The use of size reduction in tablet

manufacturing process
Pharmaceutical size reduction is used primarily for the
purposes of control – control of the rates of dissolution
and absorption, control of chemical reactions, and
control of physical characteristics

.Advantages of size reduction

1. Content uniformity– Mixing turn out to be effective only when the ingredients
are small and of uniform size. As the particle is of small size, the no of particles
per unit dose is large. And greater the no. of particles, mixing becomes more
efficient. This criterion is particularly more important for the formulations that
contain low dose drugs.
2. Uniform flow– If the size of particle is small, the flow of powder into dies during
the compression of tablets is effective.
3. Effective extraction of drugs– Penetration of solvent into tissue or cells of
organic origin becomes rapid when the particle size is smaller.
4. Effective drying– If the size of granules is small, then the drying of granular
mass becomes rapid.
5. Improved physical stability– In suspensions and emulsions, the rate of
sedimentation decreases if the particles are of small and uniform size.
6. Improvised rate of dissolution– When the surface area is larger, than the
dissolution of a substance increases. Thus size reduction facilitates in increasing
the surface area.
7. Improved absorption rate– Smaller the particle, the faster is the absorption is
the absorption because the dissolution is also enhanced.

Disadvantages of size reduction

1Drug degradation– Decomposition of drug can occur due to the excessive heat
production during milling. Another reason is increased surface area also contributes
in drug decomposition.

2 Poor mixing– Generally, very fine particles are subjected to strong cohesive forces
hence aggregation of particles takes place. But this aggregation inhibits the efficient
blending of different ingredients.

The particle size significantly affects powder flowability, bulk density,

hygroscopicity, compatibility, porosity and blend uniformity. These parameters
influence every stage of tablet manufacturing (including compression, coating,
granulation and mixing), which affects the effectiveness and shelf life of the
drug. The particle size is not only important in the last stage of the tableting
process. The PSD control is also relevant for the manufacturer of the active
pharmaceutical substance. It determines the performance of crystalline
material and the efficiency of production operations such as filtration and
drying. What is more, it also affects the material stability during storage.
 Particle size reduction in the pharmaceutical industry, or pharmaceutical size
reduction, is an important initial step in the manufacture of most medicines. The
pharmaceutical size reduction process is also referred to as comminution, diminution
or pulverizations.
 Below we discuss how pharmaceutical size reduction affects the stability,
appearance and the various properties of the product.
Eases Swallowing
Of the multiple drug delivery methods, oral delivery is the most common. Ease in
swallowing is therefore an important consideration when working on an oral tablet’s
formulation. By implementing a tablet coating that is comprised of smaller particles,
grittiness is decreased and swallowing ability is enhanced.

Improves Bioavailability
Oral drugs that are highly soluble and permeable also confer increased bioavailability.
However, the direct correlation between solubility and bioavailability is a bad omen
for poorly soluble drugs. Interestingly, decreasing a product’s particle size increases
its surface area, which raises the surface area to volume ratio. Particle size reduction
technology is therefore an effective method of increasing bioavailability of poorly
soluble drugs, without altering its chemical formulation. As an added bonus,
improved bioavailability is cost-effective for the manufacturer. Since less product
needs to be produced to achieve the same effect, a portion of manufacturing costs can
be negated. (1)

1. Stability
A product with a smaller, more uniform particle size is more stable and less
likely to separate out. This translates to a longer shelf life and less waste.

2. Appearance
The smaller and more uniform the particle size, the smoother and more
homogenous the product. This is beneficial for aesthetic as well as practical
purposes. Pharmaceutical preparations meant for external application must be
free of any sedimentation and gritty particles that may irritate the skin or eyes.

3. Properties

 Increased therapeutic efficacy: The smaller the particle,

the greater the total surface area. With an increased
surface area, the rates of dissolution and absorption are
increased. Bioavailability improves, and the therapeutic
dose can be lowered. 

 Different options for drug delivery: Oral delivery of drugs is not

always ideal. Pharmaceutical size reduction can render particles
 small enough so that drugs can be inhaled or absorbed through the
skin.
 Improved processing: The size of the individual particles affects the
bulk properties of the ingredient. A narrow particle size range
distribution means that solids and powders are easier to mix
effectively, and flow properties are improved.
BEE International: Your Partner in Pharmaceutical Size Reduction
Our high pressure homogenizers offer unique benefits for the pharmaceutical
industry. DeBEE high pressure homogenizers are used all over the world to
produce nano / micro emulsions and dispersions, lipids and suspensions for
injectables, vaccines, targeted drug delivery, inhalants, time release, anesthetics and
antibiotics. Our modular equipment allows you to optimize and control the mixing
process by varying the cavitation, shear and impact forces applied to your product.
We are keenly aware of the stringent regulations applied to pharmaceutical
manufacturing; and we’re looking forward to working with you in bringing your
product to market.
Want to learn more about how BEE International's range of high pressure
homogenizers can benefit your pharmaceutical products?

Granulation,process
Granulation, a technique of particle enlargement by agglomeration, is one of the most
significant unit operations in the production of pharmaceutical dosage forms, mostly
tablets and capsules. During the granulation process, small fine or coarse particles
are converted into large agglomerates called granules.

Generally, granulation commences after initial dry mixing of the necessary powder
ingredients along with the active pharmaceutical ingredient (API), so that a uniform
distribution of each ingredient throughout the powder mixture is achieved. Although
granules used in the pharmaceutical industry have particle size in the range of 0.2-4.0
mm, they are primarily produced as an intermediary with a size range of 0.2-0.5 mm to
be either packed as a dosage form or be mixed with other excipients before tablet
compaction or capsule filling

Granules are produced to enhance the uniformity of the API in

the final product, to increase the density of the blend so that it
occupies less volume per unit weight for better storage and
shipment, to facilitate metering or volumetric dispensing, to
reduce dust during granulation process to reduce toxic exposure
and process-related hazards, and to improve the appearance of
the product.2 Consequently, the ideal characteristics of granules
include spherical shape for improved flow, narrow particle size
distribution for content uniformity and volumetric dispensing,
 sufficient fines to fill void spaces between granules for better
compaction and compression characteristics, and adequate
moisture and hardness to prevent breaking and dust formation
during process.

Granulation is an exemplary of particle design and the

properties of the particles acquired after granulation depend on
particle size of the drug and excipients, the type, concentration,
and volume of binder and/or solvents, granulation time, type of
granulator, drying rate (temperature and time), etc. The primary
methods by which the agglomerated granules are formed
include solid bridges, sintering, chemical reaction, crystallization
and deposition of colloidal particles.1,3 Besides, binding can also
be accomplished through adhesive and cohesive forces by
utilizing high viscous binders. The series of mechanisms by
which granules are formed from the powder particles
encompass wetting and nucleation, coalescence or growth,
consolidation, and attrition or breakage

Blend of powders containing pharmaceutical excipients and API

can be compressed into tablets either by direct compression or
after making granules by agglomeration or granulation
techniques . The granulation technique may be widely
categorized in to two types, dry granulation and wet granulation,
based on the type of method used to facilitate the agglomeration
of powder particles . Dry granulation uses mechanical
compression (slugs) or compaction (roller compaction) to
facilitate the agglomeration of dry powder particles, while the
wet granulation uses granulation liquid (binder/solvent) to
facilitate the agglomeration by formation of wet mass by
adhesion. Among these two techniques, wet granulation is the
most widespread granulation technique used despite the fact
that it involves multiple unit processes such as wet massing,
drying and screening, which are complex, time consuming, and
expensive requiring large space and multiple equipment.
Several factors influence choosing the right tablet manufacturing
process:
 The compression properties of your API.
 The physical and chemical stability of the API during the manufacturing
process.
 The formulation ingredients' particle size.
 The availability of required processing equipment.
 The cost to manufacture.

Five factors to consider when designing

a tablet
Manufacturing
Tablets are still one of the most convenient methods of drug delivery
and their complexity of design has increased to meet today’s market
requirements. Steve Deakin, Business Development Manager and Steve
Osborn, Product Design Manager, I Holland, outline the major design
considerations

Good tablet design is extremely important; it has an impact upon

anticounterfeiting, tooling strength, tablet coating, durability and functionality.
It also helps to avoid downstream manufacturing problems such as tablet
sticking, picking, lamination, capping and premature tooling failures. It is
essential to consider these at the beginning of the process to ensure a
problem-free, high quality end product.

Several elements need to be considered when designing a tablet; here some

of the most important ones are considered:

1. Tablet shape and profile

The first thing to consider is the tablet shape and optimum profile. There are
two basic tablet shapes: round and non-round; however, the complexity of
non-round shapes can vary and may require specialised tool manufacturing
capability.

Once the base shape has been decided, tablet size must be determined; here
consideration should be given to the type of press available for tablet
manufacture, as this can limit the size of the tablet.

Next follows selection of the tablet. The type of profile required is influenced
by several factors; the granule, embossing requirements, coating process,
packaging and company branding. Thought should also be given to the
volume of the tablet and whether it will be coated. Successful coating is
dependent on tablet profile. Coated tablets, whether film- or sugar-coated,
present challenges for the tablet designer. The complexity of the coating
process is vast. Many of the variables are within the manufacturer’s control
but expert tablet design can help eliminate potential problems.

Typically, the centre of a tablet is lower in hardness, so

during the coating process core erosion may take place

Typically, the centre of a tablet is lower in hardness, so during the coating

process core erosion may take place. This is when the tablet comes into
contact with the coating pan and other tablets, causing wear. This
vulnerability, caused by mechanical stress during coating, can be reduced by
avoiding very deep concaves and ensuring a robust design. For film-coated
tablets, double radius profiles are the preferred choice.

For shallow tablets with hard, sharp edges, the coating process will damage
the exposed edge of the tablet, resulting in chipped edges and sometimes
cracks. Flat and shallow tablet profiles should therefore be avoided.

Double radius designs ensure a strong tablet edge and a balanced profile,
which will roll in the coating pan. Another benefit of the double radius design
is that it can accommodate most marking and branding requirements,
because it increases the usable surface area available for this.

Poor marking and branding design on the tablet can lead to ‘bridging’ (the
coating collects in the detail on the face of the tablet because it does not fully
follow the contours of the marking on the tablet core, but bridges over leaving
a void under the coating) and ‘infilling’ (when too much coating material has
filled the detail making it indistinct) during film coating. Possible causes for
this can include:

 Inadequate adhesion of the film coating – the coating supplier should

be consulted to improve the adhesion characteristics of the coating.
 Inappropriate marking design where the angle may be too acute or too
deep (bridging) – the marking should be redesigned in consultation
with the tooling supplier. It can also be due to the stroke or section of
the embossing being too wide or too shallow (in-filling).
 Inappropriate coating procedure i.e. spray rate, drying time, etc – the
coating supplier should be consulted.

Another problem is twinning: tablets sticking together during coating. This is

normally caused by the flat surfaces of the tablets coming into contact and
adhering to each other. To avoid this a slightly curved surface can be applied,
which reduces the contact area and eliminates the potential for twinning.

2. Tablet break ability

Good tablet design will enable the tablet to be broken easily and accurately,
ensuring that when it is broken, the required tolerance for dosage is achieved.
Uneven breaking of a tablet may result in significant fluctuations in the
administered dose. The degree of inaccuracy may be associated with
breakline design, tablet hardness, and/or formulation (see Figure 1).

Figure 1: Various tablet breaklines/bisect type

The following factors should be considered when selecting a breakline:

 Accuracy of breakage, which is important for equal dosage.

 Holding of the tablet and ease of breakage. This relates to tablet size
and hardness.
 Inclusion of other detail such as a logo and its influence on the
breakline. Product identification must be maintained to ensure brand
integrity when the tablet is divided.
 Robustness of the tablet during compression, coating and packing,
because the tablet’s physical qualities are changed by adding a
breakline and it may become weaker.

The breakline should penetrate into the tablet while maintaining an optimised
radius and angle. A larger radius usually makes the breakline less effective.

Where a breakline is functional and present on both sides of the tablet,

alignment of the breakline on the upper and lower punch tips is critical and
requires the turret to have a lower key facility. Also attention should be paid to
breaklines that stand above the punch tip edge. Upper and lower punches
must be set correctly for effective tablet ejection and take-off. If not set
correctly damage can occur to the breakline on the punch tip, resulting in
catastrophic failure and damage to the tooling and the tablet press. It can also
cause severe chipping of the tablet on ejection.

3. Tooling performance

Tablets are becoming more complex and exotic in both shape and profile. As
the tablets become more complex so does the tooling, which increases the
demand for tooling strength, durability and overall performance. This should
be a major consideration when designing a tablet.

Figure 2 shows a stress and fatigue analysis of a punch tip using Finite
Element Analysis, or FEA – a software-based numerical technique for
calculating the strength and behaviour of engineering structures. It is used to
calculate deflection, stress and strain to determine fatigue limits of both
material and design.

Figure 2: A stress and fatigue analysis of a punch tip using Finite Element
Analysis

One of the most important features of any tablet design is the blended land.
Often, tablet manufacturers elect not to apply a land as it may not be visually
acceptable on the finished tablet. Lands that are applied incorrectly – either
unevenly or made too large – can present a range of issues including: flashing
or lamination during compression; chipping of the land during take-off; or
build-up of coating on the edge of the tablet which eventually will chip.

The answer is always to include a blended land as, when applied correctly, it
will optimise tablet and tooling strength and performance. Figure 3 shows the
application of a blended land to a punch tip. The correct method of applying
the land is to ensure that the flat area on the tip edge is maintained while
blending the intersection between the profile and the flat. This is achieved by
applying a radius to the finished punch tip. A correctly selected and applied
blended land provides benefits to handling, loading, setting, tooling strength,
the visual appearance of the tablet and, ultimately, the brand.
 Figure 3: Blended land

4. Tablet branding

When considering the visual appearance of the tablet, it is important to think

about the type of font and logos used for branding. Typefaces and designs
must take into account practicality of tablet manufacture.

Caution is also required during the design process when applying branding to
your tablet. Failure to consult with an expert tablet design team could result in
a product that looks good on paper but is not practical to produce.

For tablets with a logo, the design and placement are very important. The
tablet designer should always seek to maximise the face area to avoid picking
and lack of distinction. Figure 4 shows a good example of the importance of
spacing on logos. The top example clearly shows the embossing within the
safe zone for this particular tablet shape. The bottom example shows
embossing that goes beyond the safe zone and on the side view it can be
seen how the embossing protrudes.

Figure 4: The importance of spacing on logos

Occasionally, when the need to exceed the safe zone is required, the best
practice is to ensure the detail is spaced far enough away from the edge of
the tip. As a general guide the embossing should sit below the landed edge of
the punch tip. If this guide is not followed then the embossing will be
unprotected and prone to damage, causing further downstream problems
during the tableting process.
The correct font style is also very important to avoid tableting problems such
as ‘picking’. Picking is compressed granule that has adhered to the detail on
the punch face, resulting in ‘picking out’ of parts from the tablet face. To
reduce picking the best practice should be to design font styles that have
large open counters and no sharp corners that could act as a trap for granule.
Selection of the right font style can also help to avoid coating problems,
tooling failures and lack of distinction.

When the font has been chosen it is important to ensure clarity of definition.
The profile of the embossing is equally important to reduce picking, ensure
good tablet coating and tooling strength. The best practice is for the stroke
angle to be between 70 and 80 degrees. The stroke depth should be 50% of
the width and the stroke break radius blends 30% of the stroke depth (Figure
5).

Figure 5: Stroke angle

Another technique used to minimise picking is a reduced counter. The

counters, which are sometimes referred to as islands, are very vulnerable to
picking and granule can easily get trapped in these areas on the punch tip
face. The counter is modified to increase the surface area by reducing stroke
depth, which will minimise the tendency for the product to pick. A tapered
peninsula (Figure 6) can also be applied. The taper is applied to blend
between the surface of the tablet face and the stroke angle. This method
softens the profile, reducing the risk of powder being trapped in the shaded
areas shown in the image. This maintains definition without reducing the
overall stroke depth of the embossing and will assist in keeping a clear brand
identity.

‘Sticking’, of course, is another major issue in the design and manufacture of

tablets. Sticking differs from picking in that it is granule adherence to the
punch tip face, rather than in and around the embossing. This is not normally
associated with design, but when picking occurs on a tablet this in turn can
result in sticking on the punch tip face by providing a key to which further
granule will adhere.
 Figure 6: Tapered peninsulas

5. Anti-counterfeiting techniques

As counterfeiters become more technologically advanced, basic tablet

designs are more easily reproduced. There are many anticounterfeiting
technologies available to manufacturers. Within tablet manufacture, this is
usually achieved by applying anticounterfeit features directly to the tablet. An
expert tablet designer can employ techniques to make counterfeiting more
difficult. These are not always visible to the naked eye but ensure that a
branded tablet can be identified as an original.

Several anticounterfeiting techniques can be used on each

product to help reduce the risk

Several anticounterfeiting techniques can be used on each product to help

reduce the risk – for example, altering the thickness of the embossing in
places, changing the angle of the lettering, or simply having the logo on
different inclines. Although hard to see with the naked eye, expert tablet
designers can see the difference between the original and the counterfeit.

In conclusion, good tablet design is imperative, and it is something that should

be strongly considered. It is important to consult with an expert tablet designer
as early on in the process as possible, as they can ensure that tablet designs
are not only unique and visually appealing, but are also robust and producible
in a rigorous tablet manufacturing environment. Making just a few simple
changes to a design can stop future problems, from picking and sticking to
counterfeit issues.

The importance of design should not be underestimated. Punches and dies

are the most critical interface with the end product, the tablet, and together
everything should be measured and taken into account before tablet
production commences.