Transcript Document 7299529

Nahla Barakat, PhD
King Saud University
Dept. of Pharmaceutics
1431/1432
5/22/2016
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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.
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Compressed tablet
Uncoated tablet
Coated tablet
A tablet prepared, usually as a large-scale production, by means
of great pressure; most compressed tablet's consist of the active
ingredient and a diluent, binder, disintegrator, and lubricant.
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Tablet tooling; punches and dies
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Caplet Shape Dies
Star Shapes Dies
Oval Shapes Dies
Round Shapes Dies
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Tablet production
Powders intended for compression into tablets must
possess two essential properties:
1- Powder fluidity
The material can be transported through the hopper
into the die to produce tablets of a consistent weight
 Powder flow can be improved mechanically by
incorporate the glidant
2- Powder compressibility
The property of forming a stable, intact compact
mass when pressure is applied
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Tablet Manufacturing
Tablet Compression Machine
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Design:
1. Hopper for holding and feeding granules or powder to be
compressed.
2. Dies that define the size and shape of the tablet.
3. Punches for compressing the granules within the dies.
4. Cam tracks for guiding the movement of the punches.
5. A feeding mechanism for moving granules from the
hopper into the dies.
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Stages of Tablet Formation (Compaction Cycle)
1- Die filling
Gravitational flow of the powder from hopper via the die
table into the die . (The die is closed at its lower end by the
lower punch).
2- Tablet formation
The upper punch descends, enters the die, the powder is
compressed until a tablet is formed.
-after maximum applied force is reached, the upper punch
leaves the powder i.e. compression phase.
3- Tablet ejection
The lower punch rises until its tip reaches the level of the
top of the die.
The tablet is subsequently removed from the die and die
table by a pushing device.
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Tabletting Process
• Basics
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powders fed into a die
Powder compressed between punches
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Tablet press
Single Punch press (Eccentric Press):
bench-top models that make one tablet at a time
(single-station presses)
Disadvantages: Production of small batches of tablets
(200 tablets per minute).
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2- Rotary Press( Multi station Press):
• It was developed to increase the output of tablets (10 000
tablets per minute), used for Large scale production.
• It consists of a number of dies and sets of punches ( from 3 up
to 60).
• The dies are mounted in a circle in the die table and both the
die table & the punches rotate together during operation of the
machine.
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Rotary Press Machine
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The term “direct compression” is defined as the process by which tablets
are compressed directly from powder mixture of API and suitable
excipients.
 It involves only two unite operations powder mixing and tabletting.
Advantages of Direct Compaction:
 Reduced production time &cost.
 product stability can be improved.
 Faster drug dissolution due to fast disintegration into primary particles.
 less number of equipments are required, less process validation
 Elimination of heat and moisture, thus increasing not only the stability but
also the suitability of the process for thermolabile and moisture sensitive
API’s.
 The chances of batch-to-batch variation are negligible, because the unit
operations required for manufacturing processes is fewer.
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Disadvantages of Direct Compaction
1. Large particles must be used → (acceptable flowability and
bulk density)
2. Many active ingredients are not compressible either in
crystalline or amorphous forms.
3. Needs directly compressible filler that is usually expensive,
e.g. microcrystalline cellulose (Avicel), spray dried lactose
4. Problems in the uniform distribution of low dose drugs.
5. High dose drugs having high bulk volume, poor flowability
and poor compressibility
are not suitable for direct
compression. For example, Aluminium Hydroxide, Magnesium
Hydroxide
6 . Non-uniform distribution of colour, especially in tablets of
deep colours
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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;
during this step, the weight of each ingredient in the mixture is determined
according to dose.
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.
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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.
Advantages associated with size reduction in tablet manufacture are as
follows:
i) It increases surface area, which may enhance an actives 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) Improved flow properties of raw materials.
iv) Improved colour and/or active ingredient dispersion in tablet excipients.
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Powder blending
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 various blenders used include blender, Oblicone blender, Container
blender, Tumbling blender, Agitated powder blender, etc.
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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.
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Tablet compression
After the preparation 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.
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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 weightit 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
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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.
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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.
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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.
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Wet Granulation
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In the pharmaceutical industry, granulation refers to the act or process in
which primary powder particles are made to adhere to form larger,
multiparticle entities called granules.
It is the process of collecting particles together by creating bonds between
them.
Bonds are formed by compression or by using a binding agent.
Granulation is extensively used in for the manufacturing of tablets, pellets
(or spheroids).
The granulation process combines one or more powders and forms a
granule that will allow tableting or spheronization process to be within
required limits.
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Granulation is carried out for various reasons, one of those is
to prevent the segregation of the constituents of powder mix.
Segregation is due to differences in the size or density of the
component of the mix.
Normally, the smaller and/or denser particles tend to
concentrate at the base of the container with the larger and/or
less dense ones on the top
An ideal granulation will contain all the constituents of the
mix in the correct proportion in each granule and segregation
of granules will not occur.
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Some powders are difficult to compact even if a readily
compactable adhesive is included in the mix,
but granules of the same powders are often more easily
compacted.
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Wet Granulation
A process of size enlarging a mix of active ingredient and excipient powder
particles into stable aggregates exhibiting desired
properties of:
Compressibility
Cohesiveness
Flowability
Bulk density
Granules may be a final product or an intermediate product that needs
further processing
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It involves massing of a mix of dry primary powder particles
using a granulating fluid.
• The fluid contain a solvent that must be volatile and non-toxic
e.g water, or organic solvent.
• The granulating solvent may contain a binding agent to
ensure particle adhesion after drying.
• Povidone, which is a polyvinyl pyrrolidone (PVP), is one of the
most commonly used pharmaceutical binders.
PVP is dissolved in water or solvent and added to the process.
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Typical liquids include:
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1.water : may adversely affect drug stability, causing
hydrolysis ,it needs a longer drying time. This increases the
length of the process. The advantage :non-flammable and
economic.
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2.Ethanol, Isopropanol ,or combination (organic solvents)
used with water sensitive drugs ,alternative to dry granulation
or when rapid drying time is required.
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The moist mass is broken up into coarse, granular aggregates (using
screens with large perforations).
• The purpose is to increase surface area to facilitate removal of moisture.
• Mixing with other tablet excipients
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(lubricant, glidant, remaining of disintegrant) and then compaction.
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Production via Wet Granulation:
Process description:
• Agitation of a powder in the presence of a liquid.
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• It forms the granules by binding the powders together with an adhesive.
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• Once the granulating liquid has been added, mixing continues until
uniform dispersion is attained (15 min. to an hour).
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Product characteristics
Dust free
Good flow behaviour
Easy to dose
Good dispersibility
Good solubility
Highly suitable for making into tablets
Compact structure
Low hygroscopicity
High bulk density
Wide grain size distribution
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Drying process
• A process of evaporating the liquid contained within
aggregates produced by a wet granulation process to a
predetermined moisture content
• Accomplished via
 1. Tray dryer (direct contact with heating medium)
 2. Fluidized bed dryer (indirect contact of the product with
the heating medium
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Single Step Technology for Wet Granulation
• Single machines utilized for both the
wet granulation and drying process in one unit
operation.
• Use Fluid Bed Dryer (FBD)
• It is a multiple step process performed
in the same vessel to mix, granulate and
dry the powders.
• Combines wetting the powders to
for granules &then, dryingthem in the
same piece of equipment.
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Advantages of
FBD
A. Reduced product handling
 B. Closed process suitable to:
 Gentle product handling.
 Intensive mixing of the solid material.
 Uniform spraying of all particles in the fluid bed.
 Uniform, reproducible product quality.
 Potent compounds
 Minimizing product/operator exposure
 Minimizing cross contamination and product loss
 Reduced cleaning and overall process time
 Reduced equipment and floor space requirements
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Fluid bed dryer
Tray dryer
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Dry Granulation
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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.
In this process the primary powder particles are aggregated under high
pressure.
Dry granulation can be conducted under two processes; either a large tablet
(slug) is produced in a heavy duty tabletting press or the powder is
squeezed between two rollers to produce a sheet of materials (roller
compactor, commonly referred to as a chilsonator).
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Tablet Produced by Compression Granulation (Dry Granulation)
• Advantage:
(1) avoid exposure of the powder to moisture and heat.
(2) Used for powders of very low bulk density to ↑ their bulk
density.
• Disadvantages:
– Tablet disintegration and dissolution may be retarded due to
double lubrication and compaction
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Methods of dry granulation
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A. Slugging technique
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B. Roller compaction technique
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Steps of Dry Granulation:
• The blend of finely divided powders is forced into the
dies of a large capacity tablet press.
• Then, compacted by means of flat faced punches
(Compacted masses are called slugs and the process is
slugging) or roll
compactor to produce sticks or sheets.
• Slugs or sheets are then milled/screened
to produce granules (flow more than the original
powder mixture).
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Dry granulation
Direct compression
Drug
Diluent
Glidant
disintegrant
Mixing
Drug
Diluent
Lubricant
Wet granulation
Mixing
compression
comminution
Drug
Diluent
Binder
solvent
Mixing
Wetting
granulation
Drying
lubricant
Mixing
Disintegrant
Glidant
Lubricant
screening
Mixing
Disintegrant
Glidant
lubricant
Screening
Mixing
Compression Mix
Fill die, Compress tablet, Eject
tablet
Metal check, dedusting, coating,
package
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WET granulation
DRY granulation
Direct compression
Milling and mixing of drugs and
excipients
Milling and mixing of drugs
and excipients
Milling and mixing of
drugs and excipients
Preparation of binder solution
Compression into slugs or roll Compression of tablet
compaction
Wet massing by addition of binder
solution or granulating solvent
Milling and screening of slugs
and compacted powder
Screening of wet mass
Mixing with lubricant and
disintegrant
Drying of the wet granules
Compression of tablet
Screening of dry granules
Blending with lubricant and
disintegrant to produce •
Compression of tablet
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Sources of Tablet Defects :
Sources of Tablet Defects
Moisture
Improper drying
High speed machines
Tools setting problem
Excess use of binders
Lack of proper lubricant selection
Air interaction
Lack of knowledge
Improper training
Abnormal ratio of excipients
Temperature adjustment
Size, shape
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1. Binding
2.Sticking,
Picking and Filming
3.Capping
4.Lamination PROCESSING PROBLEMS
5.Chipping
6.Mottling
7.Weight Variation
8.Poor flow
9. Hardness variation
10.Double impression
11.Cracking
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Binding:
It is the adhesion of the granules to the die wall and this cause
the resistance of the tablet to eject from the die, it is usually due
to insufficient lubrication, which produce tablets with rough and
vertical score marks on the edges.
Can be improved by:
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1. Increasing lubrication.
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2. Improve lubricant distribution.
3. Increasing the moisture content of the granulation
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Sticking, Picking & Filming:
Adhesion of the material to the punch faces.
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Sticking : (whole adhesion)
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is usually due to improperly dried or lubricated granulation causing the
whole tablet surface to stick to the punch faces → dull, scratched, or
rough tablet faces.
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Picking : (localized adhesion)
is a form of sticking in which a small portion of granulation sticks to
the punch face & a portion of the tablet surface is missed.
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Filming: is a slow form of sticking and is largely due to excess moisture in
the granulation
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Capping & Laminating:
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Capping occurs when the upper segment of the
tablet separates from the main portion of the tablet &
comes off as a cap.
Most annoying problem
Can appear immediately after compression, or hours, even days after
preparation.
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It is usually due to air entrapped
in the granulation which is compressed
in the die during the compression & then expands when the pressure is
released.
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Reasons of capping :
1. large amount of fines in the granulation &/or the lack of sufficient
clearance between the punch and the die wall.
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2. In new punches and dies that are tight fitting.
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3. Too dry granules.
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Lamination is due to the same causes as capping except that the tablet
splits at the sides into two or more parts.
If tablets laminate only at certain stations, the tooling is usually the cause.
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Solutions for capping & laminating:
1. Increasing the binder.
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2. Adding dry binder such as gum acacia polyvinylpyrrolidone (PVP).
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3.Decreasing the upper punch diameter.
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4. Certain degree of moisture in the granules
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4. Mottling:
It is an unequal distribution of color on the surface of the tablet.
Cause :
1. A drug that differs in color from its excipients or whose degradation
products are highly colored.
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2. Migration of a dye during drying of a granulation (change the solvent
system, reduce the drying temperature, or grind to a smaller particle
size).
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