3D Printing: Pharmacy Applications

Part 3

Compounding, Formulation Considerations, and the Future

I. Introduction

Two previous articles in this series have discussed the technology and techniques involved in 3D printing and the common aspects involved across the types of 3D printing technologies. This article will discuss the processes and formulation considerations involved in 3D printing compounding. Also, excipients will be characterized, limitations and challenges presented, quality considerations presented, and a look towards the future.

II. Processes Involved

Inkjet Printing

3-D inkjet printing consists of three separate actions:

1. Droplet formation,

2. Droplet impact and spreading, and

3. Drying or solidification

The majority of DOD (Drop on Demand) printing conducted for preparing pharmaceutical dosage forms utilizes piezoelectric actuation because thermal actuation requires the use of high vapor pressure or volatile materials. Droplet formation is a complex process influenced by fluid viscosity, density, and surface tension, among other factors. When using a suspension as the ink, particle size, suspension stability, and their effect on fluid rheology must be considered. Typically, a standoff or dropping distance of 2 to 3 mm is used with piezoelectric actuation. Generally, drying occurs via solvent evaporation, and the rate of evaporation is a function of the solvent system selected. The recrystallization of an active pharmaceutical ingredient (API) from the print fluid can lead to changes in the API's physical form, mechanical properties of the dosage form, as well as changes in release behavior; therefore, the physical stability of printed APIs must be studied individually. For example, when prednisolone was dissolved in a co-solvent system of ethanol water and glycerin, it converted the prednisolone from Form I to Form III.

One should evaluate fluid properties of the "ink," as polymer solutions can have complex rheology. The particle size of the powder bed also affects binder distribution and ultimately the final structure porosity and strength. The typical layer thickness during powder inkjet printing can be 50 µm to 200 µm; therefore, the average particle size is recommended to be 50 µm to 150 µm.

In some technologies, printing begins by forming a uniform powder layer on an existing powder layer with the aid of a rolling pin-type device. Particle-size distribution can be critical in this situation, as this property affects layer thickness and the potential risk of segregation during layering. Water content can be critical, especially when using cohesive powders. Following layering, the next step in binder deposition is jetting small binder droplets, and droplet formation depends upon both viscoelastic properties and surface tension of the binder solution.

Extrusion Printing

In the extrusion printing system, each layer of a 3D product is built line-by-line and the layer thickness depends on the printing speed, extrusion flow rate, and nozzle diameter. There are numerous materials that can be extruded. The raw material for fused filament fabrication (FFF) is a polymer filament that melts easily prior to extrusion and solidifies rapidly after extrusion. Viscoelastic properties of the filament are significant, and the melted filament rheological properties may need to be understood at multiple temperatures. In some cases, the water content may be critical since water is a potent plasticizer of many pharmaceutical polymers.

III. Example Drug Delivery Systems

Table 1 presents some examples of 3D printed drug dosage forms. The following is a brief discussion of those drug dosage forms.

Implants

In recent years, 3D printing has been utilized for the fabrication of implantable dosage forms, and devices. Polyethylene oxide has been used as a polymer matrix and polycaprolactone (PCL) as a limiting component and printed in various systems has been done.

Tablets

Early work was done using 3D powder bed printing in the preparation of tablets, and there are numerous examples shown in Table 1.

Transdermal Delivery Systems

The layer-by-layer 3D printing technologies can readily be utilized for the preparation of multilayered transdermal patches of film. Also, 3D technology offers a unique advantage for the printing of drug-loaded microneedles as an advantage for the printing of four transdermal deliveries. Microneedles are prepared to be generally less than 500 µm in height and are designed to penetrate the stratum corneum 10 µm to 15 µm to deliver APIs. Microneedles should be sufficiently strong to penetrate the epidermis but not so strong as to cause pain or irritation. Clinical studies have shown little to no pain reported with the use of 750-µm microneedles against a 26-gauge needle control.

IV. Process/Formulation Considerations

Raw Material Controls

The printability of raw materials must be considered and requires an understanding of the physics and chemistry of the printing process. The raw materials for binder deposition include a binder solvent and powder residing in a printing bed, with the binders typically being polymers.

Process Controls

During printing, process controls that must be considered include:

• Equipment design
  
  
• Product orientation
  
  
• Layer thickness
  
  
• Printer height
  
  
• Printing speed
  
  
• Printing pattern

Also, most 3D printing processes recycle unprinted materials. In addition, printing operations can be sensitive to water content and solidification conditions.

For binder deposition, transport depends on powder handling and layer thickness, jetting rate, jetting temperature, and drying conditions. For extrusion, transport properties include extruder pressure, extruder temperature, and linear extrusion speed. And for fusion, energy input is a function of laser energy, laser angle of incidence, duty cycle, spot size, and scan strategy. Also, jetting systems will need control over dot per inch resolution or liquid fill height within the print head.

V. Excipients

Thermoplastic polymers, such as polylactic acid (PLA), polyvinyl alcohol (PVA), and acrylonitrile butadiene styrene (ABS) are used with the Fused Deposition Modeling (FDM) process. They are commercially available as preprocessed coiled filaments to allow for easy feeding into FDM printing systems. As a filament is fed by the rollers, it is heated by heating elements to a molten state to allow for extrusion through the nozzle tip; upon deposition, the material cools or is cooled and solidified.

Both PLA and PVA filaments are commercially available as feed for the FDM process and have application in pharmaceutical dosage form design. Studies have been done impregnating these filaments with API or to reprocess the filaments by extrusion to incorporate the API to create drug-loaded filaments for use with FDM. With processing temperatures around 200°C for the PLA and PVA, spacing the thermal stability of an API must be considered.

PLA is a biodegradable polymer with significant application in the manufacture of implants and injectable microspheres. With a melting point of 150°C to 160°C, with reported melt viscosities of less than 1000 Pas at temperatures above 200°C and less than 100 Pas with the application of shear stress at elevated temperatures, PLA is considered an appropriate polymer for processing by FDM.

PVA is a water-soluble polymer often used in oral dosage forms as a binder, space control release agent, or polymer carrier for amorphous solid dispersions. Although PVA has a higher melting point of 200°C, PVA's melt viscosity has been reported at around 1000 Pas, or lower, at temperatures above 190°C. Commercially produced PVA filament was loaded with a model drug by swelling of the polymer in ethanoic drug solution, achieving a 0.29% w/w loading.

ABS [(C₈H₈)_x·(C₄H₆)_y·(C₃H₃N)_z] is a common thermoplastic polymer with a glass transition temperature of approximately 105°C. ABS is amorphous and, therefore, has no true melting point. It is a terpolymer made by polymerizing styrene and acrylonitrile in the presence of polybutadiene with proportions that can vary from 15% to 35% acrylonitrile, 5% to 30% butadiene, and 40% to 60% styrene. The result is a long chain of polybutadiene criss-crossed with shorter chains of poly(styrene-co-acrylonitrile). The nitrile groups from neighboring chains, being polar, attract each other, and bind the chains together, making ABS stronger than pure polystyrene. The styrene gives the plastic a shiny, impervious surface. The polybutadiene, a rubbery substance, provides toughness even at low temperatures. For the majority of applications, ABS can be used between -20°C and 80°C, as its mechanical properties vary with temperature. The properties are created by rubber toughening, where fine particles of elastomer are distributed throughout the rigid matrix.

Kollidon SR is a polyvinyl acetate (80%)- and povidone (19%)-based matrix retarding agent that is particularly suitable for manufacturing of pH-independent, sustained-release matrix tablets by direct compression or hot melt extrusion. The remaining 1% is made of sodium lauryl sulfate (0.8%) and silica (0.2%). It occurs as a white or slightly yellowish, free-flowing powder. Polyvinyl acetate is a very plastic material that produces a coherent matrix even under low compression forces. When a solid dosage form is introduced into gastric or intestinal fluid, the water soluble povidone is leached out to form pores through which the active ingredient slowly diffuses outwards. Kollidon SR contains no ionic groups and is therefore inert to drug substances. Its sustained-release properties are unaffected by ions or salts. It is insoluble in water (the povidone part is soluble but the PVA part is insoluble), and it is very soluble in N-methylpyrrolidone.

Hypromellose (HPMC, hydroxypropyl methylcellulose, cellulose, hydroxypropyl methyl ether; Methocel; Methocel K100M, Pharmacoat) occurs as an odorless and tasteless, white or creamy-white colored fibrous or granular powder. It is used as a coating agent, film-former, rate-controlling polymer, stabilizing agent, suspending agent, tablet binder, and viscosity-increasing agent. It is soluble in cold water, forming a viscous colloidal solution, and is practically insoluble in alcohol. It is available in a wide range of viscosity types. The commonly used Methocel E4M has a nominal viscosity of 4000 mPas for a 2% w/v aqueous solution at 20°C.

Polyacrylic Acids (PAA, Carbomers) are synthetic, high-molecular weight polymers composed of acrylic acid cross-linked with either allyl sucrose or allyl ethers of pentaerythritol. They occur as white-colored, fluffy, acidic, hygroscopic powders with a slight characteristic odor. They are soluble in water and, after neutralization, in 95% ethanol and glycerin. When carbomers are dispersed in water, an acidic colloidal solution of low viscosity will form which will thicken when an alkaline material, such as triethanolamine, is added.

VI. Compounding Requirements

A number of activities must be accomplished that are necessary before 3D printing of compounded pharmaceutical dosage forms can become a reality and include the following.

Inkjet Based

1. Solutions containing stable, known concentrations of APIs in suitable fluid matrices for delivery through printer inkjet heads. Either solution or suspension systems can be utilized with solutions being the easiest to use. The drug must be both physically and chemically stable in the solution used for depositing the drug onto the matrix. The effect of the solution on the bed matrix must be considered for preparing a robust dosage form.
   
   
2. Suitable bed matrix for processing. A number of different options can be selected for the bed matrix depending upon the process to be used and whether or not the interaction between the solution forms a dosage form where the excess bed matrix (powder) is removed or the process is designed to result in the final desired product.
   
   
3. Appropriate 3D printing device that has been validated. The 3D printed dosage form must meet the requirements of any monographs specific for the drug product or for the general default specification of 90% to 110% of the labeled amount of the drug. Validation must also include stability studies of the drug exposed to the process.
   
   
4. Appropriate software that has been validated. A number of different software programs are available, but it would be preferable to minimize the number of different programs utilized in 3D printing of pharmaceuticals. Once a software program has been selected, modified (if needed) and validated, then it may be transferable to different facilities utilizing the same equipment. Drug-specific compounded preparations may be developed and become a part of the portable software.

Extrusion Based

1. Filaments containing stable, known concentrations of APIs in solid form that can be used in extrusion devices must be developed and produced. This will require the selection of appropriate extrusion-based matrices and the incorporation of APIs at known concentrations. They must also be tested for stability during the preparation of the filaments as well as during the 3D printing processes.
2. Appropriate 3D printing device that has been validated. See #3 above.
3. Appropriate software that has been validated. See #4 above.

VII. Quality Considerations

Some apparent defects that are unique can occur with 3D printing and include the following:

• Band Formation: Ripples on the sides of a product caused by vibration in the x-y plane during printing
• Leaning of Product: Off-axis products caused by drift in the x-y plane during printing
• Warping: Product distortion caused by thermal expansion/contraction
• String Formation: Wisps of filament caused by filament elongation during an extruder's off-phase
• Collapse: Loss of porosity caused by sagging layers
• Residual Formation: Unbound powder or un-crosslinked monomer caused by incomplete printing

VIII. The Future

3D printing has promise for drug product formulation now and in the future in both manufactured and compounded dosage forms. Future example advances that can enable and support its growth and unique applications include the following:

• Printing 3D structures slowly but with better spatial resolution
• Printing with novel materials and creating material gradients during printing
• Developing models and process analytical technology for 3-D printing to improve process understanding and characterization
• The ability to prepare dosage forms at the point of care
• Printing conventional dosage forms such as tablets and individualized dosage forms by printing active solution or suspension onto an edible substrate such as paper or other orally administered item or onto a tablet

A number of additional 3D printing methods have not yet been used but may be possible in the future, including focused energy, laminated object manufacturing, electrospinning, and voxel printing.

Focused Energy (Laser or Electron-beam)

Involves directed energy deposition is a process where raw materials are melted as they are being deposited. This process is similar to extrusion but allows the use of powders or other raw materials that cannot be extruded.

Laminated Object Manufacturing

Automated laser cutting followed with sheet-by-sheet assembly of products. It is a quick and inexpensive method but is also low-resolution and more wasteful than most printing methods.

Electro Spinning

Electrospun fibers and random woven mats are common in drug delivery research. Combinations of electro spinning with extrusion and sacrificial molding to prepare 3-D electrospun structures for tissue engineering has been investigated and may find some usefulness in the future.

Voxel Printing (or Rapid Assembly)

A hybrid of 3D printing and assembly where the raw materials include ordered microstructure parts (electronic circuits microfluidic channels or interlocking subunits, etc.). This is a departure from other 3D printing methods which use relatively simple raw materials like powders liquids filaments and semi solids.

IX. Summary and Conclusions

3D printing technology refers to different processes based on layer-by-layer emergent production. It involves a layer-by-layer automated process capable of producing complex personalized products on demand. There are numerous 3D printing technologies and innovations that continue to be made to improve the safety efficacy and tolerability of pharmaceuticals, including inkjet and extrusion printing. Each technique has its pros and cons. The use of methods utilizing heat during the process or post-production is still limited by the low number of FDA-approved thermoplastic polymers and potential instability of the incorporated drug.

Actually, the development of 3D printing processes in the pharmaceutical field is still in its infancy and, in the future, pharmacists and pharmaceutical companies may pay closer attention to these techniques to develop personalized medicines. The capabilities of accurate, low-dose dispensing can lead to better control, uniformity, and safety with low-dose and/or potent compounds.

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. Examples of 3D Printed Drug Dosage Forms.

HPMC = hydroxypropyl methylcellulose; DOP = Drop on Powder; FDM = Fused Deposition Modeling; PAM = pressure assisted microsyringes; PCL = polycaprolactone; PLGA = poly lactic-co-glycolic acid; PLLA = poly-l-lactide acid; PVA = polyvinyl alcohol; PVP = polyvinylpyrrolidone; RDT = rapid-dissolving tablet

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