Operations involved in tablet manufacturing | dotty

1.7.1 Introduction

The manufacture of oral solid dosage
forms such as tablets is a complex multi-stage process under which the starting
materials change their physical characteristics a number of times before the
final dosage form is produced.

Traditionally, tablets have been made by granulation, a
process that imparts two primary requisites to formulate: compactibility and
fluidity. Both wet granulation and dry granulation (slugging and roll
compaction) are used. Regardless of weather tablets are made by direct
compression or granulation, the first step, milling and mixing, is the same;
subsequent step differ.

Numerous unit processes are involved in making tablets, including
particle size reduction and sizing, blending, granulation, drying, compaction,
and (frequently) coating. Various factors associated with these processes can
seriously affect content uniformity, bioavailability, or stability.

Figure.20. Various Unit Operation Sequences In Tablet Manufacturing

Figure.21. Typical Manufacturing Process Of Tablet

Table.22. Typical Unit Operation Involved In Wet Granulation, Dry Granulation And Direct Compression(13)

WET GRANULATION	DRY GRANULATION		DIRECT COMPRESSION
1. Milling and mixing of drugs and excipients	1. Milling and mixing of drugs and excipients	1. Milling and mixing of drugs and excipients
2. Preparation of binder solution	2. Compression into slugs or roll compaction	2. Compression of tablet
3. Wet massing by addition of binder solution or granulating solvent	3. Milling and screening of slugs and compacted powder
4. Screening of wet mass	4. Mixing with lubricant and disintegrant
5. Drying of the wet granules	5. Compression of tablet
6. Screening of dry granules
7. Blending with lubricant and disintegrant to produce “running powder”
8. Compression of tablet

1.7.2 Dispensing (weighing and measuring)

Dispensing is the first step in any
pharmaceutical manufacturing process. Dispensing is one of the most critical
steps in pharmaceutical manufacturing; as during this step, the weight of each
ingredient in the mixture is determined according to dose.

Dispensing may be done by purely manual
by hand scooping from primary containers and weighing each ingredient by hand
on a weigh scale, manual weighing with material lifting assistance like Vacuum
transfer and Bag lifters, manual or assisted transfer with automated weighing
on weigh table, manual or assisted filling of loss-in weight dispensing system,
automated dispensaries with mechanical devices such as vacuum loading system
and screw feed system.

Issues like
weighing accuracy, dust control (laminar air flow booths, glove boxes), during
manual handling, lot control of each ingredient, material movement into and out
of dispensary should be considered during dispensing.

1.7.3 Sizing

The sizing (size reduction, milling, crushing, grinding,
pulverization) is an impotent step (unit operation) involved in the tablet
manufacturing.

In manufacturing of compressed tablet, the mixing or blending of several solid
ingredients of pharmaceuticals is easier and more uniform if the ingredients
are approximately of same size. This provides a greater uniformity of dose. A
fine particle size is essential in case of lubricant mixing with granules for
its proper function.

Advantages associated with size reduction in tablet
manufacture are as follows:

i) It increases surface area, which may enhance an active ingredient’s dissolution
rate and hence bioavailability.

ii)Improved the tablet-to-tablet content uniformity by virtue of the increased number of
particles per unit weight.

iii)Controlled particle size distribution of dry granulation or mix to promote better flow of
mixture in tablet machine.

iv)Improved flow properties of raw materials.

v)Improved colour and/or active ingredient dispersion in tablet excipients.

vi)Uniformly sized wet granulation to promote uniform drying.

There are also certain disadvantages associated with this unit operation if not
controlled properly. They are as follows:

i)A possible change in polymorphic form of the active ingredient, rendering it less
or totally inactive, or unstable.

ii) A decrease in bulk density of active compound and/or excipients, which may cause
flow problem and segregation in the mix.

iii)An increase in surface area from size reduction may promote the adsorption of air, which may
inhibit wettability of the drug to the extent that it becomes the limiting
factor in dissolution rate.

A number of different types of machine
may be used for the dry sizing or milling process depending on whether gentle screening
or particle milling is needed. The
ranges of equipment employed for this process includes Fluid energy mill,
Colloidal mill, Ball mill, Hammer mill, Cutting mill, Roller mill, Conical
mill, etc.

1.7.4 Powder blending

The successful mixing of powder is acknowledged to be more
difficult unit operation because, unlike the situation with liquid, perfect
homogeneity is practically unattainable.

In practice, problems also arise because of the inherent cohesiveness and
resistance to movement between the individual particles. The process is further
complicated in many system, by the presence of substantial segregation
influencing the powder mix. They arise because of difference in size, shape,
and density of the component particles.

The powder/granules blending
are involved at stage of pre granulation and/or post granulation stage of
tablet manufacturing. Each process of mixing has optimum mixing time and so
prolonged mixing may result in an undesired product. So, the optimum mixing
time and mixing speed are to be evaluated. Blending step prior to compression
is normally achieved in a simple tumble blender. The Blender may be a fixed
blender into which the powders are charged, blended and discharged. It is now
common to use a bin blender which blends.

In special cases of mixing a lubricant, over mixing should
be particularly monitered.

The various blenders used include “V”
blender, Oblicone blender, Container blender, Tumbling blender, Agitated powder
blender, etc.

But now a days to
optimize the manufacturing process particularly in wet granulation the various
improved equipments which combines several of processing steps (mixing,
granulation and/or drying) are used. They are “Mixer granulator” or “High shear
mixing machine”.

1.7.5 Granulation

Following particle size reduction and
blending, the formulation may be granulated, which provides homogeneity of drug
distribution in blend.

1.7.6 Drying

Drying is a most important step in the formulation and
development of pharmaceutical product. It is important to keep the residual
moisture low enough to prevent product deterioration and ensure free flowing
properties.

The commonly used dryer includes Fluidized – bed dryer,
Vacuum tray dryer, Microwave dryer, Spray dryer, Freeze dryer, Turbo - tray
dryer, Pan dryer, etc.

1.7.7 Tablet compression

After the preparation of granules (in case of wet
granulation) or sized slugs (in case of dry granulation) or mixing of
ingredients (in case of direct compression), they are compressed to get final
product. The compression is done either by single punch machine (stamping
press) or by multi station machine (rotary press).

The tablet press
is a high-speed mechanical device. It 'squeezes' the ingredients into the
required tablet shape with extreme precision. It can make the tablet in many
shapes, although they are usually round or oval. Also, it can press the name of
the manufacturer or the product into the top of the tablet.

Each tablet is made by
pressing the granules inside a die, made up of hardened steel. The die is a
disc shape with a hole cut through its centre. The powder is compressed in the
centre of the die by two hardened steel punches that fit into the top and
bottom of the die.

The punches and dies are fixed to a turret that spins round.
As it spins, the punches are driven together by two fixed cams - an upper cam
and lower cam. The top of the upper punch (the punch head) sits on the upper
cam edge .The bottom of the lower punch sits on the lower cam edge.

The shapes of the two cams
determine the sequence of movements of the two punches. This sequence is
repeated over and over because the turret is spinning round.

The force exerted on the ingredients in the dies is very
carefully controlled. This ensures that each tablet is perfectly formed. Because
of the high speeds, they need very sophisticated lubrication systems. The
lubricating oil is recycled and filtered to ensure a continuous supply.

Common stages occurring during compression

Stage 1: Top punch is withdrawn from the die
by the upper cam

Bottom punch is low in the die so powder falls in through the hole and fills the die

Stage 2: Bottom punch moves up to adjust the powder
weight-it raises and expels some powder

Stage 3: Top punch is driven into the die by upper cam

Bottom punch is raised by lower cam

Both punch heads pass between heavy rollers to compress the powder

Stage 4: Top punch is withdraw by the upper cam

Lower punch is pushed up and expels the tablet

Tablet is removed from the die surface by surface plate

Stage 5: Return to stage 1

Figure.22. Stage Occurring During Compression

1.7.8 Auxiliary Equipments ⁽¹⁾

I. Granulation Feeding Device:

In many cases, speed of die table is such that the time of
die under feed frame is too short to allow adequate or consistent gravity
filling of die with granules, resulting in weight variation and content
uniformity. These also seen with poorly flowing granules. To avoid these
problems, mechanized feeder can employ to force granules into die cavity.

II.Tablet weight monitoring devices:-

High rate of tablet output with
modern press requires continuous tablet weight monitoring with electronic
monitoring devices like Thomas Tablet Sentinel,
Pharmakontroll and Killan control System-MC. They monitors force at each
compression station by starin gage technology which is then correlated with
tablet weight.

III. Tablet Deduster : -

In almost all cases, tablets coming out of a tablet machine
bear excess powder on its surface and are run through the tablet deduster to
remove that excess powder.

IV. Fette machine

Fette machine is device that chills the compression
components to allow the compression of low melting point substance such as
waxes and thereby making it possible to compress product with low meting
points.

1.7.9 Packaging

Pharmaceutical
manufacturers have to pack their medicines before they can be sent out for
distribution. The type of packaging will depend on the formulation of the
medicine.

'Blister packs' are a common
form of packaging used for a wide variety of products. They are safe and easy
to use and they allow the consumer to see the contents without opening the
pack. Many pharmaceutical companies use a standard size of blister pack. This
saves the cost of different tools and to change the production machinery
between products. Sometimes the pack may be perforated so that individual tablets
can be detached. This means that the expiry date and the name of the product
have to be printed on each part of the package. The blister pack itself must
remain absolutely flat as it travels through the packaging processes,
especially when it is inserted into a carton. This poses interesting problems
for the designers. Extra ribs are added to the blister pack to improve its
stiffness.

Key Phrases

The manufacturing of tablet involves numerous unit
processes including

ØParticle size reduction and sizing

ØBlending

ØGranulation

ØDrying,compaction

ØCoating.