3 D PRINTING IN PHARMACEUTICALS

AN INSIGHT OF 3D PRINTING TECHNOLOGY IN

PHARMACEUTICAL DEVELOPMENT AND APPLICATION

❖ Introduction

• Three-dimensional printing (3DP) has become one of the most innovative

technologies in the pharmaceutical field.[1]

• Nowadays, three-dimensional printing is one of the fastest developing branch of

technology, art and science, and still broadens the applications.
• The term three-dimensional Printing was defined by International Standard
Organization (ISO) as fabrication of objects through the deposition of a material using
a print head, nozzle, or another printer technology^.
• In contrast to commonly used subtractive and formative manufacturing
methodologies, this technique is one of the methods of additive manufacturing (AM)
in which the parts are prepared from 3D model data in the process of joining materials
layer by layer.
• The practical approach of AM is called rapid prototyping (RP) [2]and its advantages
include the reduction of prototyping time and costs, easy modifications of a product at
a designed level, the possibility of manufacturing of small objects, individualized
product series or structures impossible to be formed with subtractive techniques [3].
• The application of 3D printing in the science and engineering has grown since 2012.
• The number of scientific papers recorded in Web of Science Core Collection
containing a term B3D printing^ or B3D printed^ in the title increased from 59 in
2012 to 1573 in 2017.
• Moreover, the number of citations of these papers in the same period grown from 209
to 12,411.
• Narrowing the searching results to the category of pharmacy/pharmacology gives no
result in 2012, however 77 records were found up to 2017, which also shows a great
interest in the 3DP methods in pharmaceutical sciences.
• This review is aimed at the newest development and achievements in the field of
pharmaceutical and biomedical research from the literature items that have been
published within the last 3 years.
• The novel approaches in the formulation of solid dosage forms for individualized
therapy are particularly focused, however transdermal drug Delivery as well as
biomedical applications of additive manufacturing technique including implants,
surgical models, bio printed materials and bio robotics are also mentioned.
• The parallel development of additive manufacturing used in pharmaceutical
technology and bioprinting is summarized and compared with a special effort made to
point out the evolution of bioprinting.
• Due to the fact that the pharmaceutical applications of additive manufacturing is on
the early stage of development and implementation not many regulatory is available
however the important issues that have been introduced by the FDA in 2017 are
mentioned.
• Gaining immense interest both in academic and industrial sector is the concept of
three dimensional (3D) printing (3DP) technologies. Domains like aerospace,
engineering, FMCG, architecture, military, fashion industry, chemical industry, and
medical field are by no way Untouched by this technology [4,5].
• 3DP has a wide range of applications like tissue design, printing of organ, diagnostics,
manufacture of biomedical devices, and the design of drug and delivery systems in
the medical field [6,7].
• From the data originated by various techniques like computed tomography (CT) scan
and magnetic resonance imaging (MRI), complex anatomical and medical structures
according to the need of patient can be fabricated [8,9].
• Replacing and repairing the defective organs like kidney, heart etc. or all together
creating a new organ that mimics the same functions as that of original are some
additional uses of this technology [10].

• This technology is so widespread that its applications include things that are an
integral part of human life like clothing, eyeglasses, jewellery, parts of cars, and drugs
that can be printed in almost any geometry and shape as per the requirement
• of the user [11].
• In this technology a concept is transformed into prototype by taking help from 3D
computer-aided design (CAD) files, hence digitally controlled and customized
product can be fabricated [12].
• This technology utilizes a bottom-up approach in which layers of materials like living
cells, wood, alloy, thermoplastic, metals etc. are placed on top of each other in order
to make the required 3D object [13].
• Therefore, 3D printing is also known by other terminologies such as layered
manufacturing, additive manufacturing, computer automated manufacturing, rapid
prototyping, or solid freeform technology (SFF) [12].
• In subtractive methodology or conventional method, the product is designed from the
bulk substance and due to non-advanced tools used non-standard geometries
and objects Made from many materials cannot be made with high quality [14,15].
• In contrast to the conventional method, 3DP technology is more automated, rapid and
easy to use, customized and sophisticated and cost-effective In recent years, the use of
this technology in medicine preparation has demonstrated such potential.[16,17]
• This is why experts around the world point out that the pharmaceutical field has
finally been given, after two centuries, the opportunity to make a significant
technological jump.
 HISTORY

• 3D Printing posed as a possible platform for personalized medicine in the 1990s. There
are major achievements in 3D printed medical device, and Radiological Health (CDRH)
has reviewed and cleared 3DP medical devices. [18]

• The first 3D printing technique used in pharmaceutics was achieved by inkjet printing a
binder solution onto a powder bed, binding therefore the particles together.

• The process was repeated until the final desired structure was obtained. This first
happened in the early 90’s at the Massachusetts Institute Technology invented and
patented by Sachs et al [19].

• In 1989, Scott Crump, filed a patent on another 3D printing technology: fused

deposition modelling, where extruded polymer filaments heated into a semi-liquid state
were extruded through a heated nozzle and deposited onto a build platform layer by
layer to harden [20,21].

• Inkjet printing was the method used to manufacture Spritam (levetiracetam) tablets for
oral use, the first 3D printed drug approved by the Food and Drug Administration
(FDA) in 2016 by Aprecia Pharmaceuticals [20].

• 3D printing is more advanced in the fields of automobile, aerospace, biomedical and

tissue engineering than in the pharmaceutical industry where it is in its initial phase.

• FDA encourages the development of advanced manufacturing technologies, including

3Dprinting, using risk-based approaches. Regulatory Expectations US FDA, 2017
issued guidance on Technical.[22]

• The idea of 3DP has evolved from early 70′ of the twentieth century when Pierre A.L
Ciraud described the method of application of powdered material and subsequent
solidification of each layer through the action of high energy beam.
• In this case meltable materials such as plastics or metals can be theoretically used for
object preparation.

• In early 80′ in a patent entitles: BA molding process for forming a three dimensional
article in layers^, Ross Housholder described an idea of sand binding by different
materials and Carl Deckard developed a method of solidification of powdered bed by
laser beam called selective laser sintering (SLS).

• The first commercially available technology created by Chuck Hull was

stereolithography (SLA).

• This method was based on photopolymerization of liquid resin by ultraviolet light.

• At the end of 80’s Scott Crump filed a patent for fused deposition modelling– a
technique which used thermoplastic material for object preparation.

• In the 90’s Emanuel Sachs - MIT scientist with co-workers patented B

Threedimensional printing techniques^ based on joining the selected regions of powder
by binding material [23].

The most important achievements in 3D printing in pharmaceutical such as :

Achievement and challenges
Possibilities with the 3D printing techniques
• 3D printing is applied in industries such as food, aerospace, automotive, jewellery,
military, medical and dental.
• It is often used for rapid prototyping but within the aerospace industry it is used for
actual production of final parts.
• The possibility to modify the design of a given part at will is a huge benefit for
production
• . Within the pharmaceutical industry the ability to play with e.g. surface area and
shape in general may provide interesting possibilities.
• 3D printing aka solid free-form technology (SFF), rapid prototyping (RP) and additive
manufacturing (AM).
• 1986 Charles Hull field first stereolithographic patent alongside starting the company
“3D systems” and developing the .STL file format
• . 1990 Fused deposition modeling (FDM) was developed by Scott Crump at Stratasys.
1993 MIT Professors Emanuel Sachs and Michael Cima patented first device named
”3D printer” that could print plastic, metal and ceramic parts.
• 3D printing enables more flexible manufacturing. Thus may also enable more flexible
manufacturing of pharmaceuticals. Aprecia Pharmaceuticals have recently Received
FDA approval for a 3D printed orally disintegrating tablet and have started
production[23]
 Types of 3D Printing

1. FDM Fused Deposition Modelling :-

• Fused Deposition Modelling, is an additive manufacturing technology commonly
used for modelling, prototyping, and production applications.

• F.D.M, works on an "additive" principle by laying down material in layers.

• A plastic filament or metal wire is unwound from a coil and supplies material to an
extrusion nozzle which can turn the flow on and off.

• The nozzle is heated to melt the material and can be moved in both horizontal and
vertical directions by a numerically controlled mechanism, directly controlled by a
computer-aided manufacturing (C.A.M) software package.

• model or part is produced by extruding small beads of thermoplastic material to form

layers as the material hardens immediately after extrusion from the nozzle.

• Stepper motors or servo motors are typically employed to move the extrusion head.
FDM, a prominent form of rapid prototyping, is used for prototyping and rapid
manufacturing.

• Rapid prototyping facilitates iterative testing, and for very short runs, rapid
manufacturing can be a relatively inexpensive alternative. [24,25]
 2. SLA-Stereolithography:-
• Stereolithography is an additive manufacturing process which employs a vat of liquid
ultraviolet curable photopolymer "resin" and an ultraviolet laser to build parts' layers
one at a time.
• For each layer, the laser beam traces a cross-section of the part pattern on the surface
of the liquid resin.
• Exposure to the ultraviolet laser light cures and solidifies the pattern traced on the
resin and joins it to the layer below.

• After the pattern has been traced, the SLA's elevator platform descends by a distance
equal to the thickness of a single layer, typically 0.05 mm to 0.15 mm (0.002" to
0.006").

• Then, a resin- filled blade sweeps across the cross section of the part, re-coating it
with fresh material. On this new liquid surface, the subsequent layer pattern is traced,
joining the previous layer.

• A complete 3-D part is formed by this process. After being built, parts are immersed
in a chemical bath in order to be cleaned of excess resin and are subsequently cured in
an ultraviolet oven.

• Stereolithography requires the use of supporting structures which serve to attach the
part to the elevator platform, prevent deflection due to gravity and hold the cross
sections in place so that they resist lateral pressure from the re-coater blade.

• Supports are generated automatically during the preparation of 3D Computer Aided

Design models for use on the stereolithography machine, although they may be
manipulated manually

• Supports must be removed from the finished product manually, unlike in other, less
costly, rapid prototyping technologies.[26,27]
 3. SLS-Selective laser sintering:-
• Selective laser sintering is an additive manufacturing technique that uses a high power
laser (for example, a carbon dioxide laser) to fuse small particles of plastic, metal
(direct metal laser sintering), ceramic, or glass powders into a mass that has a desired
three-dimensional shape.

• The laser selectively fuses powdered material by scanning cross-sections generated

from a 3-D digital description of the part (for example from a C.A.D, file or scan
data) on the surface of a powder bed.

• After each cross-section is scanned, the powder bed is lowered by one-layer thickness,
a new layer of material is applied on top, and the process is repeated until the part is
completed

• Because finished part density depends on peak laser power, rather than laser duration,
a S.L.S, machine typically uses a pulsed laser.

• The S.L.S, machine preheats the bulk powder material in the powder bed somewhat
below its melting point, to make it easier for the laser to raise the temperature of the
selected regions the rest of the way to the melting point.

• Some S.L.S, machines use single component powder, such as direct metal laser
sintering.

• However, most S.L.S, machines use two-component powders, typically either coated
powder or a powder mixture.

• In single-component powders, the laser melts only the outer surface of the particles
(surface melting), fusing the solid non-melted cores to each other and to the previous
layer.
• Compared with other methods of additive manufacturing, SLS can produce parts from
a relatively wide range of commercially available powder materials. [28,29]

4. Inkjet Printing :-
• Inkjet printing is a type of computer printing that recreates a digital image by
propelling droplets of ink onto paper and plastic substrates.

• Inkjet printers were the most commonly used type of printer in 2008, and range from
small inexpensive consumer models to expensive professional machines.

• The concept of inkjet printing originated in the 20th century, and the technology was
first extensively developed in the early 1950s.

• While working at Canon in Japan, Ichiro Endo suggested the idea for a "Bubble jet"
printer, while around the same time Jon Vaught at HP was developing a similar
idea.[4]

• In the late 1970s, inkjet printers that could reproduce digital images generated by
computers were developed, mainly by Epson, HewlettPackard (HP) and Canon. In
 the worldwide consumer market, four manufacturers account for the majority of
inkjet printer sales: Canon, HP, Epson and Brother [30,31]

Advantages of 3DP in the Pharmaceutical Sector :-

• Improved productivity: 3D printing works faster than traditional methods, especially

when fabricating materials such as implants and prosthetics with the added advantage
of better precision and accuracy, repeatability and reliability.

• Customized and Personalized medicines: One of the prominent advantages of this

technology is the flexibility to create customized medical equipment and products.
Personalized implants, surgical instruments, prosthetics, can be a great blessing to
both patients and physicians. Accurate dosing of a potent drug, high drug loading can
be achieved with this technique.

• Cost-effective: Products made with 3D printing are less expensive due to less wastage
of materials.
• Sustainable/eco-friendly: 3 DP technology being a novel and innovative technique is
ecofriendly as it uses less energy and better quality material, ultimately producing
minimum waste.

• Time-saving: Three-dimensional printers are time efficient which shortens the product
development design cycles.

• Tool-less: 3DP can eliminate the need for tool production and therefore, reduced cost,
time and labour associated with it .[ 32,33]

Disadvantages of 3D Printing
• In inkjet printing, proper flow of ink can only be achieved with ink that has precise
viscosity [34].

• Ink formulation material should have the property of self-binding but should not bind
to other printer elements. In some formulation when the ink does not possess adequate
selfbinding property or it binds with other elements of printer then the resultant
formulation does not have required hardness [35].

• Rate of drug release may get affected due to binding of ink with other printer
materials[36]
• Limited material

• Restricted bulk size

• Large volume

• Reduction in manufacturing job

• Design inaccuracies

• Copy right issue

• Lack of precision with regard to droplet size and droplet placement

Timeline of the development of 3D printing technology in Pharmaceutical
field [37,38]
• The different 3D printed dosage form with corresponding printing technologies [39,40]
 Application of 3D Printing in Medical [41,42]

•
 Conclusion
• The versatility and the promising developments of 3DP technology since its first
invention around 30 years ago as can be analysed from the review exhibit that this
technique will be a vital and a potential tool in the field of pharmacy and health care
in the near future.

• Although the progress is in its infancy stage, 3DP technology has made the fabrication
of extremely sophisticated and intricated dosage forms feasible.

• Innovative 3DP has shown a promising way for novel drug delivery systems to
efficiently achieve better patient compliance, optimum drug release profiles, better
shelf life and stability, cheap and on-demand patient-specific dosage forms.

• The researchers and scientists believe that this technology has immense potential to
revolutionize the pharma industry.

• Despite numerous advantages and benefits in pharmaceutical and health care systems,
there are a number of technical and regulatory challenges obstructing its extensive
utilization.

• The incessant innovation and progress of 3DP systems will address many challenges
such as mechanical, scientific and even regulatory limitations and ultimately the
rapidly evolving 3DP technologies will be more refined and appropriate for a wide
range of dosage forms and even for on-demand personalized medicines at a nominal
cost in days to come.

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