As a
consequence, the complexities of the manufacturing process, particularly for
complex dosage forms, are often not recognized Yu,2008. As the major goal of
using SFF techniques is to produce individual dosage forms, these could push
the boundaries of mass medication to personalized medicine. Probably due to the
increased interest of therapeutic biological and sensitive (e.g. anticancer
drugs) molecules, which often need specific formulation processes, the FDA
initiated quality-by-design and processanalytical technology in 2003 to build
quality into the product right from the beginning of the manufacturing. This
was done to decrease unpredictability in scaling up and rejection of batches that
do not comply with specification, and consequently to increase effectiveness by
decreasing cost Charro et al., 2012. Such an approach is more suitable for
identifying critical process parameters of new manufacturing methods, such as
three-dimensional printing. In the future, much effort should be made to adapt
good manufacturing practice, standard of operating procedures and quality
control to individual production lines. Nevertheless, the recent approval of the
printed product Spritam® by the FDA
demonstrates that the industrial production of a printed drug delivery system
is already possible and recent developments of 3DP technologies seems to indicate
that both improvement of the current SFF processes to make adjustment of the
actual formulation limitations and the ability to industrially produce printed
drug delivery systems will be achieved.

 

 

dosage forms to
targeted-release drug delivery systems. Indeed, the necessity of controlling
the

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drug release
profile to modulate the absorption, the distribution, the metabolization and
the

elimination of
the drug rapidly appeared as a key factor for improving product efficacy and
safety as well as to increase the compliance of the patients.

Therefore,
conventional fabrication methods used to produce immediate-release systems
(e.g.

direct
tableting, capsule filling) progressively evolved towards multi-step
manufacturing

technologies,
including granulation, extrusion or coating processes, to allow the development
of

controlled-release
systems. Then, due to recent advances in biotherapy and personalized medicine,novel
concepts of formulation have emerged (e.g. nano-scale medicines, biomimetic
particles, functionalized liposomes) as well as more sophisticated
manufacturing methods. In parallel, the development of new carriers seems to be
mandatory to reach individualized treatments but it could lead to industrial
issues due to safety and regulatory considerations.

Nowadays, global
regulatory, manufacturing and consumer trends are driving a need for change in current
pharmaceutical sector business models, with specific focus on the inherently
expensive

research costs,
high-risk capital-intensive scale-up and the traditional centralized batch

manufacturing
paradigm. Rapid prototyping (RP) naturally appeared to be an essential tool in

research and
development area to fit with actual industrial directions of reducing both time
and

costs in the
early stage of a novel manufacturing concept, reducing the inherent risk of new

development to
fail at later stages.

Originally, RP
was developed to produce prototypes of new products to increase the speed of

production
significantly, especially during the development stage Melchels et al., 2010.
Today,

RP could easily
be confused with the general term “3D printing process” (3DP), which is one of

the numerous
existing RP techniques. Therefore, RP should preferably be defined as an
umbrella

term that
includes a plethora of manufacturing processes using three-dimensional computer
aided

design (CAD)
data where no tooling is required Wang et al 2013. Because all RP techniques
are

based on
digitally-controlled depositing of materials layer-by-layer to create freeform
geometry,

RP could be
referred as additive manufacturing (AM) or, more preferably, as solid freeform

fabrication
(SFF) processes.

In order to
better define RP, the common element in all the SFF techniques – i.e. how a
layered

solid structure
is designed – may be used. Briefly, underlying all current RP techniques is the

construction of
a CAD model, which is exported in rapid prototyping stereolitography (.stl)
file

5

format. While
the CAD-file describes the geometry and size of the parts to be built, the .stl
format

file lists the
coordinates of triangles that together make up the surface of the designed 3D
structure

Melchels et
al., 2010. The RP machine then processes the .stl file by creating sliced
layers of the

model. Three
dimensions are built by subsequent overprinting and, when the first layer is

deposited, the
model is reduced by the thickness of the next layer. The process is repeated
until

completion of
the desired structure; for this to work, every layer must solidify.

The first RP
method became available in the early ’90s from Sachs et al. at MIT (Cambridge,
MA)

Sachs et al,
1993. It was used to produce prototype models quickly, easily, cheaply and

automatically.
They patented a powder-based freeform fabrication method in which, using a

standard inkjet
print head, binders are printed onto loose powders in a powder bed. In the abstract

of their patent,
the authors described their technique as “a process for making a component by

depositing a
first layer of a fluent porous material, such as powder, in a confined region
and then

depositing a
binder material to selected regions of the layer of powder material at the
selected

region. Such
steps are repeated a selected number of times to produce successive layers of
selected

regions of bound
powder material so as to form the desired component. The unbound powder

material is then
removed”. This invention aimed to increase industrial productivity as well as

competitiveness
by reducing the time needed to make a new product flexibly in small quantities.

Due to the ease
of utilization and the evident economic benefits of RP, more than 30 different

techniques have
been applied in diverse industries such as plastic, wood, ceramic or metal
product

manufacturing
Chu et al., 2008.

 

Charles Hull is
considered the pioneer of 3D printing, as hedeveloped, patented and
commercialized the first apparatus for the3D printing of objects in the mid
1980s10–12, as well as developedthe STL file format that interfaced with
existing CAD software. Hull’s

technique,
stereolithography (SL), consists of a laser that movesacross the surface of a
liquid resin, curing the resin, before the stageis again submerged to allow for
the curing of another layer; this

process is
repeated layer by layer until the desired geometry is

printed.

The
basic needs of a man are food, Shelter, Clothes. But is it really in these
days? No. Not for sure. Because no man is satisfied with what they have. People
have always been wanted and needed something extraordinary. This is why may be
we are at the stage of where we are. In the world of computers and
technologies. Everything is getting computerized at this stage. Man has
achieved so much with the god gifted brains that we can see the satellite from
home.

           If we focus onto medical field,
technology has changed medical field too very extensively. People started
treating themselves not in the hospital but at their own houses. Pharmaceutical
companies and researchers have made the medical solutions easier for peopleby
introducing 3D Printing.3D printing is also known as additive manufacturing

 3D printing is the type of manufacturing of
tablets or capsules, or a dosage by composition of chemistry with high accuracy
and precision to cure disease. There are three most common Printer technologies
in medical applications : Selective laser Sintering, Thermal Inkjet printing
&  Fused Deposition Modeling. There
are about two dozen 3D printing processes, which use varying printer
technologies, speeds, and resolutions, and hundreds of materials.9 These technologies can build a 3D object in almost any
shape imaginable as defined in a computer-aided design (CAD) file.

            It is a prototyping technology that
has advantages of customizing solid dosages.3D Printing is flexible and Time
saving for not only to the pharmaceutical companies but also for general
people. This also gives ease manufacturing in pre formulation to validate drug
delivery. The ability to modulate the dose simply by adjusting the volume of
thedosage form without modifying the formulation reveals real advantages. 3DP
should already be interestingly used in pre-development or pre-clinicaland
clinical studies.

Formulation

3D
printing involves making solid objects from a digital file by thinly sliced,
horizontal layers in any shape.

At
the first, visual design of the drug creates using CAD software or animation
modeling software. Then the file is sent to the 3D printer. The 3d printer
throws material softly on the build plate and creates layers. Within the powder
it drops liquid into the material to createsdherence to the final product on
the build plate.

FDA
approval of the first
3D printed tablet, Spritam_, there is now precedence set for the
utilization

of
3D printing for the preparation of drug delivery systems. The capabilities for
dispensing low volumes with

accuracy,
precise spatial control and layer-by-layer assembly allow 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 active pharmaceutical ingredients with complex
and tailored

release
profiles. A unique opportunity for this technology for the preparation of personalized
doses to

address
individual patient needs. This review will highlight the 3D printing
technologies being utilized for

the
fabrication of drug delivery systems, as well as the formulation and processing
parameters for

consideration.
This article will also summarize the range of dosage forms that have been
prepared using

these
technologies, specifically over the last 10 years.

Advantage

The benefits of using additive manufacturing techniques for

dosage form design include the ability to accurately control the

spatial distribution of an active pharmaceutical ingredient (API)

within a dosage form, produce complex geometries, deposit very

small amounts of API, reduce waste and allow for rapid fabrication
of

varying compositions to allow for screening activities or
preparation

of individualized dose strengths5–8. Business incentives
associated

with printing pharmaceuticals include moving away from
traditionally

complex, slow and expensive supply chains, reducing manufacturing

and inventory waste, as well as allowing for more

individualized dosage forms (i.e. varying dose strengths) without

the
need for a high volume manufacture9.

Formulation

3D inkjet printing and FDM techniques have found their way into

drug product research and development. The implementation of

these technologies in dosage form design has spurred the
fabrication

of novel, multifunctional and customizable dosage forms.

3D inkjet and 3D powder bed printing

Inkjet printing is based on the Lord Rayleigh’s instability theory

developed in 1878, which explains the breaking of a liquid stream
or

jet into droplets17. This concept was used to develop continuous jet

(CJ) and drop on demand (DOD) printing, both of which are used in

traditional desktop printing18. CJ printing utilizes a
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, as shown in Figure 1.

DOD is considered more precise and less wasteful in that it can

produce droplet volumes as low as 1–100 pL at very high speeds,

but only as needed. The two most common types of actuation with

DOD printing are thermal (sometimes called bubble) and piezoelectric.

Micro-electro-mechanical systems, electrostatic and other

methods of droplet actuation are available or under investigation

but will not be discussed here.

A thermal print head utilizes a resister that upon receipt of

electrical pulses rapidly heats and forms a vapor bubble in the
ink

reservoir, as shown in Figure 2(a).
This bubble then forces ink out of

the print head; the bubble then collapses, producing a negative

pressure that draws ink from the reservoir to refill the chamber.

Thermal inkjet printing can produce high local temperatures near

the resistor. Although the short duration and small contact area

makes thermal degradation of the ink a low risk, it is something
to

be considered. Additionally, the thermal print heads require
the use

of a high vapor pressure or
volatile solvent, which may limit its

pharmaceutical application7.

Piezoelectric
print heads utilize a piezoelectric element, such as

crystal
or ceramic that produces a mechanical movement when a

voltage
is applied, as shown in Figure 2(b). The deformation of the

element
creates a pressure wave that ejects the fluid from the

nozzle20. Piezoelectric printing has
been shown to allow for more

control
of droplet formation and does not operate by heat

generation,
making it more desirable for use in drug

development4,21.

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, as shown in

Figure 3.

Formulation and process parameters for consideration

3D inkjet printing can be separated into three parts: (1)
droplet

formation, (2) droplet impact
and spreading and (3) drying or

solidification. Note that the majority of DOD printing conducted
for

preparation of pharmaceutical dosage forms utilizes piezoelectric

actuation, as thermal actuation requires the use of high vapor

pressure or volatile materials. Droplet formation is a complex

process, which is influenced by fluid viscosity, density and
surface

tension, among other factors.
Many dimensionless values have been

developed to predict fluid
behavior, including Reynolds (Re),
Weber

(We), and Ohnesorge (Oh) numbers, shown in Equation (1),

Equation (2), and Equation (3), respectively. The inverse of the
Oh

number, Z¼1/Oh, as a function of Re number was used to define

areas for stable drop generation and We number was used to

determine areas where energy was sufficient to eject a drop from

the nozzle19,22,23,
as represented in Figure 4. Generally speaking, Z

values of 1–10 are classified as printable fluids23.
Hon et al.

summarized some of the performance and fluid properties used

with typical commercial inkjet systems, which is shown in Table 124.

Reynolds (Re) number

Re ¼

__a

_

ð1Þ

Weber (We) number

We ¼

_2_a

_

ð2Þ

Early work with 3D printing of tablet dosage forms was conducted

using 3D powder bed printing5,8,80. Katstra et al. highlighted
the

ability to achieve appreciably low drug deposition, measuring 10_12

moles or 0.34 ng per droplet, using a 10.6 mg/mL active
solution. He

also conducted physical characterization of the resulting tablets

showing the ability to obtain comparable hardness and friability
to

DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY 1023

compressed dosage forms by
increasing polymer/binder concentrations

8; however, 3D inkjet printing
generally produces more

porous and therefore more
friable tablets that those prepared by

compression81.
The increased porosity with 3D inkjet printing has

been attributed to incomplete interaction with the printed binder

solution, leading to areas of ”unbound” particles18.
Aprecia

Pharmaceuticals took advantage of this increased porosity to

createorodispersible tablets that rapidly dissolve (10 s) with
very

small amounts of water (15 mL or less)82. Their patented ZipDose_

technology is adapted from the powder bed printing technology

developed at MIT and boasts the ability to support drug loading up

to 1000 mg. This technology led to the development and approval

ofSpritam_ (levetiracetam) for the treatment of epilepsy,
particularly

in pediatric and geriatric patient populations that have

difficulty swallowing tablets. The rapid dissolution allows for
rapid

onset of action with Tmaxachieved in as little as 9 min82.

Rowe et al. emphasized the
ability of 3D fabrication to produce

complex dosage forms by
producing tablets with IR and extended

release (ER) components, delayed
release, pulsatory drug release,

inclusion of multiple APIs, and
breakaway tablets that generate

smaller fixed geometries with
tailored erosion rates5. Using this

flexibility for the printing of
geometries that are not readily

prepared through tablet
compression, Yu et al.
prepared tablets in

a doughnut shape, as shown in Figure 783. This shape had been

previously shown to produce zero-order release by controlling

surface area during erosion84,85; however, manufacturing these

tablet geometries required complex compression processes. Yu

et al. made a structure with the top and bottom layers comprised

ethylcellulose (EC) to produce impermeable layers; the inner core

was prepared using an active blend of acetaminophen (APAP) with

the binder used for the outer surface (shown in gray in Figure 7)

consisting of 2% EC to create a slower release rate from the outer

surface. 3D inkjet printing allowed for the fabrication of very
thin,

but functional barrier layers on the top and bottom, as well as an

EC-containing outer surface. Theoretically, this geometry allows
for

the decrease in the surface area due to the outward releasing

portion and the increase in the surface area of the inward releasing

portion to be more synchronized to produce a zero-order release.

Zero-order release was seen for the printed tablet with the
release

rate varying with the thickness of the rate-controlling membrane

and tablet height. Moreover, no burst release was seen, as can be

the
issue with many sustained release formulations.

after printing40, further emphasizing the need for an appropriate

solvent system selection.

With 3D powder bed printing, the binder concentration may be

critical to the strength of the final structure. Patirupanusara et
al.

investigated the impact of binder concentration of maltodextrin
and

polyvinyl alcohol (PVA) as binders for a polymethyl methacrylate

structure41. With this system, at least 10% binder was needed
in the

powder bed for successful fabrication. Increase in binder
concentration

led to decreased porosity and
increased strength;
however,

at over 40%, deformation in the structure shape was seen.

Patirupanusaradescribed the mechanism of binding as dissolution

of binder in the printed liquid,
followed by infiltration into the

powder bed, and finally
solidification upon drying.
Alternatively, one

could print with binder in the ink solution, as the spraying of
wetted

binder can lead to more efficient migration in the powder bed and

potentially enhanced mechanical properties42–44. In this case,
one

should evaluate fluid properties of the ink, as polymer solutions
can

have complex rheology. Particle size of the
powder bed also effects

binder
distribution and ultimately the final structure porosity and

strength.
Typical layer thickness during powder be inkjet printing

can be
50–200 mm,
therefore, average particle size is recommended

to be
50–150 mm45.

Other processing parameters that
should be considered include

nozzle diameter, droplet
spacing, print head speed, and droplet

frequency and velocity, which
can be controlled by the amplitude of

the piezoelectric actuation pulse.

Limitation

An alternative
was quickly proposed and was based on the dispersion of the drug in the

polymer using an
HME process to create loaded filaments before printing Pietrzak et al., 2015.

The
incorporation of another material (i.e. a drug) in a polymer modified its
thermoplastic

properties and
may lead to technical issues such as nozzle clogging or unsuitable flexibility
of the

filament. Furthermore, as well as
printing-based inkjet systems,

 

 

 

 

 

Future
Prospect and scope

As
3d printing entered into the pharmaceutical industry it has been changing the
structure of traditional pharmaceutical system. It changes the way of medicine
manufacturing. Because of 3d printing is new in this industry we couldn’t see
the fast growth. maybe because of research and development. But it steadily
moving ahead. It came up with big vision.

It’s
not just for any pharmaceutical industry or any hospitals. It will be available
for all of us. So it is a big vision and requires big amount of money to
fulfill the every pharma need. Because now it’s not only question of similar
dosage to everyone, here they are providing different dosage for genetically
different person. and if that printerare going to available to each and every
person then their price matters it should be affordable for everyone.

Also
with this technology we don’t need to go anywhere for medicine. It can be
easily available at home.

But
sales of medicine in shop will reduce and it will be greatly impact on shops or
medical store. After use of machine cleaning is very important and also a
chemical which is important in this also made available easily and their
formula for combination. Because without chemical we cant make itand also they
have to find out different techniques to simplify this work.

 

 

 

 

 

 

 

 

 

 

 

 

 

Professorsat

MIT were credited with first using the term ”3D printer” with
their

invention of a layering technique using a standard inkjet print
head

to deposit ”ink” or a binder solution onto a powder bed to bind

powder, again repeating this process layer-by-layer to produce a

desired geometry. The un-bonded or loose powder, which acts as a

support during processing, is then removed. The structure can be

further treated, for example with heat, to enforce the bonding14.
This

process is generally referred to as 3D printing. In this review,
this

technique will be referred to as 3D powder bed or powder bed
inkjet

printing.

The
increased use of 3D printing technologies in the preparation of

drug
delivery systems is driven by a myriad of factors. The

technology
allows for the preparation of multifaceted dosage

forms
with accurate deposition of materials, greater spatial control

and
geometric flexibility. These features allow for the formulation

and
manufacture of highly innovative products, such as combination

drug
products with multimechanism release behaviors, which

can
greatly increase compliance by patients with complex dosing

regimens.
3D printing systems are inherently scalable, with the

ability
to be set up as semi-continuous or continuous manufacturing

lines,
to address small volume (e.g. orphan products) to commercial

scale
(e.g. generics) manufacturing. The capabilities of accurate, low

dose
dispensing can lead to better control, uniformity and safety

with
low dose and/or potent compounds. In a pharmacy or

ambulatory
setting, 3D printing allows for the preparation of

various
dose strengths, providing an unprecedented ability to

individualize
dose per patient needs. Additionally, the ability to print

dosage
forms at the point of care may allow for more therapeutic

options
available for patients.

Future work to enable drug product manufacture using 3D

printing
technologies should include the identification and characterization

of
additional pharmaceutical materials amenable to

processing.
Polymeric materials for FDM, specifically, should be

investigated
to allow a wider formulation design space. Both

processes,
powder bed inkjet printing and FDM, can yield porous

and/or
partially fused structures with a relatively rough surface

finish,
which have implications on the mechanical strength of the

final
structure. It may be possible to address this by optimizing the

formulation
(i.e. decrease particle size of powder in powder bed,

increase
binder ink concentration) or process parameters (i.e.

increase
envelope temperature during FDM fabrication).

With
an exceptionally high degree of control and flexibility, 3D

printing
technologies are well suited for pharmaceutical

manufacturing
of customized, complex and innovate dosage

forms.
Their use in the screening, development and manufacturing

of
drug delivery systems will only increase as there is more

understanding
of and need for tailored drug release profiles and

personalized
dose strengths to better address complex dosing

regimens and
heterogeneous patient populations.

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