Granules

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Granules

• Presented By
• Dr. Abdel Naser Zaid

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• Granules are aggregations of fine particles of
  powders in a mass of about spherical shape.

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• Why we prepare granules when we have powders?
• To avoid powder segregation,
• if the powder is composed of particles with
  different dimensions different densities, a
  separation between these particles will occur.
• To enhance the flow of powder,
• Higher flowability gives better filling of the
  dies or containers, during a volumetric dosage.

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• Granules have higher porosity than powders,
• To improve the compressibility of powders.
• The granulation of toxic materials will reduce
  the hazard of generation of toxic dust, which may
  arise during the handling of the powders.
• Materials, which are slightly hygroscope, may
  adhere form a cake if stored as a powder.

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• Technologically, granules are used according to
  two visions
• As a true proper pharmaceutical dosage form
  form,
• These granules are used to prepare an instant
  solution or suspension.
• Granules, can be packaged as
• Bulk granules (Multi-dosage containers),
• Divided granules (Mono-dosage containers ).

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• Semi-finished products for the preparation of
  tablets or other dosage forms.
• Usually, granules have an excellent
  compressibility,

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• Methods of Granulation
• Some of the available methods in the industrial
  field for the preparation of granules
• Wet Granulation.
• Dry granulation methods.
• Granulation by Crystallization.
• Granulation by Crystallization.
• This method exploits the presence of
  crystallization water in the active material
  this method is rarely used.

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• Dry Granulation.
• Pharmaceutical powders that were mixed
  homogeneously together are compressed to obtain
  large tablets.
• The high compression forces are obtained by using
  one of the following procedures
• Tabling machines (see industrial pharmacy).
• These machines are provided with dies of 2-3 cm
  diameters (the fine powders have low flowability)
  
• So,
• large dies are easily filled in this case, the
  dies travel between two punches, which press the
  powder forming large tablets, with 2-3 cm of
  diameters.

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• Roller compaction (see industrial pharmacy).
• The powder mixture flow between two rollers to
  form a compressed sheet.
• These large tablets or sheets are milled.
• The milled sheets are sieved.

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• The sieving process gives three fractions of
  granules
• Very coarse granules, which return back to the
  milling process.
• Very fine fraction, which return back to the
  compaction.
• Fraction with optimal dimensions for following
  manufacturing steps.

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• This system produces granules with
• irregular shape,
• low rate of dissolution due to the high
  compression force used to aggregate the powders.
• These granules are poorly water-permeable due to
  the low porosity.
• So, water cant permeate them easily in order to
  disintegrate dissolve them.
• This will extremely reduce the velocity of
  dissolution so the bioavailability of the
  active material.

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• Vice versa if the granules have high porosity the
  molecules of water can penetrate easily into the
  pores, disintegrate the granules.
• High Porosity means high specific surface area,
  leading to an increasing in the dissolution
  velocity of the granules, thus their
  bioavailability.
• Thus, we can say that the dry granulation method
  is used only for those powders, which cannot be
  granulated with the wet granulation method.

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• Wet Granulation
• This is the most used method to prepare granules.
• The main disadvantage of this method is the
  higher number of steps present in this process
  when compared with the other two methods.

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• Steps of Wet Granulation
• The 1st step is the wetting of the powder with a
  liquid or solution to form a paste.
• Characteristics of the granulating liquid
• It should have all required characteristics of
  pharmaceutical excipient,
• It should dissolve the powder only within a
  certain limit (mild solvent)
• If the powder is soluble in the solvent, a
  solution or suspension will be obtained instead
  of the paste.

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• From another side, if the solvent cannot
  absolutely dissolve the powder, we cannot obtain
  the liquid forces, which stick together the
  powder particles.
• The fraction of powder, which dissolves in the
  solvent, then re-crystallizes, after the
  drying, will form bridges between the particles
  of the powder.

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• When two particles become in contact between each
  other by certain forces, they institute
• forces of electrostatic nature (week forces)
• forces of viscous or/and adhesive natures (which
  are the most important) so the particles remain
  attached to each others.
• Thus the used liquid in the wet granulation must
  be mild solvent for the powder.

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• There is a few number of solvents available for
  pharmaceutical granulation.
• This is because we cant totally eliminate the
  solvent, so if traces of the solvent remain in
  the formula at the end of the manufacturing,
  these traces must be non toxic for the patient.

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• The most used solvents in wet granulation
• Water.
• Ethanol.
• Isopropanol.
• If we want to use water for granulation, the
  powder must be
• fairly or discreetly soluble in the water,
• compatible with it.
• If the powder is very soluble in water, we can
  use another liquid or the following arrangements
• Water Solutions.

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• Simple Syrup
• This syrup has less dissolving capacity than the
  pure water, because the majority of water
  molecules are involved in the hydration
  dissolving of the sugar molecules instead of the
  powder molecules.
• But if the powder is water insoluble,
• A co-solvent is recommended.
• This is a mixture between water another
  water-soluble pharmaceutical solvent with high
  dissolving capacity toward the powder.
• We can also use a water solution of polymers,
• The evaporation of water can determine the
  adhesion between the particles of the powder.

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• Polymers solutions that can be used in the wet
  granulation
• Gelatin solution at 5-10.
• Such viscose solutions determine the adhesion of
  the particles of the powders,
• When water evaporates the gelatin solidifies
  between the two particles of powder and maintain
  them stuck together.
• Starch past 5 -10.
• Pre-gelatinized starch, which has the
  characteristic to swell in a cold water.
• Semi-synthetic polymers like CMC, MC.
• Synthetic polymers like P.V.P.

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• Some of these compounds can be used in organic
  solvent like ethanol,
• This is useful in case of thermo-sensitive
  compounds,
• To reduce the cost of production.
• The granules obtained in this way are called
  agglutinated granules.

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• The 2nd step is the granulation or the formation
  of granules starting from the paste.
• To achieve this, many granulators are available
  (see industrial pharmacy)
• Rotative granulator,
• Oscillating granulator,
• High speed mixer granulator,
• Fluidized bed granulator,
• Freund granulator,
• Roller compaction granulator.

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• The quality of the granules depends on the
• Granulation solvent,
• Type of granulator,
• Powder nature.
• The paste that we have to obtain mustnt drains
  between the fingers of the hand, which means that
  must remain aggregated easily crumbled.
• This is a very coarse reference, but nowadays
  there is the possibility to have a qualitative
  evaluation.

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• we can measure the energy that we must provide to
  the system in which we carry out the wetting
  process.
• How?
• Put the powder for granulation in the granulator,
• Add gradually the granulating liquid,
• Then mix by the use of electrical motor
• This motor measures the absorbed power in
  function of the time so in function of the
  putted liquid.

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• How can we calculate the exact volume of
  granulating liquid for powder kneading?
• We can evaluate the liquid quantity for the
  kneading process by measuring continuously the
  absorbed power during the addition of the
  granulating liquid.
• The increase in the required power is connected
  with the increase of the viscosity of the dough
  mass, due to the formation of the liquid bonds
  (adhesive viscous types).
• Generally, all instruments are able to form a
  curve, as in the following figure

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• Perform the curve by putting the absorbed power
  in Y- axis, the volume of the granulating
  liquid in X- axis.
• Interpretation of the obtained curve
• Initially, the addition of the granulating liquid
  doesnt produce a significant change in the
  absorbed power,
• At point 2 we fined that any added quantity of
  the granulating liquid, increases proportionally
  the absorbed power.

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• At this point we have initial formation of
• Electrostatic bonds (less important),
• Liquid bonds (more important).
• These bonds start to bind together the powder
  particles to form the granules.
• Therefore the equipment meet higher resistance to
  maintain constant the number of rounds/minute.

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• Then continuing in the liquid addition, we note
  that the absorbed power will be stabilized on a
  certain value (interval between 3-4), this means
  that the system was reached an equilibrium state.
• At points 3-4, we have an excellent adhesion
  between the various particles of powder
• The granule shape depends on the type of the
  used granulator.

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• The addition of further liquid, will give phase 5
  where we note a sharp drop in the absorbed power,
  because the granulate will be transformed in a
  suspension.
• In this manner we have an idea about the
  percentage quantity of the granulating liquid,
  which we have to add, by evaluating the curve.

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• This curve can subdivide the granulators in
• Slow granulator (fluidized bed granulator and
  dryer).
• Speed granulators (e.g. plates and rotate
  granulatorsetc, see industrial pharmacy).
• The 3rd step is the Drying Process.
• Water is more difficult to be eliminated than the
  organic solvents, therefore the water gives some
  problems
• When the powder is thermosensitive the heating
  for long period of time can alter the stability
  of the powder,
• The consumption of energy is higher than the
  organic solvents.

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• We have three kinds of water in the granulate
  mass
• Water of Crystallization,
• It is very difficult to be eliminated without
  causing the decomposition of the product or
  variation of its crystalline form.
• Adsorped water,
• The amount of water, which was absorbed by a
  drug present in a moist air, this amount depends
  on the nature of the drug the relative humidity
  of the air.
• Imbibition of water,
• The amount of water, which impregnates the
  granules, this water is easy to be eliminated by
  simple evaporation.

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• According to the used dryer, we can eliminate the
  total amount of imbibitions water a portion of
  the adsorpted water.
• The elimination of the total amount of the
  adsorbed water is not advisable.
• For example the elimination of the total amount
  of the adsorbed water, may create electrostatic
  charges,
• This lead to the attraction or repulsion of the
  granules between themselves the walls of the
  equipment,
• This type of granules are very difficult to be
  managed.

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• If we use a hydrophilic polymer solution, as a
  granulating liquid, we proceed for long time in
  the drying process, the hydrophilic polymer will
  assume a glassy consistency.
• These glassy characteristics cause the
  fragmentation of the granules during the
  following manufacturing processes.
• Thus, a certain quantity of moisture is useful to
  improve the manipulation of the granules.

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• The dryers are (see industrial pharmacy)
• Static Oven,
• Rotary Drier,
• Fluidized Bed Drier,
• Vacuum Oven,
• Microwave Drier,
• Spray Drier,
• Rotary Atomizer,
• I.R Drier.

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• The 4th step is the Classification of the
  granules.
• The last step is the classification according to
  particles dimension
• Coarse granules, which must be milled,
• Fine granules, which must be re-granulated.
• Optimum granules with optimum dimensions, which
  are ready for use.

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• We have two problems correlated to the size of
  granules
• Concerning the filling of big volume (i.e.
  sachets or bottles).
• If we have big granules we can use big measuring
  tool, while if the granules have small size, we
  can use small measuring tool.
• The most critical problem is
• when we must to fill the die of the tableting
  machine in order to prepare the tablet.
• In this case
• it is not only important to have granules with
  equal dimensions, but
• it is also important that the size of these
  granules are within a certain range, which is in
  function with the diameter of the die.

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• The essential concept when producing tablets, is
  that the granules which we want to fill the die
  with, must be more fine as the die becomes
  smaller.
• In fact there are well-defined relations between
  the size of the granules the diameters of the
  die, in order to have a filling uniformity of the
  die,
• so to obtain tablets, which remain within the
  limits of the weight uniformity.

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• For example
• If we have a die with diameter of 3/16 of inch,
  we should prepare granules, which pass through a
  sieve with mesh 20 (20 mesh /1 linear inch).
• If we have a die with diameters of 7/16 inch, we
  have to have granules with dimensions that pass
  through a sieve of mesh 12.

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• Quality Controls
• Weight uniformity test.
• Dissolution profile.
• Friability test.
• The granules must be
• packaged in order to be used as final
  pharmaceutical dosage form, or
• added to other substances for example to prepare
  the tablets,
• So, we must avoid the transformation of the
  granules into powder during the manipulation
  processes.

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Friability tester
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• Some Particular Granules
• Sustained release granules.
• Enteric coated granules.
• Effervescent granules.