PILOT PLANT DESIGN FOR TABLETS AND CAPSULES

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PILOT PLANT DESIGN FOR TABLETS AND CAPSULES
Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D
By
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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
• Fluorescent lighting fixtures should be the
  ceiling flush type.
• The various operating areas should have floor
  drains to simplify cleaning.
• The area should be air-conditioned and humidity
  controlled.
• High -density concrete floors should be
  installed.
• The walls in the processing and packaging areas
  should be enamel cement finish on concrete.
• Equipment in the pharmaceutical pilot plant
  should be similar to that used by production
  division- manufacture of tablets.

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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
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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
• To impart good flow properties to the material,
• To increase the apparent density of the powders,
• To change the particle size distribution,
• 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
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• 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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Dept. of Pharmaceutics
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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 ¾ 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
• Filling of empty die cavity with granulation.
• Precompression of granulation (optional).
• Compression of granules.
• 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.
• Granulation feed rate.
• Delivery system should not change the particle
  size distribution.
• System should not cause segregation of coarse and
  fine particles, nor it 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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MULTI ROTARY MACHINE
HIGH SPEED ROTARY MACHINE
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DOUBLE ROTARY MACHINE
UPPER PUNCH AND 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
WET GRANULATION
DRY BLENDING
DRY GRANULATION
WEIGHING SIZING BLENDING LUBRICATION COMPRESSION
COATING
WEIGHING SIZING GRANULATION DRYING BLENDING LUBRIC
ATION COMPRESSION
WEIGHING SIZING BLENDING COMPACTION MILLING LUBRIC
ATION 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
• Mixing of ingredient
• Granulation and lubrication
• Making of capsules
• Filling of capsules
• Uniformity testing
• 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

• 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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• Shell manufacture

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• 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.
• 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.

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• 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.
• Stripping
• A series of bronze jaws strip the cap and body
  portions of the capsules from the pins.

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• 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.
• Joining
• The cap and body portions are aligned
  concentrically in channels and the two portions
  are slowly pushed together.

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• 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.
• 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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• Sizes and shapes
• For human use, empty gelatin capsules are
  manufactured in eight sizes, ranging from 000 to
  5.
• Capsule capacities in table

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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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• 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.
• 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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HOFLIGER KARG AUTOMATIC CAPSULE FILLING MACHINE
ZANASI AUTOMATIC 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

• 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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• 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
• Water immiscible, volatile or more likely more
  volatile liquids such as vegetable oils, mineral
  oils, medium-chain triglycerides and acetylated
  glycerides.
• 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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• Manufacture process
• 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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• 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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• 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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• 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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• 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.
• Thixotropic formulations,
• Thermal-setting formulations,
• 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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AUTO MATIC CAPSULE ARRANGEMNT
CAPSULE POLISHING MACHINE
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References

• The theory and practice of industrial pharmacy.
  Leon Lachman, Herbert A. Lieberman, Joseph L.
  Kanig. Third edition. Varghese publishing house.
  Page no. 681-703.
• Pharmaceutical dosage forms Tablets. Volume 3.
  second edition. Leon Lachman, Herbert A.
  Lieberman, Joseph B. Schwartz. Page no. 303-365.
• Pharmaceutical process scale up edited by
  Michael Levin.
• Modern pharmaceutics. Edited by Gilbert S.
  Banker Christopher T. Rhodes. 4th edition.
• www.google.com

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E-mail bknanjwade_at_yahoo.co.in Cell No
09742431000
Tuesday, January 22, 2013
Dept. of Pharmaceutics
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