The equipment used for blending are:

 V- blender
 Double cone blender
 Ribbon blender
 Slant cone blender
 Bin blender
 Orbiting screw blenders vertical and horizontal high
intensity mixers.
SCALE UP CONSIDERATIONS
 Time of blending .
 Blender loading.
 Size of blender.
08 June 2009 SRTM University, NandedDept. of Pharmaceutics 1
 V – cone blender Double cone blender
08 June 2009 SRTM University, NandedDept. of Pharmaceutics 2
 Ribbon blender

08 June 2009 SRTM University, NandedDept. of Pharmaceutics 3

 Granulation
The most common reasons given to justify granulating
are:
1. To impart good flow properties to the material,
2. To increase the apparent density of the powders,
3. To change the particle size distribution,
4. Uniform dispersion of active ingredient.

Traditionally, wet granulation has been carried out using,

 Sigma blade mixer,
 Heavy-duty planetary mixer.
08 June 2009 SRTM University, NandedDept. of Pharmaceutics 4
 Sigma blade mixer Planetary mixer
08 June 2009 SRTM University, NandedDept. of Pharmaceutics 5
 Wet granulation can
also be prepared using
tumble blenders
equipped with high-
speed chopper blades.

08 June 2009 SRTM University, NandedDept. of Pharmaceutics 6

 More recently, the use of multifunctional “processors” that
are capable of performing all functions required to prepare
a finished granulation, such as dry blending, wet
granulation, drying, sizing and lubrication in a continuous
process in a single equipment.

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 Binders:

Used in tablet formulations to make powders more

compressible and to produce tablets that are more resistant
to breakage during handling.

In some instances the binding agent imparts viscosity to the

granulating solution so that transfer of fluid becomes
difficult.

This problem can be overcome by adding some or all

binding agents in the dry powder prior to granulation.
08 June 2009 SRTM University, NandedDept. of Pharmaceutics 8
 Some granulation, when prepared in production sized
equipment, take on a dough-like consistency and may
have to be subdivided to a more granular and porous mass
to facilitate drying.
This can be accomplished by passing the wet mass
through an oscillating type granulator with a suitably large
screen or a hammer mill with either a suitably large screen
or no screen at all.

08 June 2009 SRTM University, NandedDept. of Pharmaceutics 9

 Drying
The most common conventional method of drying a
granulation continues to be the circulating hot air oven,
which is heated by either steam or electricity.
The important factor to consider as part of scale-up of an
oven drying operation are airflow, air temperature, and the
depth of the granulation on the trays.
If the granulation bed is too deep or too dense, the drying
process will be inefficient, and if soluble dyes are involved,
migration of the dye to the surface of the granules.
Drying times at specified temperatures and airflow rates
must be established for each product, and for each particular
oven load.
08 June 2009 SRTM University, NandedDept. of Pharmaceutics 10
 Fluidized bed dryers are
an attractive alternative to
the circulating hot air
ovens.
The important factor
considered as part of scale
up fluidized bed dryer are
optimum loads, rate of
airflow, inlet air
temperature and humidity.

08 June 2009 SRTM University, NandedDept. of Pharmaceutics 11

 Reduction of Particle size
Compression factors that may be affected by the particle
size distribution are flowability, compressibility, uniformity
of tablet weight, content uniformity, tablet hardness, and
tablet color uniformity.
First step in this process is to determine the particle size
distribution of granulation using a series of “stacked” sieves
of decreasing mesh openings.
Particle size reduction of the dried granulation of production
size batches can be carried out by passing all the material
through an oscillating granulator, a hammer mill, a
mechanical sieving device, or in some cases, a screening
device.
08 June 2009 SRTM University, NandedDept. of Pharmaceutics 12
 Oscillating type granulator Hammer mill
08 June 2009 SRTM University, NandedDept. of Pharmaceutics 13
 Equipments used for mixing
Sigma blade mixer.
Planetary mixer.
Twin shell blender.
High shear mixer

08 June 2009 SRTM University, NandedDept. of Pharmaceutics 14

08 June 2009 SRTM University, NandedDept. of Pharmaceutics 15
08 June 2009 SRTM University, NandedDept. of Pharmaceutics 16
 Compression
The ultimate test of a tablet formulation and granulation
process is whether the granulation can be compressed on a
high-speed tablet press.

During compression, the tablet press performs the following

functions:
1. Filling of empty die cavity with granulation.
2. Precompression of granulation (optional).
3. Compression of granules.
4. Ejection of the tablet from the die cavity and take-off of
compressed tablet.
08 June 2009 SRTM University, NandedDept. of Pharmaceutics 17
 When evaluating the compression characteristics of a particular
formulation, prolonged trial runs at press speeds equal to that to
be used in normal production should be tried.
Only then are potential problems such as sticking to the punch
surface, tablet hardness, capping, and weight variation detected.
High-speed tablet compression depends on the ability of the
press to interact with granulation.
Following are the parameters to be considered while choosing
speed of press.
1. Granulation feed rate.
2. Delivery system should not change the particle size distribution.
3. System should not cause segregation of coarse and fine
particles, nor it should induce static charges.
08 June 2009 SRTM University, NandedDept. of Pharmaceutics 18
 The die feed system must be able to fill the die cavities
adequately in the short period of time that the die is
passing under the feed frame.
The smaller the tablet , the more difficult it is to get a
uniform fill a high press speeds.
For high-speed machines, induced die feed systems is
necessary.
These are available with a variety of feed paddles and
with variable speed capabilities.
So that optimum feed for every granulation can be
obtained.

08 June 2009 SRTM University, NandedDept. of Pharmaceutics 19

 After the die cavities are filled ,the excess is removed by the feed
frame to the center of the die table.
Compression of the granulation usually occurs as a single event
as the heads of the punches pass over the lower and under the
upper pressure rollers.
This cause the punches to the penetrate the die to a preset depth,
compacting the granulation to the thickness of the gap set
between the punches.
The rapidity and dwell time in between this press event occurs is
determined by the speed at which the press is rotating and by the
size of compression rollers.
Larger the compressions roller, the more gradually compression
force is applied and released.

08 June 2009 SRTM University, NandedDept. of Pharmaceutics 20

 Slowing down the press speed or using larger compression
rollers can often reduce capping in a formulation.
The final event is ejection of compressed tablets from die
cavity.
During compression, the granulation is compacted to form
tablet, bonds within compressible material must be formed
which results in sticking.
High level of lubricant or over blending can result in a soft
tablet, decrease in wettability of the powder and an
extension of the dissolution time.
Binding to die walls can also be overcome by designing the
die to be 0.001 to 0.005 inch wider at the upper portion than
at the center in order to relieve pressure during ejection.
08 June 2009 SRTM University, NandedDept. of Pharmaceutics 21
 DIFFERENT PUNCHES &DIES

08 June 2009 SRTM University, NandedDept. of Pharmaceutics 22

 HIGH SPEED ROTARY
MULTI ROTARY MACHINE
MACHINE

08 June 2009 SRTM University, NandedDept. of Pharmaceutics 23

 DOUBLE ROTARY
UPPER PUNCH AND
MACHINE
LOWER PUNCH

08 June 2009 SRTM University, NandedDept. of Pharmaceutics 24

 SINGLE ROTARY MACHINE

08 June 2009 SRTM University, NandedDept. of Pharmaceutics 25

 Tablet Coating
Sugar coating is carried out in conventional coating pans,
has undergone many changes because of new
developments in coating technology and changes in safety
and environmental regulations.
The conventional sugar coating pan has given way to
perforated pans or fluidized-bed coating columns.
The development of new polymeric materials has resulted
in a change from aqueous sugar coating and more recently,
to aqueous film coating.
The tablets must be sufficiently hard to withstand the
tumbling to which they are subjected in either the coating
pan or the coating column.
08 June 2009 SRTM University, NandedDept. of Pharmaceutics 26
 Some tablet core materials are naturally hydrophobic, and
in these cases, film coating with an aqueous system may
require special formulation of the tablet core and/or the
coating solution.
A film coating solution may have been found to work well
with a particular tablet in small lab coating pan but may be
totally unacceptable on a production scale.
This is because of increased pressure & abrasion to which
tablets are subjected when batch size is large & different
in temperature and humidity to which tablets are exposed
while coating and drying process.

08 June 2009 SRTM University, NandedDept. of Pharmaceutics 27

08 June 2009 SRTM University, NandedDept. of Pharmaceutics 28
 METHODS
DRY BLENDING WET DRY
GRANULATION GRANULATION

WEIGHING WEIGHING
WEIGHING
SIZING SIZING
SIZING
BLENDING GRANULATION
BLENDING
LUBRICATION DRYING
COMPACTION
COMPRESSION BLENDING
MILLING
COATING LUBRICATION
LUBRICATION
COMPRESSION
COMPRESSION

08 June 2009 SRTM University, NandedDept. of Pharmaceutics 29

 Compression rates of typical production
presses

08 June 2009 SRTM University, NandedDept. of Pharmaceutics 30

 Pilot Plant scale-up techniques
for Capsule
Capsules are solid dosage forms in which the drug substance
is enclosed in either a hard or soft soluble container or shell
of a suitable form of gelatin.
Steps in capsule production
1. Mixing of ingredient
2. Granulation and lubrication
3. Making of capsules
4. Filling of capsules
5. Uniformity testing
6. Packing and labeling
08 June 2009 SRTM University, NandedDept. of Pharmaceutics 31
 The manufacturing process for capsulated products often
same to that tablets.
Both tablets & capsules are produced from ingredients
that may be either dry blended or wet granulated to
produce a dry powder or granule mix with uniformly
dispersed active ingredients.
To produce capsules on high speed equipment ,the powder
blend must have the uniform particle size distribution,
bulk density & compressibility required to promote good
flow properties & result in the formation of compact of
the right size and sufficient cohesiveness to be filled in to
capsule shells.
08 June 2009 SRTM University, NandedDept. of Pharmaceutics 32
 Manufacture of Hard Gelatin
Capsules
1. Shell composition :
Gelatin :
 Prepared by the hydrolysis of collagen.
 Gelatin in its chemical and physical properties, depending
upon the source of the collagen and extraction.
 There are two basic types of gelatin:
Type – A and Type – B.
 The two types can be differentiated by their isoelectric
points (7.0 – 9.0 for type A and 4.8 – 5.0 for type B) and by
their viscosity and film forming characteristics.

08 June 2009 SRTM University, NandedDept. of Pharmaceutics 33

  Combination of pork skin and bone gelatin are often used
to optimize shell characteristics.
 The physicochemical properties of gelatin of most interest
to shell manufactures are the bloom strength and viscosity.

Colorants :
 Various soluble synthetic dyes (“coal tar dyes”) and
insoluble pigments are used.
 Not only play a role in identifying the product, but also
may play a role in improving patient compliance.
E.g., white, analgesia; lavender, hallucinogenic effects;
orange or yellow, stimulants and antidepressants.
08 June 2009 SRTM University, NandedDept. of Pharmaceutics 34
 Opaquing agents :
 Titanium dioxide may be included to render the shell
opaque.
 Opaque capsules may be employed to provide protection
against light or to conceal the contents.

Preservatives :
 When preservatives are employed, parabens are often
selected.

08 June 2009 SRTM University, NandedDept. of Pharmaceutics 35

 2) Shell manufacture :

08 June 2009 SRTM University, NandedDept. of Pharmaceutics 36

 I. Dipping :
 Pairs of the stainless steel pins are dipped into the dipping
solution to simultaneously form the caps and bodies.
 The pins are at ambient temperature; whereas the dipping
solution is maintained at a temperature of about 50 0C in a
heated, jacketed dipping pan.
 The length of time to cast the film has been reported to be
about 12 sec.
II. Rotation :
 After dipping, pins are elevated and rotated 2-1/2 times until
they are facing upward.
 This rotation helps to distribute the gelatin over the pins
uniformly and to avoid the formation of a bead at the capsule
ends.
08 June 2009 SRTM University, NandedDept. of Pharmaceutics 37
 III. Drying :
 The racks of gelatin coated pins then pass into a series
of four drying oven.
 Drying is mainly done by dehumidification.
 A temperature elevation of only a less degrees is
permissible to prevent film melting.
 Under drying will leave the films too sticky for
subsequent operation.
IV. Stripping :
 A series of bronze jaws strip the cap and body portions
of the capsules from the pins.

08 June 2009 SRTM University, NandedDept. of Pharmaceutics 38

 V. Trimming :
 The stripped cap and body portions are delivered to
collects in which they are firmly held.
 As the collects rotate, knives are brought against the
shells to trim them to the required length.
VI. Joining :
 The cap and body portions are aligned concentrically in
channels and the two portions are slowly pushed
together.

08 June 2009 SRTM University, NandedDept. of Pharmaceutics 39

 3) Sorting :
 The moisture content of the capsules as they are from the
machine will be in the range of 15 – 18% w/w.
 During sorting, the capsules passing on a lighted moving
conveyor are examined visually by inspectors.
 Defects are generally classified according to their nature
and potential to cause problems in use.
4) Printing :
 In general, capsules are printed before filling.
 Generally, printing is done on offset rotary presses
having throughput capabilities as high as three-quarter
million capsules per hour.
08 June 2009 SRTM University, NandedDept. of Pharmaceutics 40
 5) Sizes and shapes :
 For human use, empty gelatin capsules are
manufactured in eight sizes, ranging from 000 to 5.
 Capsule capacities in table:
Size Volume Fill weight(g) at 0.8
g/cm3 powder density
000 1.37 1.096
00 0.95 0.760
0 0.68 0.544
1 0.50 0.400
2 0.37 0.296
3 0.30 0.240
4 0.21 0.168
5 0.15 0.104
08 June 2009 SRTM University, NandedDept. of Pharmaceutics 41
  The largest size normally acceptable to patient is a No: 0.
 Three larger size are available for veterinary use: 10, 11,
and 12 having capacities of about 30, 15, and 7.5 g,
respectively.
 The standard shape of capsules is traditional, symmetrical
bullet shape.
 Some manufactures have employed distinctive shapes.
e.g. Lilly’s pulvule tapers to a bluntly pointed end.
Smith Kline Beacham’s spansule capsules taper at
both the cap and body ends.

08 June 2009 SRTM University, NandedDept. of Pharmaceutics 42

 6) Sealing :
 Capsules are sealed and somewhat reshaped in the
Etaseal process.
 This thermal welding process forms an indented ring
around the waist of the capsule where the cap overlaps
the body.
7) Storage :
 Finished capsules normally contain an equilibrium
moisture content of 13-16%.
 To maintain a relative humidity of 40-60% when
handling and storing capsules.

08 June 2009 SRTM University, NandedDept. of Pharmaceutics 43

 Filling of hard gelatin
capsules
Equipment used in capsule filling operations involves one
often of two types of filling systems.
Zanasi or Martelli encapsulator:
 Forms slugs in a dosatar which is a hollow tube with a
plunger to eject capsule plug.
Hofliger-Karg machine:
 Formation of compacts in a die plate using tamping pins
to form a compact.

08 June 2009 SRTM University, NandedDept. of Pharmaceutics 44

 ZANASI AUTOMATIC HOFLIGER KARG AUTOMATIC
CAPSULE FILLING MACHINE CAPSULE FILLING MACHINE

08 June 2009 SRTM University, NandedDept. of Pharmaceutics 45

 In this both system, the scale-up process involve bulk
density, powder flow, compressibility, and lubricant
distribution.
Overly lubricated granules are responsible for delaying
capsule disintegration and dissolution.

08 June 2009 SRTM University, NandedDept. of Pharmaceutics 46

 OSAKA MODEL R-180
SEMI AUTOMATIC CAPSULE
FILLING MACHINE

08 June 2009 SRTM University, NandedDept. of Pharmaceutics 47

 Manufacture of Soft Gelatin
Capsules
I. Composition of the shell:
 Similar to hard gelatin shells, the basic component of
soft gelatin shell is gelatin; however, the shell has been
plasticized.
 The ratio of dry plasticizer to dry gelatin determines the
“hardness” of the shell and can vary from 0.3-1.0 for
very hard shell to 1.0-1.8 for very soft shell.
 Up to 5% sugar may be included to give a “chewable”
quality to the shell.
 The residual shell moisture content of finished capsules
will be in the range of 6-10%.
08 June 2009 SRTM University, NandedDept. of Pharmaceutics 48
 II. Formulation :
 Formulation for soft gelatin capsules involves liquid,
rather than powder technology.
 Materials are generally formulated to produce the
smallest possible capsule consistent with maximum
stability, therapeutic effectiveness and manufacture
efficiency.
 The liquids are limited to those that do not have an
adverse effect on gelatin walls.
 The pH of the lipid can be between 2.5 and 7.5.
 Emulsion can not be filled because water will be
released that will affect the shell.
08 June 2009 SRTM University, NandedDept. of Pharmaceutics 49
 The types of vehicles used in soft gelatin capsules fall in
to two main groups:
1. Water immiscible, volatile or more likely more volatile
liquids such as vegetable oils, mineral oils, medium-chain
triglycerides and acetylated glycerides.
2. Water miscible, nonvolatile liquids such as low molecular
weight PEG have come in to use more recently because
of their ability to mix with water readily and accelerate
dissolution of dissolved or suspended drugs.
 All liquids used for filling must flow by gravity at a
temperature of 350c or less.
 The sealing temperature of gelatin films is 37-400C.

08 June 2009 SRTM University, NandedDept. of Pharmaceutics 50

 III. Manufacture process :
A. Plate process :
The process involved
 Placing the upper half of a plasticized gelatin sheet
over a die plate containing numerous die pockets,
 Application of vacuum to draw the sheet in to the die
pockets,
 Filling the pockets with liquor or paste,
 Folding the lower half of gelatin sheet back over the
filled pockets, and
 Inserting the “ sandwich” under a die press where the
capsules are formed and cut out.
08 June 2009 SRTM University, NandedDept. of Pharmaceutics 51
 B. Rotary die press:
 In this process, the die cavities are machined in to the
outer surface of the two rollers.
 The die pockets on the left hand roller form the left side
of the capsule and the die pockets on the right hand
roller form the right side of the capsule.
 Two plasticized gelatin ribbons are continuously and
simultaneously fed with the liquid or paste fill between
the rollers of the rotary die mechanism.
 As the die rolls rotate, the convergence of the matching
die pockets seals and cuts out the filled capsules.

08 June 2009 SRTM University, NandedDept. of Pharmaceutics 52

08 June 2009 SRTM University, NandedDept. of Pharmaceutics 53
 C. Accogel process:
 In general, this is another rotary process involving
 A measuring roll,
 A die roll, and
 A sealing roll.
 As the measuring roll and die rolls rotate, the measured
doses are transferred to the gelatin-linked pockets of the
die roll.
 The continued rotation of the filled die converges with
the rotating sealing roll where a second gelatin sheet is
applied to form the other half of the capsule.
 Pressure developed between the die roll and sealing roll
seals and cuts out the capsules.
08 June 2009 SRTM University, NandedDept. of Pharmaceutics 54
 4. Bubble method:
 The Globex Mark II capsulator produces truly seamless,
one-piece soft gelatin capsules by a “bubble method”.

08 June 2009 SRTM University, NandedDept. of Pharmaceutics 55

  A concentric tube dispenser simultaneously discharges
the molten gelatin from the outer annulus and the liquid
content from the tube.
 By means of a pulsating pump mechanism, the liquids
are discharged from the concentric tube orifice into a
chilled-oil column as droplets that consists of a liquid
medicament core within a molten gelatin envelop.
 The droplets assume a spherical shape under surface
tension forces and the gelatin congeals on cooling.
 The finished capsules must be degreased and dried.

08 June 2009 SRTM University, NandedDept. of Pharmaceutics 56

 IV. Soft/Liquid-filled hard gelatin capsules:
 Important reason: the standard for liquid filled capsules
was inability to prevent leakage from hard gelatin
capsules.
 As banding and of self-locking hard gelatin capsules,
together with the development of high-resting state
viscosity fills, has now made liquid/semisolid-filled
hard gelatin capsules.
 As with soft gelatin capsules, any materials filled into
hard capsules must not dissolve, alter or otherwise
adversely affect the integrity of the shell.
 Generally, the fill material must be pumpable.
08 June 2009 SRTM University, NandedDept. of Pharmaceutics 57
  Three formulation strategies based on having a high
resting viscosity after filling have been described.
1. Thixotropic formulations,

2. Thermal-setting formulations,

3. Mixed thermal-Thixotropic systems.

 The more lipophilic contents, the slower the release rate.

 Thus, by selecting excipients with varying HLB balance,

varying release rate may be achieved.

08 June 2009 SRTM University, NandedDept. of Pharmaceutics 58

 CAPSULE AUTO MATIC
POLISHING CAPSULE
MACHINE ARRANGEMNT

08 June 2009 SRTM University, NandedDept. of Pharmaceutics 59

 References
1. The theory and practice of industrial pharmacy. Leon
Lachman, Herbert A. Lieberman, Joseph L. Kanig. Third
edition. Varghese publishing house. Page no. 681-703.
2. Pharmaceutical dosage forms: Tablets. Volume 3. second
edition. Leon Lachman, Herbert A. Lieberman, Joseph B.
Schwartz. Page no. 303-365.
3. Pharmaceutical process scale –up edited by Michael
Levin.
4. Modern pharmaceutics. Edited by Gilbert S. Banker &
Christopher T. Rhodes. 4th edition.
5. www.google.com
08 June 2009 SRTM University, NandedDept. of Pharmaceutics 60
 E-mail: bknanjwade@yahoo.co.in
Cell No: 09742431000

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Dept. University,
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NandedDept. of Pharmaceutics 61