therefore is a function of particle size and shape,
to binder deposition, the requirements and necessary temperature, and the relative arrangement and density
parameters of the materials used are relatively straight- of particles. Particle size also contributes to another
forward. Factors that impact the printability include important material property, one which is shared with
particle size, binder viscosity, droplet size of the binder the binder deposition method: the flowability of the
solution, the concentration of the binder solutions, and powder. Flowability refers to the ease of spreading
[40]
the thickness of each powder layer . The powder size pre cisely controlled layers of desired thickness; this
must not be too small as to cause low flowability, nor para meter is directly related to the granulometry and
[47]
may it be too large such that high density printed parts mor phology of the particles . For instance, small par-
are not feasible. Additionally, the binder solution must ticles at high density lead to lower flowability. On the
be of low enough viscosity and high surface tension to other hand, high density powder is better suited for
precisely form small droplets, while also being able to accuracy and strength of the sintered part. To balance
penetrate the layer of powder. This is interdependent on these characteristics, particles are preferred to be near-
[49]
the requirement that the powder layer be thin enough for spherical and flowability agents are often added .
binder saturation, but thick enough to prevent excessive 3.2 Fused Deposition of Solid Materials
binding. In most cases of binder deposition printing,
the binder solution acts as a solvent for the powder, Fused deposition modeling (FDM) 3D printers are a
whereby the powder is dissolved upon contact with the specific category of extrusion-based printers which use
binder [41,42] . The binder-powder mixture may either dry a solid, polymer filament. The filament is fed through an
to form the solid part, or the materials may react to cause electronically controlled nozzle which melts the filament
localized polymerization, curing or bonding. Examples and deposits it onto the print bed where the melted
of such powders may include soluble polymers, plastics filament solidifies into the final 3D printed form. Such
and starches, while binders include chloroform and printers are simple and versatile, and are compatible
water, among other solvents. with filaments such as poly(lactic acid) (PLA), poly(vinyl
Selective laser sintering has more complexity in- alcohol) (PVA), and ethylene vinyl acetate (EVA) [50–52] .
volved with material selection. Powders that have Due to the polymer nature of the filaments, they exhibit
been previously studied include polyamides, poly-ε- considerable structural stability after printing and
caprolactone (PCL), hydroxyapatite (HA), polyethylene solidifying. These filaments are also largely water-
(PE) and poly(lactic acid) (PLA) [43–46] . By nature of soluble, and are capable of being loaded with a drug
SLS, a laser applies localized heat to selectively melt in solution. Filament can be loaded with varying con-
the powder where the laser strikes. To facilitate this centrations of drugs for specified doses by dissolving
process, the entire powder bed may be maintained the drug in an ethanolic solution and submerging the
at a temperature just below the melting point of the unprinted, solid filament in the solution [53,54] . Filament
powder [27] . The powder material must withstand the can also be loaded with drugs by melting the filament
elevated temperature of the print bed without degrading and re-solidifying it after the addition of the drugs [55] .
or agglomerating [47] . Ideally, the powder possesses a Once the 3D printed drug product is placed in vivo,
high melting point and a relatively lower glass transition the drug itself will diffuse out of the print, while the
temperature, which is often seen if the material exists biodegradable filament will dissolve over time.
as a semi-crystalline polymer at room temperature [28] . 3.3 Natural and Synthetic Hydrogels
These thermal properties make the material suitable
for printing at high temperatures. In the case of semi- As opposed to the solid nature of polymer-based fila-
crystalline polymers, the powder bed would be held at a ments used in FDM printing, hydrogels are viscous
temperature above the glass transition temperature, close and capable of being extruded or deposited as droplets
to the melting point. At this state, the laser only needs via extrusion-based printing and inkjet-based printing,
to introduce enough energy to exceed the point of phase respectively. Implementing a controllable gelling hydro-
transition, while minimizing the temperature increase in gel system, many layers of drug-loaded hydrogels can
the surrounding powder . be printed into 3D structures, characterized by pores
[47]
The powders used in SLS can range in particle size and channels which can be printed into the materials
4 International Journal of Bioprinting (2018)–Volume 4, Issue 1