Selasa, 03 Februari 2009

The Granulation Process



his article presents the basic technologies for preparing
powders for tablet making. Granulation is the process of
collecting particles together by creating bonds between
them. Bonds are formed by compression or by using a
binding agent. If one were to make tablets from granulated sugar
versus powdered sugar, for example, powdered sugar would be
difficult to compress into a tablet and granulated sugar would
be easy to compress. Powdered sugar’s small particles have poor
flow and compression characteristics. These small particles
would have to be compressed very slowly for a long period of
time to make a worthwhile tablet. Unless the powdered sugar
is granulated, it could not efficiently be made into a tablet that
has good tablet characteristics such as uniform content or consistent
hardness. The granulation process combines one or more
powders and forms a granule that will allow the tableting process
to be predictable and will produce quality tablets within the required
tablet-press speed range.
A tablet formulation contains several ingredients, and the active
ingredient is the most important among them. The remaining
ingredients are necessary because a suitable tablet cannot
be composed of active ingredients alone. The tablet may
require variations such as additional bulk, improved flow, better
compressibility, flavoring, improved disintegration characteristics,
or enhanced appearance.
If the active ingredient in a formulation represents a very
small portion of the overall tablet, then the challenge is to ensure
that each tablet has the same amount of active ingredient.
Sometimes, blending the ingredients is not enough. The active
ingredient may segregate from the other ingredients in the blending
process. The ingredients may be incompatible because of
particle size, particle density, flow characteristics, compressibility,
and moisture content. These incompatibilities can cause
problems such as segregation during blending or during transfer
of the product to the press as well as separation of the active
on the tablet press.
Granulating the active by itself and then blending it with the
rest of the ingredients is one solution to the segregation problem.
Or, all or most of the ingredients could be granulated together.
The best course of action to ensure that each tablet contains
the correct amount of active ingredient, especially if the
active is only a small percentage of the tablet ingredients, is to
mix the active thoroughly with some or most of the other ingredients
and then granulate the blend (i.e., form the blend into
granules). Each granule would contain a little of each of the ingredients,
and the active ingredient would be distributed evenly
8 Pharmaceutical Technology TABLETING & GRANULATION 2002 www.pharmtech.com
The Granulation Process 101
Basic Technologies for Tablet Making
Michael D.Tousey
Michael D. Tousey is the technical
services director and owner of Dorado
International, Inc., a pharmaceutical
equipment and training company, 152
Wilkerson Drive, Westminster, SC 29693,
tel. 864.647.5400, mike@
doradointernational.com.
T
A tablet with good characteristics is not
made on a tablet press; it is made in the
granulation process. Joining particles
within a given granulation process will
improve flow and compression
characteristics, reduce segregation,
improve content uniformity, and eliminate
excessive amounts of fine particles.The
results will be improved yields, reduced
tablet defects, increased productivity,and
reduced down time.The objective of the
process is to combine ingredients to
produce a quality tablet.
IMAGE 100
10 Pharmaceutical Technology TABLETING & GRANULATION 2002 www.pharmtech.com
throughout the blend. The link between particles in each granule
must hold the particles together and keep them from breaking
apart before they are compressed.
If the active ingredient represents a high overall percentage
of the total tablet, then the active must flow, compress, and eject
from the tablet press and disintegrate properly. Even in this case,
most actives do not cooperate. To solve this problem, the active
must be granulated by itself, blended with the other ingredients
in the formulation, and compressed on the tablet press.
The nature of the active must be understood and its characteristics
may have to be improved to make this process work. Some
actives are very fine, small particles that are lighter than other
particles. Even if the active is the correct size it may not flow
smoothly, and flowability is very important to making a good
tablet. Furthermore, the active could be the right particle size
and it may flow well, but it may not blend well with the other
ingredients. The active may be too dry or too moist, which prevents
proper compression. Once the challenges to making an
active perform well are determined, the objective can be identified
and granulation can begin.
This article explains in simple terms the fundamentals of
the granulation process. Three basic techniques are used to
prepare powders for compression into a tablet: direct compression,
wet granulation, and dry granulation. Ten different
formulations would probably require that the powders for each
of the formulations be prepared in various combinations. This
article investigates the three techniques and discusses how to
determine which method is best for individual formulations.
Direct compression
Direct compression is used when a group of ingredients can be
blended, placed onto a tablet press, and made into a perfect tablet
without any of the ingredients having to be changed. Powders
that can be blended and compressed are commonly referred to
as directly compressible or as direct-blend formulations. Blending
the powders, putting them onto a tablet press, and seeing what
happens is the most direct way to make a tablet. Sometimes the
tablet will fall apart, the active ingredient won’t be in all the
tablets (no content uniformity), or all the powders won’t fit into
the die cavity (the place where powders are filled on the tablet
press). Simply blending powders does not form a granule.When
powders do not compress correctly, they must be granulated.
Nevertheless, not all products must be granulated.Many processes
are unnecessarily implemented because the objective and reason
for choosing a process path were incorrect. Before choosing
a means to process a formula, the best course of action is to put
the product on the press to see what happens.
Excipients
Ingredients in a tablet other than the active ingredient are called
excipients. Excipients can help powders become more fluid. This
fluid motion is very important for transferring powders into
the die cavity for compaction. Many years ago a high-speed
tablet press could produce 50 tablets/min. Now a tablet press
that runs this slowly is called a laboratory development press,
and it is good only for basic feasibility studies. Today’s highspeed
tablet presses can produce up to 12,000 tablets/min, and
the average tablet press speed is 3000 tablets/min. Therefore,
excipients are used not only to enhance the performance of active
ingredients, but also to simply make the active work better
on the tablet press.
Many types of excipients are used in tablet formulations to
help in other ways. They include
● binders, which help powders fuse or link particles to one
another
● fillers, which bulk up a tablet
● lubricants, which prevent powders from sticking to the metal
components of the tablet press and tablet-press tooling
● disintegrants, which help the tablet break up after it is ingested
by the patient
Several other excipients can be added to a formula to improve
flow, compression, hardness, taste, and tablet performance.
Flowability
As mentioned previously, press speed requires powders to be
very fluid, a property commonly referred to as product flowability.
Good flow characteristics are necessary because the mechanical
action of the tablet press requires a volume of fill. As
shown in Figure 1, the volume of fill represents the actual tablet
weight. A tablet press does not weigh the precise amount of powder
for each tablet. To achieve consistent tablet weights, the formula
must be designed to flow consistently and to fill volumetrically.
Thus the powders in the formula must possess a consistent
particle-size distribution and density to attain proper flow and
achieve volume of fill (i.e., tablet weight). In other words, the
powders must flow consistently to attain consistent results.
Compressibility
Other excipients in a formula enhance the ability of the powders
to compact. All powders have very different characteristics.
Remember your first chemistry class and the sessions during
which you began to understand the periodic table? The
basic structure of an atom has physical characteristics: shape,
density, and structure. Compressing a tablet of many different
powders that have varying physical characteristics can be dif-
Figure 1: A tablet press does not weigh the granulation; weight is
equal to the volume of fill within the die cavity. (Figure provided by
Thomas Engineering Inc.)
Pharmaceutical Technology TABLETING & GRANULATION 2002 11
ficult. Think about the example of making a snowball to throw
at your buddy: If the snowflakes are rather large and wet, then
they compact very easily into a snowball. However, if the
snowflakes are very light, fluffy, and dry, then compaction is
more difficult. Every kid knows that to make a snowball with
light, fluffy, and dry snowflakes, they must hold the snowball
together for a longer period of time (dwell time) and be careful
not to overcompress. If the snowball is overcompressed,
then the flakes no longer lock together but instead laminate
(flatten out) and fall apart. The same is true of powders used
in pharmaceutical tablets. If the formula has some of both
characteristics—large particles with high moisture content and
small, dry particles—then the tablet may or may not compress
well and probably will have difficulty holding together. One of
the main reasons to granulate powders is to make them more
compressible.
Wet granulation
When powders are very fine, fluffy, will not stay blended, or will
not compress, then they must be granulated. Fluffy is not a technical
term, but it fits the problem well; it means that the required
quantity of powder physically will not fit into the die
cavity on the tablet press. The volume of fill (bulk density) is
greater than that which is mechanically allowed.
Wet granulation, the process of adding a liquid solution to
powders, is one of the most common ways to granulate. The
process can be very simple or very complex depending on the
characteristics of the powders, the final objective of tablet making,
and the equipment that is available.
Some powders require the addition of only small amounts
of a liquid solution to form granules. The liquid solution can
be either aqueous based or solvent based. Aqueous solutions
have the advantage of being safer to deal with than solvents. Although
some granulation processes require only water, many
actives are not compatible with water.Water mixed into the
powders can form bonds between powder particles that are
strong enough to lock them together.However, once the water
dries, the powders may fall apart. Therefore, water may not be
strong enough to create and hold a bond. In such instances, a
liquid solution that includes a binder (pharmaceutical glue) is
required. Povidone, which is a polyvinyl pyrrolidone (PVP), is
one of the most commonly used pharmaceutical binders. PVP
is not soluble in water, so a solvent must be used to carry the
PVP particles in a liquid solution.
When PVP and a solvent are
mixed with powders, PVP forms
a bond with the powders during
the process, and the solvent evaporates
(dries). Once the solvent has
been dried and the powders have
formed a more densely held mass,
then the granulation is milled.
This process results in the formation
of granules.
Many different types of binders
exist. Some binders, called wet
binders, only work when added as
a solution. Dry binders are preprocessed powders that when
mixed with other powders help bind the ingredients together.
Binders that can be used wet or dry are also available.
Density
The density of each granule is increased by increasing the
amount of binding solution as well as the mechanical action of
the mixer. Therefore, controlling the amounts of solution, binder,
and mechanical action allows one to control the strength and
density of the granule.Machines that are used for this process
are called granulators. Granulators can be low shear, medium
shear, or high shear. Shear is the amount of mechanical force
of the granulator. A low-shear granulator uses very little mechanical
force to combine powders and binding solution. The
fluid-bed granulator, the most commonly used low-shear granulator,
uses a high volume of air flow to elevate powders in a
chamber while a binding solution is sprayed onto the particles
to form a light bond. A fluid-bed granulator does not impart
mechanical energy but instead relies on the powder characteristics
and the binding solution to form the lightly held powders
into granules. A low-shear granulator will not produce a dense
granule, and a high-shear granulator will not produce a light
granule. Again, the objective must be understood before the
granulation equipment is chosen.
Figure 2 shows a Lodige, a high-shear mixer. The high speed
of its mechanical sweeps produces a very dense granule. The
main objective of a granulator is to produce the correct granule
density. One granulator will not work for all powders. Overgranulating
or overdensifying powders can produce a very excellent
granule, but the granule could be too dense. For example,
if the objective is to make an effective headache remedy and the
product is overgranulated, then the tablet may take a long time
to disintegrate and dissolve into the blood stream. If my
headache remedy takes two hours to work, I probably won’t be
in business very long.
Traditional wet granulation
Traditional wet granulation,which is still commonly used, is the
process of mixing and adding solution and then transferring the
product to a tray dryer (see Figure 3).Wet massing is the process
of adding a solution to a blended powder and mixing for a predetermined
period of time at a given mechanical speed. Once
the process is complete, the wet mass is milled, spread on trays,
Figure 2: (a) A fluid-bed granulator (Glatt, Ramsey, NJ); (b) the fluid-bed process; (c) a Lodige highshear
mixer (Littleford Brothers, Florence, KY); (d) internal view of a Lodige mixer.
12 Pharmaceutical Technology TABLETING & GRANULATION 2002 www.pharmtech.com
and dried in a tray dryer. The wet mass usually is passed through
a low-shear mill and then dried for 8–24 h. A drying process that
is too short will produce granules that have entrapped moisture;
if the process is too long, then the granules become very dry and
friable. If granules that have been dried only on the outside reach
the tablet press, then moisture will escape the granules during
compression and cause the granules to stick to the tablet-press
tooling, a problem called case hardening.
Air flow and temperature control must be uniform throughout
the entire drying chamber of a tray dryer. If the dryer has
poor air circulation, then the product on the top trays will become
drier than the product on the bottom trays. Overly dry
product breaks apart easily and is no longer in a granular state.
When an overly dry granulation is milled, it produces fine dry
particles commonly referred to as fines. Fines do not flow well
on a tablet press and thereby cause weight variations. In addition,
fines do not compress well and can contribute to capping
and lamination, which are common tablet defects.
On the other hand, compressing the lower-tray granulations,
which may contain too much moisture, can cause granules to
stick to the tablet-press tooling, another situation that produces
defective tablets. The error that is most common to granulation
processes is the mixing of overdried granules, overwetted
granules, and good granules. Once this mixture is on the tablet
press, the full range of the previously described problems ensues:
capping, lamination, picking, sticking, and tablet weight
and hardness variation.
Problems on the tablet press
Measurement and sampling within a tray dryer can reveal potential
problems before they reach the tablet press, but problems
with granulation may not show up until the product
reaches the tablet press. Capping and lamination can be controlled
to some extent by making the tablet high in the die and
by slowing the machine down and extending dwell time, which
gives the granules and powders time to lock together and form
a good tablet. If moisture escapes the case-hardened granule,
then the product sticks to the punches. This problem is called
picking or sticking. The press operator can increase pressure to
allow the granules that are stuck to the
metal punch tip to restick or adhere to
the tablet instead of the tooling.When
compressing case-hardened granules,
making the tablet softer may help prevent
entrapped moisture from reaching
the surface of the granule.However,
this course of action may result in
tablets that are too soft, thereby failing
to completely eliminate the problem of
granulation sticking in the punch tips.
In these circumstances, press operators
often remove the punches and polish
them.
Polishing the punches with a paste
leaves a slight residue that acts as a
mold-release agent and halts the sticking
for a short period of time. Cleaning
the punch tips with isopropyl alcohol, however, hinders
mold release, and the sticking problem reappears. Operators
must question whether the polishing is truly a better choice
than the simple application of a mold-release agent.Many sticky
granulations require a few minutes to fine-tune on a tablet press,
and once the settings for weight, thickness, and hardness are
just right, the sticking will be minimized and may completely
disappear.
Stopping the press once the sticking problem is eliminated
requires that the start-up cycle on the tablet press begin again,
including polishing of the punches (or adding a mold-release
agent). This cycle can become endless.An entire industry is focused
on punch-polishing equipment and technology, the socalled
Band-Aid approach. If punches must be polished during
a run, then perhaps the granulation process is incorrect. Blame
should not fall to the tablet press, press tooling, polishing, or
the press operator; the problem shoould be corrected in the
granulating department.
A common complaint about product development is that an
adequate quantity of active ingredients is not available to properly
study real granulation problems. Substitutes are sometimes
used that do not replicate the active ingredient correctly, making
feasibility studies difficult. Once a product is scaled up, the
real problems that weren’t fully discovered in development hit
the production floor.When the problems are met head on at
the production level, the solution often is to polish the punches.
In reality, the product may not have been fully developed and
may remain a problem while it is in production.
Dry granulation
The dry granulation process is used to form granules without
using a liquid solution because the product to be granulated may
be sensitive to moisture and heat. Forming granules without
moisture requires compacting and densifying the powders. Dry
granulation can be conducted on a tablet press using slugging
tooling or on a roller compactor commonly referred to as a
chilsonator (see Figure 4).When a tablet press is used for dry
granulation, the powders may not possess enough natural flow
to feed the product uniformly into the die cavity, resulting in
Figure 3: A tray drying oven (O’Hara
Technologies, Inc., Richmond Hill, ON,
Canada).
Figure 4: A chilsonator with mill (Fitzpatrick,
Elmhurst, IL).
Pharmaceutical Technology TABLETING & GRANULATION 2002 13
varying degrees of densification. The roller
compactor uses an auger-feed system that
will consistently deliver powder uniformly
between two pressure rollers. The powders
are compacted into a ribbon or small
pellets between these rollers and milled
through a low-shear mill.When the product
is compacted properly, then it can be
passed through a mill and final blend before
tablet compression.
Roller-compaction or dry-granulation
equipment offers a wide range of pressures
and roll types to attain proper densification.
This equipment is loud and
dusty compared with other process machinery.
Material feed rates are critical
for attaining the final objective. The
process may require repeated compaction
steps to attain the proper granular end
point. Typically, a percentage of product
does not get compacted and may require
screening to remove excessive fines.
Again, successful compaction depends
on the compatibility of the products
being compressed. If fines are not removed
or reprocessed, then the batch
may contain too many of them, a situation
that can contribute to capping, laminating,
weight, and hardness problems
on the tablet press. The need for screening
large amounts of fines is common to
roller compaction, and the degree to
which it can be managed depends on the
nature of the ingredients. Any product
that is removed from the rest of the batch
because of particle size must be analyzed
to determine what is being removed.
Roller compacting the complete formula
is not usually necessary. The object is to
densify powders and form granules of the products in the formula
that must be compacted,mill the granules, and then blend
them back in with the rest of the formula’s ingredients. Most
dry-granulated products do not have problems with picking
and sticking because moisture is not present.
Summary
In the pharmaceutical industry, most products are manufactured
using the wet granulation process.Wet granulation offers
a wide range of capabilites for forming granules, from the production
of light granules to the production of very dense granules.
More than 70% of the global industry’s granulations are
made using this method.
Directly compressible materials are preprocessed or are found
naturally in the granular state. Ingredients that are preprocessed
are subject to some variation in particle-size distribution and
density variation, leaving the user subject to the quality of the
supplier’s product. The reduced number of processing steps required
by directly compressible materials allows for less equipment
and shorter process times in comparison with wet- or
dry-granulation processes.
When products are dry granulated, the process times are often
reduced and equipment requirements are streamlined; therefore,
the cost is reduced. However, dry granulation often produces
a higher percentage of fines or noncompacted products,
which can lead to compromised tablet quality or yield problems
if the product is not compacted correctly.
Pharmaceutical products are processed all over the
world using the direct-compressing, wet-granulation, or drygranulation
methods.Which method is chosen depends on the
ingredients’ individual characteristics and ability to properly
flow, compress, eject, and disintegrate. Choosing a method requires
thorough investigation of each ingredient in the formula,
the combination of ingredients, and how they work
with each other. Then the proper granulation process can be
applied. PT
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