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By

Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D


CONTENTS
Introduction

Objectives of the Pilot Plant

Reasons for pilot plant

Significance of pilot plant

Importance of the Pilot Plant

Pilot plant design for tablets

Pilot plant scale-up techniques for capsules

References
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Introduction
What is Pilot plant :
Defined as a part of the pharmaceutical
industry where a lab scale formula is transformed into a viable
product by the development of liable practical procedure for
manufacture.

R&D Production

Pilot Plant

Scale-up :
The art of designing of prototype using the data
obtained from the pilot plant model.
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Objectives of Pilot Plant
Find mistakes on small scale and make profit on
large scale.
To produce physically and chemically stable therapeutic
dosage forms.
Review of the processing equipment.
Guidelines for productions and process control.
Evaluation and validation.
To identify the critical features of the process.
To provide master manufacturing formula.

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REASONS FOR BUILDING A PILOT PLANT

To evaluate on process of large change in scale up


operation.
To find and examine all by-products or waste .
To produce a trail lot of quantities of material.
Clinical studies ,analytical development ,process
development, stability testing.

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SIGNIFICANCE OF PILOT PLANT
Examination of formulae.
Review of range of relevant processing equipments.
production rate adjustment.
Idea about physical space required.
Appropriate records and reports to support GMP.
Identification of critical features to maintain quality.

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Importance of Pilot Plant
Examination of formulae.

Review of range of relevant processing equipments.

The specification of the raw materials.

Production rates.

The physical space required.

Appropriate records and reports to support GMP.

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Pilot Plant design for Tablets
The primary responsibility of the pilot plant staff is to
ensure that the newly formulated tablets developed by
product development personnel will prove to be
efficiently, economically, and consistently reproducible on
a production scale.
The design and construction of the pharmaceutical pilot
plant for tablet development should incorporate features
necessary to facilitate maintenance and cleanliness.
If possible, it should be located on the ground floor to
expedite the delivery and shipment of supplies.

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Extraneous and microbiological contamination must be
guarded against by incorporating the following features in the
pilot plant design:
1. Fluorescent lighting fixtures should be the ceiling flush
type.
2. The various operating areas should have floor drains to
simplify cleaning.
3. The area should be air-conditioned and humidity controlled.
4. High -density concrete floors should be installed.
5. The walls in the processing and packaging areas should be
enamel cement finish on concrete.
6. Equipment in the pharmaceutical pilot plant should be
similar to that used by production division- manufacture of
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2009 SRTM University, NandedDept. of Pharmaceutics 9
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Material handling system
In the laboratory, materials are simply scooped or poured by
hand, but in intermediate- or large-scale operations,
handling of this materials often become necessary.
If a system is used to transfer materials for more than one
product steps must be taken to prevent cross contamination.
Any material handling system must deliver the accurate
amount of the ingredient to the destination.
The type of system selected also depends on the
characteristics of the materials.
More sophisticated methods of handling materials such as
vacuum loading systems, metering pumps, screw feed
system.
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Vacuum loading machine
08 June 2009 SRTM University, NandedDept. of Pharmaceutics 13
Dry Blending
Powders to be used for encapsulation or to be granulated
must be well blended to ensure good drug distribution.
Inadequate blending at this stage could result in discrete
portion of the batch being either high or low in potency.
Steps should also be taken to ensure that all the
ingredients are free of lumps and agglomerates.
For these reasons, screening and/or milling of the
ingredients usually makes the process more reliable and
reproducible.

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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.
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V cone blender Double cone blender
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Ribbon blender

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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.
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Sigma blade mixer Planetary mixer
08 June 2009 SRTM University, NandedDept. of Pharmaceutics 19
Wet granulation can
also be prepared using
tumble blenders
equipped with high-
speed chopper blades.

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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.
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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.

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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.
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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.

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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.
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Oscillating type granulator Hammer mill
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As part of the scale-up of a milling or sieving operation,
the lubricants and glidants, which in the laboratory are
usually added directly to the final blend, are usually added
to the dried granulation during the sizing operation.

This is done because some of these additives, especially


magnesium stearate, tend to agglomerate when added in
large quantities to the granulation in a blender.

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Blending
Type of blending equipment often differs from that using
in laboratory.
In any blending operation, both segregation and mixing
occur simultaneously are a function of particle size, shape,
hardness, and density, and of the dynamics of the mixing
action.
Particle abrasion is more likely to occur when high-shear
mixers with spiral screws or blades are used.
When a low dose active ingredient is to be blended it may
be sandwiched between two portions of directly
compressible excipients to avoid loss to the surface of the
blender.
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Equipments used for mixing
Sigma blade mixer.
Planetary mixer.
Twin shell blender.
High shear mixer

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Slugging (Dry Granulation)
A dry powder blend that cannot be directly compressed because
of poor flow or compression properties.
This is done on a tablet press designed for slugging, which
operates at pressures of about 15 tons, compared with a normal
tablet press, which operates at pressure of 4 tons or less.
Slugs range in diameter from 1 inch, for the more easily
slugged material, to inch in diameter for materials that are
more difficult to compress and require more pressure per unit
area to yield satisfactory compacts.
If an excessive amount of fine powder is generated during the
milling operation the material must be screened & fines
recycled through the slugging operation.
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Dry Compaction
Granulation by dry compaction can also be achieved by passing
powders between two rollers that compact the material at
pressure of up to 10 tons per linear inch.
Materials of very low density require roller compaction to
achieve a bulk density sufficient to allow encapsulation or
compression.
One of the best examples of this process is the densification of
aluminum hydroxide.
Pilot plant personnel should determine whether the final drug
blend or the active ingredient could be more efficiently
processed in this manner than by conventional processing in
order to produce a granulation with the required tabletting or
encapsulation properties.
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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.
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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
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should induce static charges.
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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.

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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.

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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.
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DIFFERENT PUNCHES &DIES

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HIGH SPEED ROTARY
MULTI ROTARY MACHINE
MACHINE

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DOUBLE ROTARY
UPPER PUNCH AND
MACHINE
LOWER PUNCH

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SINGLE ROTARY MACHINE

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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.
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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.

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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

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Compression rates of typical production
presses

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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
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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.
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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.
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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.
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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.

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2) Shell manufacture :

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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 500C 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.SRTM University, NandedDept. of Pharmaceutics
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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.

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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.

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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.
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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
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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. Lillys pulvule tapers to a bluntly pointed end.
Smith Kline Beachams spansule capsules taper at
both the cap and body ends.

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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.

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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.

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ZANASI AUTOMATIC HOFLIGER KARG AUTOMATIC
CAPSULE FILLING MACHINE CAPSULE FILLING MACHINE

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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.

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OSAKA MODEL R-180
SEMI AUTOMATIC CAPSULE
FILLING MACHINE

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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%.
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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.
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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.

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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.
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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.

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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.
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4. Bubble method:
The Globex Mark II capsulator produces truly seamless,
one-piece soft gelatin capsules by a bubble method.

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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.

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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.
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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.

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CAPSULE AUTO MATIC
POLISHING CAPSULE
MACHINE ARRANGEMNT
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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
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E-mail: bknanjwade@yahoo.co.in
Cell No: 09742431000

08 June 2009December 6, 2017


Wednesday, SRTMof
Dept. University,
Pharmaceutics
NandedDept. of Pharmaceutics 79

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