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3D Printing: Pharmacy Applications
Part 2
Technologies
There are numerous different technologies available for three-dimensional (3D) printing, as summarized in Table 1. Technologies can include ink-jet, hot-melt extrusion (HME), powder bed fusion and others, some of which are being adapted to pharmaceuticals from other fields. Time and additional research will bring the most beneficial to the forefront; also, there are literally hundreds of different materials that can potentially be used in 3D printing.
Common Aspects of 3D-Printing Technologies
There is a common denominator in many of the 3D-printing processes as most of them follow the same basic procedure for manufacturing solid products from digital designs, as follows:
- CAD Design Software: The intended product design is digitally rendered in 3D or into 2D as a series of images corresponding to the to-be-printed layers.
- Machine-Readable Design Format Conversions: 3D designs are typically converted to the ".stl" file format describing the external surface of a 3D model. The software next slices the surfaces into distinct printable layers and transfers layer-by-layer instructions digitally to the printer. For freestanding object designs, software can also design support material and its location to provide scaffolding for the end process print.
- Raw Material Processing: Raw materials may be processed using different forms, including granules, filaments, or binder solutions, to facilitate the printing process.
- Printing: Incorporated raw materials are solidified in an automatic layer-by-layer manner to produce the desired product.
- Removal and Post-processing: Following printing, products may require drying, sintering, and/or polishing or other post-processing steps. At this stage, unprinted material may be harvested and recycled for continuous use in the printing process.
When compared to other pharmaceutical processes, 3D printing is unique in terms of product complexity, flexibility, and throughput. As a layer-by-layer process, 3D printing trades throughput for complexity. 3D printing can trade-off manufacturing tolerance for personalization. Also, as an automated process with minimal operating costs, 3D printing can trade "scale" for "on-demand" production. One must recognize that the differences between 3D printing and traditional pharmaceutical processes create opportunities for advancing drug delivery.
Inkjet Technologies
The phrase "inkjet" is an overall generic term used to describe systems that are able to adjust and digitally control the formation and placement of small liquid drops onto a substrate using a pattern-generating device. There are basically two types of printing-based inkjet systems:
- Continuous inkjet printing (CIJ), and
- Drop-on-demand (DOD) inkjet printing
Both methods are characterized by the presence of a printer head, either thermal (bubble) or piezoelectric, and the need to control both drop formation velocity and fluid viscosity.
Thermal printheads use resistive elements to create a current. As the current pulses through the electrical resistance in these elements, the temperature rises up to 300°C, which leads to the evaporation of a small volume of liquid. The resulting bubble expands and imparts the energy required to eject a droplet. Due to the high temperatures generated, thermal DOD inkjet systems use water as a solvent.
In the piezoelectric method, the shape of the piezoelectric crystal rapidly changes, causing a sudden volume change. This change generates an acoustic pulse that exposes the fluid to shear rates producing sufficient pressure to eject a droplet. Compared to thermal printheads, which are restricted to volatile liquids, piezoelectric printheads can be used with a larger range of inks.
Both types of printheads can produce droplets with diameters ranging from 10 µm to 50 µm, which corresponds to a volume between 1 and 70 picoliters.
Continuous Inkjet Printing
CIJ printing uses pressurized flow to produce a continuous stream of droplets; the droplets are charged upon exiting the nozzle and directed by electrostatic plates to the substrate or to waste to be recirculated.
Drop-on-demand Inkjet Printing
A DOD inkjet printing method is able to produce microscale dosage forms. It is a direct writing inkjet printing method that is able to create microscopic drug delivery systems with different geometries and relatively high drug loadings.
A DOD printhead usually contains multiple nozzles (from 100 to 1000). When the printer head delivers the formulated droplets onto each other to produce a solid layer of the building material, the DOD model is called drop-on-drop deposition; when it delivers droplets on the solid material, it is known as drop-on-solid deposition. In 3D printing, drop-on-solid deposition is also called drop-on-powder or drop-on-bed deposition as droplets of binder are delivered onto the powder material.
Whereas drop-on-drop deposition techniques are more difficult to implement, drop-on-solid deposition onto a powder bed appears to be suitable for printing a wide range of active pharmaceutical ingredients (APIs). Dropping a drug onto a solid carrier allows the delivery of a wide range of APIs from chemical entities to biomolecules. Using this technology, 2D printing opens the way to formulating personalized dose medications. The printhead can be filled with the liquid containing the API and, when ejected, it creates droplets that are absorbed onto a porous oral film that can be made of potato starch or other suitable solid powder.
A powder bed is not necessary for 3D printing with inkjets, which can also print freeform structures that solidify drop-by-drop. Commonly jetted materials include:
- Molten polymers and waxes
- Utraviolet (UV) curable resins
- Solutions
- Suspensions
- Complex multi-component fluids
Material jetting differs substantially from binder deposition, and it can be more challenging to implement. The entire formulation needs to be formulated for jetting and rapid solidification, and product geometry becomes highly dependent on droplet flight path, droplet impact, and surface wetting. One advantage material jetting has over binder jetting and other methods is resolution: inkjet droplets are about 100 µm in diameter and layer thicknesses for material jetting are smaller than droplet diameters (due to surface wetting, solvent evaporation, or shrinkage).
Capabilities are available for dispensing low volumes accurately with precise spatial control and layer-by-layer assembly for the preparation of complex compositions and geometries.
The high degree of flexibility and control with 3D printing enables the preparation of dosage forms with multiple APIs with complex and tailored release profiles. This technique has been used to prepare polyethylene glycol droplets of ibuprofen that could be imbibed into a porous substrate made of hydroxypropyl methylcellulose.
The use of poly-lactic-co-glycolic acid and polylactic acid (PLA) allows the DOD inkjet printing technique for 3D printing. In this case, the printable fluid and the building structure are one and the same material. The principle is to print a first droplet containing both drug and polymer. A thermal stimulus then causes evaporation of the solvent and solidification of the polymer allowing the deposition of a second droplet; the multi-droplets overlap and allow the construction of high-resolution 3D structures.
The conventional DOD inkjet printer consists of a cartridge inkjet head with multi-nozzles, a printhead driver, an X-Y stage plate, and a host computer with software. A piezoelectric printhead is usually used because it does not restrict the choice of solvents. The nozzles are activated by the firing voltage (amplitude and width) and the frequency. Both the cartridge and the substrate plate may be thermostated. Generated droplets are characterized by a volume of several pLs which corresponds to a common range of 18 µm to 50 µm.
As can be seen, the physical properties of the ink can be considered as the most critical point in a polymer inkjet printing system. Polymer construction influences inkjet printability through viscosity; it should not be too high to allow ejection through the nozzles and not too low to avoid uncontrollable spreading. It has been reported that the suitable viscosity range is between 3 mPas and 20 mPas.
Drop-on-solid
3D powder bed printing is the deposition of a liquid or ink onto a powder bed to bind the powder. The powder bed is then lowered, a new powder layer is spread, and the process repeated to bind powder layer by layer to produce the final geometry.
A standard inkjet printhead is used to deposit "ink" or a "binder solution" onto a powder bed to bind powder; repeating this process layer by layer produces a desired geometry. Any unbonded or loose powder acting as a support during processing, is then removed.
Drop-on-powder
The primary 3D-printing technology used for pharmaceuticals is inkjet deposition on powder beds. In this process, inkjet printers spray formulations of drugs or binders in small droplets at precise speeds, motions, and sizes onto a powder bed. Unbound powder serves as the support material for freestanding or porous structures. The liquid formulation inside the printer may contain a binder only, and the powder bed may contain the API with additional excipients. Alternatively, APIs can be jetted onto powder beds as solutions of nanoparticulate suspensions.
Solidification mechanisms for binder deposition are identical to the mechanisms used in producing a wet granulation (i.e., formation of binder-based bridges between particles or joining of particles by dissolution and re-crystallization). For inkjet printing, as in granulation, solvent choice and powder properties can impact the API polymorphic form after drying. Because of its commonalities with granulation, a ubiquitous process in pharmaceutical manufacturing, inkjet deposition on powder beds has a wide scope of processable raw materials and potential drug delivery applications.
Extrusion
Global Extrusion
Global extrusion is the most widely used 3D-printing technology, and interest in this method is growing in pharmaceutical manufacturing. In an extrusion process, material is extruded or forced through robotically actuated nozzles. Unlike binder deposition which requires a powder bed, extrusion methods can print on any substrate or even a plate with subsequent removal of the product.
Hot-melt Extrusion
Due to the lack of a powder bed, extruded objects often require access to a support material. A variety of materials can be extruded for 3D printing, including:
- Molten polymers pastes
- Colloidal suspensions
- Silicones
- Other semisolids
Fused Filament Fabrication
A particularly useful and common type of extrusion printing is fused filament fabrication (FFF), also known by the trademark name "fused deposition modelingTM" or FDM®. Whereas other extrusion systems use liquid or semisolid formulations for printing, FFF systems use solid polymeric filaments. A gear system drives the filament into a heated nozzle assembly for extrusion, and the use of relatively nonvolatile and non-aerosolizing raw materials places FFF systems as the most popular 3D-printing systems for home use. Some advantages include low-cost consumer FFF systems utilizing PLA, polyvinyl alcohol (PVA), and ethylene vinyl acetate-based polymers for the filaments.
Compared to inkjet systems, FFF and other extrusion systems have simpler equipment and greater diversity in input materials—especially complex pharmaceutically-relevant materials such as polymers, suspensions, and silicones. Potential disadvantages of FFF include:
- A requirement for heat; solvents or cross-linking chemistries for processing and solidification
- Difficult to reprocess support materials, and
- Slow printing speed
Extruded material is typically more viscous than jetted material, which can increase the time required to start and stop flow during printing; also, the entire product and support structure has to be printed, whereas in binder deposition, only the binder solution is printed.
Although extrusion technology has limitations, it is simple and versatile and has been widely used for 3D printing of drug products (i.e., APAP 3D-printed products have been prepared using filament extruder APAP 4% loaded filaments of PVA).
In fused deposition modeling, or FDM, a molten thermoplastic polymer filament is extruded by two rollers through a high-temperature nozzle which later solidifies onto a build plate. The printhead can be within the X- and Y-axes, whereas the platform, which can be thermostated, can move vertically on the Z-axis, creating 3-D structures layer by layer by fusing the layers together.
The setting of the temperature is closely dependent on the nature of the thermoplastic polymer which is used. Thermoplastic polymers are commonly used due to their relatively low melting points, which makes them able to melt with a viscosity that is high enough to be built but low enough to be extruded. PVA is widely used; it is a biocompatible, water-soluble, synthetic polymer that is able to swell up on contact with aqueous fluids. Its melting point may range from 180°C to 228°C, which makes it robust for subsequent polymer casting. PVA is used as either a filament with the drugs loaded by impregnation or as granules, with the drugs incorporated by HME during the extemporaneous fabrication of the filament.
The filament-loading process is based on passive diffusion impregnation and requires the use of highly concentrated solutions of drug to incorporate very small amounts of drug; this makes impregnation an expensive and time-consuming process.
The polymer, drug, and additives, such as a plasticizer, are melted together at an appropriate temperature and homogenized in the extruder before being extruded into filaments. Processing parameters for FDM include:
- Nozzle diameter
- Feed rate
- Block and nozzle temperatures
- Head speed
- Envelope temperature
These parameters should be optimized for a given feed material so that there is accurate deposition and sufficient bond formation to impart strength into the fabricated structure. Bond formation between two filaments is driven by surface contact, coalescence or neck growth, and potentially molecular diffusion and pull polymer chain entanglement.
The cooling profile is a function of the thermal conductivity of the extruded material that is greatly influenced by the surrounding environment, including the envelope temperature and convective conditions during fabrication. The conditions can be adjusted to enable the material to stay at or above glass transition temperatures for longer duration, allowing for greater bond formation, reduction avoids, and a corresponding increase in bond and overall structure strength.
Pen-based
Pen-based 3D printing is an extension of the extrusion 3D-printing process where the layer-by-layer assembly is manually controlled with a handheld device. This approach for deposition of 3D-structured materials is being considered for applications during surgery.
Pressure-assisted Microsyringes
The pressure-assisted microsyringes printing method was used extensively in the early 2000s to create soft-tissue scaffolds. It is based on extruding a viscous semiliquid material from a syringe to create a desired 3-D shape. The process can be performed in a continuous flow at room temperature. The dispenser is usually based on a pressured air piston.
A paste can be used that is characterized by suitable apparent viscoelastic properties and yield stress under shearing and compression to be smooth and homogenous to avoid nozzle blockage. Sustained-release guaifenesin bilayer tablets have been made using this method involving a double-syringe printer head. A matrix gel of Methocel E5 was extruded to make the immediate release layer, and the matrix gel of Methocel K100M with Carbopol 974P was used for the sustained-release layer.
The major drawback of this technique is that a printing based inkjet system requires the use of solvents.
Powder Bed Fusion
Powder bed fusion involves sintering (partial surface melting and congealing) or binding of high melting-point particles with a low-melting point binder. Both cases require heat which is typically supplied by a laser; a more recent alternative for heating powders is high-speed sintering (inkjet deposition of a dye followed by targeted infrared radiation absorption). Powder bed fusion is a more rapid, but also more complex, alternative to extrusion for heat processable material such as PLA.
Selective Laser Sintering
Selective laser sintering is a process whereby a laser beam is scanned over a powder bed to sinter or fuse the powder, the powder bed is then lowered, fresh powder is spread, and the process is repeated to produce a solid object.
Polymerization
Polymerization (laser or UV-based light-based stereolithography) involves exposing liquid resins to UV or other high-energy light source to induce polymerization reactions. Their primary limitation is the need for photopolymerizable raw materials that are relatively uncommon in pharmaceuticals.
Also, residual resin can represent a toxicology risk because the uncured material is chemically distinct from the printed product and may contain functional groups that are possible structural alerts for genotoxicity.
Selective laser sintering is a process whereby a laser beam is scanned over a powder bed to sinter or fuse the powder. The powder bed is then lowered, fresh powder is spread, and the process is repeated to produce a solid object.
In terms of potential advantages, photopolymerization systems tend to be among the fastest and highest resolution 3D printers available. An example drug delivery application is 3D printing of photopolymerizable hydrogels.
Loyd V. Allen, Jr., PhD, RPh
Editor-in-Chief
International Journal of Pharmaceutical Compounding
Remington: The Science and Practice of Pharmacy, Twenty-second edition
Table 1. 3D Printing Technologies.
Inkjet
Continuous Inkjet Printing (CIJ)
Drop on Demand (DOD)
Drop on Drop (DOD)
Drop on Solid (DOS)
Drop on Powder (DOP)
Drop on Bed (DOB)
Extrusion
Global
Hot-Melt Extrusion (HME)
Fused Filament Fabrication (FFF, FDM)
Pen-Based
Pressure Assisted Microsyringes (PAM)
Powder Bed Fusion
Selective Laser Sintering
Polymerization (Laser or UV-Based, Stereolithography)
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