Granulation and theories of granulation

Question 1

What is granulation?

Answer 1

Granulation is a pharmaceutical technology unit operation or process which involves the size enlargement of fine or coarse particles wherein primary powder particles are made to adhere to form physically stronger, larger, multi-
particulate entities or agglomerates called granules using granulating fluid(binder) or by compression.

Question 2

Bonds between the primary particles are formed by?

Answer 2

compression, or by using a
binding agent.

Question 3

Granule sizes range from?

Answer 3

0.2 and 0.5 mm

Question 4

Give 5 advantages of granulation

Answer 4

1. It helps prevent the separation or segregation of the primary ingredients in the powder mixture as well as
   improves the flow of the properties of the mixture.
2. Granulation leads to larger more homogenous particles with better flow characteristics, improving the
   tablet making process.
3. Compacted granules occupy less volume/unit weight compared with powder and is easier to store and ship.
4. It improves the compression of the materials
5. It improves the appearance of the product
6. The granulation process can modify or improve the drug release profile.

Question 5

Granulation techniques are classified based on?

Answer 5

The type of binder and process used.

Question 6

Common granulation
techniques include?

Answer 6

Wet granulation, dry granulation, and hot melt granulation.

Question 7

Explain wet granulation

Answer 7

In wet granulation, a liquid, generally a binder solution, is added to facilitate wetting and agglomeration of a
powder blend (Kristensen & Schaefer, 1987). The wet mass subsequently is dried and screened to obtain
granules with desired size.

Question 8

Explain dry granulation

Answer 8

Dry granulation involves granulation using dry binders without the aid of any liquid and is particularly useful
for drugs that are sensitive to moisture or heat and, therefore, cannot be processed using wet granulation. In
this technique, powder particles are agglomerated under high pressure either by using the process of slugging
or roller compaction. The slugs or compacts then are milled to the desired size range granules

Question 9

What is hot melt granulation?

Answer 9

Hot melt granulation is used as an alternate to wet granulation and employs binders that facilitate granulation
in their molten form (Passerini, Calogera, Albertini, & Rodriguez, 2010). After granules are formed, they are
cooled and screened to achieve proper size. The process is carried out in a high-shear granulator fitted with
heating device or using the relatively new technique of hot melt extrusion.

Question 10

What are the advantages of wet granulation?

Answer 10

1. More uniform mixing is achieved than dry
   granulation
2. More binding is achieved with less quantity of
   binder
3. Has better content uniformity
4. Is suitable for very low to very high drug content
5. Reduces sticking of blend to compression tooling

Question 11

Advantages of dry granulation

Answer 11

1. Suitable for moisture and temperature sensitive APIs
2. Suitable for low to high drug contents
3. Time and cost effective, as unit operation of drying
   not involved
4. High force is involved in compaction

Question 12

Give advantages of hot melt granulation

Answer 12

1. Intimate mixing sometimes up to molecular
   level, can produce solid dispersions and lead
   to improvement in solubility and
   bioavailability
2. It is time and cost effective, unit operation of
   drying not involved

Question 13

What are disadvantages of wet granulation?

Answer 13

1. Not favourable for moisture sensitive products
2. Time consuming due to involvement of additional
   unit operation of drying

Question 14

What are the disadvantages of dry granulation

Answer 14

1. Results in greater chances of generation of dust and
   environmental contamination
2. High force is involved in compaction

Question 15

What are disadvantages of hot melt granulation

Answer 15

1. It is not suitable for thermo-labile drugs
2. It is a non-traditional process that requires
   greater effort in polymer screening and
   training on instrument
3. Binders with low melting points, which can
   soften during storage and handling are
   utilized

Question 16

Bonds between particles can be created either by or what?

Answer 16

By the presence of
appropriate liquid (binder) or forces due to application of pressure

Question 17

Agglomerated granules are formed by

Answer 17

solid bridges, sintering, chemical
reaction, crystallization and deposition of colloidal particles

Question 18

What are the five recognized bonds that form between particles

Answer 18

1. Adhesive and cohesive forces in the immobile liquid between particles
2. Interfacial forces in mobile liquid films within granules
3. Formation of a solid bridge after subsequent solvent evaporation – the main mechanism
   in dry granulation
4. Attractive forces between solid particles – presence of liquid not required
5. Mechanical interlocking of particles often between fibrous or flat particles

Question 19

What is the first and most important phase in granule formation.

Answer 19

Wetting and Nucleation

Question 20

Wetting and nucleation involves?

Answer 20

It involves the initial wetting of powder bed and existing granules by the
granulating fluid to form nuclei.

Question 21

Wetting and Nucleation is largely influenced by

Answer 21

spray rate, fluid distribution, feed formulation properties,

Question 22

The nucleation process is?

Answer 22

the initial coalescence of primary particles in the
immediate vicinity of the larger wetting drop

Question 23

What is involved in the coalescence or ball growth stage

Answer 23

Partially wetted primary particles and
larger nuclei come together to form granules composed of several particles. Further collision (coalescence) of two granules could occur to form a new
and larger granule.

Question 24

The extent of the consolidation depends on?

Answer 24

The agitation in the granulation
equipment and the resistance of the granules to deformation.

Question 25

What happens in the Consolidation stage?

Answer 25

As granules increase in size, they are consolidated by compaction forces due to bed agitation.

Question 26

The consolidation phase in granule formation controls?

Answer 26

Internal granule porosity, and therefore final properties of the granules e.g., granule strength, hardness, or dissolution.

Question 27

What are the Steps involved in the wet granulation

Answer 27

Mixing of the drugs and excipients Preparation of binder solution Mixing of binder solution with powder mixture to form wet mass. Coarse screening of wet mass using a suitable sieve (6-12 screens)

Question 28

In wet granulation, Granules are formed by the addition of ______________ onto a _________ which is under the influence of _____

Answer 28

a granulation liquid (usually an aqueous solution), powder bed, an impeller(in a high-shear granulator), screws (in a twin screw granulator) or air (in a fluidized bed granulator).

Question 29

Name three types of granulators

Answer 29

a high-shear granulator, a twin screw granulator, or a fluidized bed granulator

Question 30

What produces bonding between the primary powder particles to produce wet granules.

Answer 30

Agitation of the particles along with the added liquid

Question 30

Give three examples of volatile liquids added in wet granulation

Answer 30

water, ethanol or isopropanol

Question 31

Organic solvents are safer to use than aqueous liquids. T or F?

Answer 31

False. aqueous liquids are safer to use than organic solvents.

Question 32

Why are Aqueous binder solutions are preferred to aqueous solutions alone

Answer 32

because of better binder capacity

Question 32

Give exaples of aqueous binder solutions

Answer 32

polyvinyl pyrollidone (PVP), starch mucilage tragacanth, acacia

Question 33

In wet granulation the added liquid to the powder system causes what?

Answer 33

a thin and immobile film of liquid to form between particles.

Question 34

a thin and immobile film of liquid forming between particles causes what?

Answer 34

an effective decrease in inter-particulate distance and an increase in contact area between particles.

Question 35

The shortening of the inter-particulate distance causes what?

Answer 35

increases the Van der Waals forces of attraction.

Question 36

More liquid is usually added in wet granulation to form what?

Answer 36

a mobile liquid film.

Question 37

The three states that can describe the distribution of liquid between particles are:

Answer 37

Pendular state Funicular state – Capillary state

Question 38

what is the Pendular state

Answer 38

this usually occurs at low moisture level, this is when the particles are held together by lens-shaped rings of liquid, but it is mainly air between the particles.

Question 39

what is the Funicular state –

Answer 39

this is an intermediary state where air starts to displace from between particles

Question 40

what is the Capillary state

Answer 40

this is when all air has been displaced from between the particles.

Question 41

What happens In the capillary state,

Answer 41

liquid penetrate the pores of the particles to form solid bridges between particles, giving the strongest form of adhesion, when the liquid evaporates.

Question 42

Nucleation of granules in wet granulation starts with?

Answer 42

a number of particles joining together in the pendular state.

Question 43

What happens if agitation is continued too far?

Answer 43

the granules will coalesce to form unusable over-massed spheres of material.

Question 44

What affects the required mixing time, as well as the type of mixer.

Answer 44

The amount of liquid added and the nature of the starting materials

Question 45

High shear mixers often require less liquid than low–shear mixers. True or false?

Answer 45

True

Question 46

High impeller rotation speeds can cause what?

Answer 46

local heating of the mixture and loss of solvent by evaporation

Question 47

What are The primary advantages of dry granulation?

Answer 47

1. its simplicity and low cost. 2. The powder mixture is compressed without the use of heat and solvent.

Question 48

There are three common methods of dry granulation. They are?

Answer 48

Direct compression Slugging Roller compaction

Question 49

What is Direct compression:

Answer 49

This method simply combines the drug-substance powder with the excipient powders in a blender. The blend is then directly compressed to a tablet or filled into a capsule

Question 50

what is Slugging.

Answer 50

In this method, poor-flowing blends are compressed using a rotary tablet press fitted with a die much larger than the die used to make the final tablet to form “slugs.”  Slugs are typically 1 inch in diameter or larger, and there is little attention paid to weight variation or compression properties Slugs are passed through a mill, blended with other excipients and transferred to a tablet press or capsule filling machine.

Question 51

what is Roller compaction:

Answer 51

Typically used with moisture-sensitive drug substances and formulations with poor flow characteristics, The material flows between two rollers that compact it. The rollers come in a variety of designs so the formulator can produce compacts of the correct hardness. The compacts are subsequently milled, blended, and made into tablets or filled into capsules.

Question 52

What are the advantages of roller compaction?

Answer 52

In addition to its ability to process poor-flowing and moisture-sensitive materials, roller compaction entails low labor costs and can be adapted for continuous production

Question 53

What are the characteristics of dry granulation?

Answer 53

It is characterized by granule formation without using liquid solution. Therefore, it requires compacting and densifying the powders. Used for materials sensitive to heat and moisture In this process the primary powder particles are aggregated under high pressure.

Question 54

 Dry Granulation is characterized by two types of irresistible attractive physical forces between particles :

Answer 54

 Electrostatic forces – there are generally weak but may cause cohesion when the material is mixed initially.  Van der Waals forces – these are stronger than electrostatic forces and they increase as the inter-particulate distances decrease during the compression of powders.

Question 55

The pressure applied in dry granulation increases and decreases what?

Answer 55

The pressure applied in dry granulation increases the contact area between the adsorption layers of particles and decreases the inter-particulate distances, thereby contributing to the final strength of the material.

Question 56

What will cause the particles will bind together and crystallization may take place in dry granulation?

Answer 56

The pressure applied may also melt low melting-point materials where the particles touch and high pressures are developed. When this happens the particles will bind together and crystallization may take place when the pressure is relieved.

Question 57

List the ADVANCED GRANULATION TECHNIQUES

Answer 57

Melt Agglomeration/ Thermoplastic Granulation Foam Granulation Freeze Granulation Technology Moisture Activated Dry Granulation Extrusion-Spheronization Granulation Fluidized Bed Granulation Spray Drying Granulation Steam Granulation Thermal Adhesion Granulation Pneumatic Dry Granulation

Question 58

Explain the process of Melt Agglomeration/ Thermoplastic Granulation

Answer 58

This technique consists of the agglomeration of powder particles using binders that, which melts or softens at relatively low temperature (50–90°C). Solid fine particles are bound together into agglomerates by agitation, kneading, and layering in the presence of molten binding liquid. After cooling of the agglomerated powder and the consequent solidification of the molten or soften binder complete the formation of the granules.

Question 59

Melt Agglomeration/ Thermoplastic Granulation utilizes two methods which are?

Answer 59

1. spray on method that involves spraying of the molten binder onto the powder and by simple cooling of the product at room temperature followed by milling to obtain dried granules. 2. In situ melt granulation method that employs a solid binder which is heated above its melting point by hot air, when it is processed in fluidized bed processor.

Question 60

List the advantages of Melt Agglomeration/ Thermoplastic Granulation

Answer 60

Less time consuming and economical process. No requirement of any solvent either aqueous or non-aqueous. Uniform dispersion of fine particle. Release profile of drugs can be controlled and modified. Suitable for enhancing dissolution profile and bioavailability of poorly water soluble drugs by forming solid dispersion. Improved product stability.

Question 61

List the disadvantage of Melt Agglomeration/ Thermoplastic Granulation

Answer 61

Not suitable for thermo-labile materials. There is need of high energy input. During handling and storage of agglomerates melting or softening of binder may occur.

Question 62

Explain the process of Foam Granulation

Answer 62

This technique is analogous to spray agglomeration; it involves the addition of liquid/ aqueous binder as foam instead of spraying or pouring liquid onto the powder particles. Adding the binder solution as foam rather than a spray eliminates the problems of inconsistent and unpredictable binder distribution that can affect tablet hardness and drug release A foam generator is used in the binder solution tank with high-shear granulator or fluid bed granulator to introduce the binder as foam rather than spraying or pouring in binder onto the moving powder particles.

Question 63

List the advantages of Foam Granulation

Answer 63

No need of spray nozzle. Less water required Economical process Suitable for water sensitive formulations.

Question 64

Explain the process of Freeze Granulation Technology

Answer 64

This technique enables preservation of the homogeneity from suspension to dry granules. The powder suspension are sprayed into liquid nitrogen such that the drops are instantly frozen into granules, and by freeze drying process, the granules are dried by sublimation of ice without any segregation effects. This results into spherical, free flowing granules, with optimal homogeneity.

Question 65

List the advantages of Freeze Granulation Technology

Answer 65

Advantages Granule density can be controlled by the solids content of the suspension. Cavities in the granules can be avoided. High yield, less wastage of material. Easy cleaning of equipment. Organic solvents can be recycled.

Question 66

Explain the process of Moisture Activated Dry Granulation

Answer 66

This technique is a variation of conventional wet granulation technique. This technology is widely used in granulation of moisture sensitive active pharmaceutical ingredients. This process involves the utilization of very little granulating fluid, to activate granule formation and it also eliminates the drying steps by using moisture absorbing materials like microcrystalline cellulose, potato starch, a mixture of MCC and potato starch (50% w/w to remove excess of moisture present in the granulate. The moisture absorbents absorb the moisture from the agglomerates, resulting in moisture redistribution within the powder mixture, leading to relatively dry granule mixture.

Question 67

The process of Moisture Activated Dry Granulation is accomplished by what two major steps

Answer 67

agglomeration and moisture distribution.

Question 68

List the advantages of Moisture Activated Dry Granulation

Answer 68

A simple, clean, lean process that utilizes very little granulating fluid. Produce granules with more uniform particle size distribution (particle size range of 150–500 μm) and excellent flowability. Economical and time efficient, as requires less energy and eliminates drying step. Suitable for continuous processing. Used for preparation of floating and sustained release products. Applicable to more than 90% of the granulation need for pharmaceutical, food and Nutritional industry.

Question 69

Explain the process of Extrusion-Spheronization Granulation

Answer 69

This technique involve in production of granules or pellets of uniform size with high drug loading capacity. It consists of multiple steps of wet mass extrusion followed by spheronization to produce uniform sized spherical particles with narrow size distribution. It is mainly used in multi particulates for oral controlled drug delivery system.

Question 69

List the disadvantage of Moisture Activated Dry Granulation

Answer 69

1. Unsuitable for thermo-labile, moisture sensitive, high moisture absorbing substances. 2. Formulations with high drug loading are difficult to develop.

Question 70

What are the steps involved in Extrusion-Spheronization Granulation

Answer 70

Dry mixing of materials for homogeneous dispersion. Wet granulation of the mixture to form wet mass. Extrusion of wet mass to form rod shaped particles. Rounding off the rod shaped particles using spheronizer. Drying

Question 71

List the advantages of Extrusion-Spheronization Granulation

Answer 71

Suitable for higher levels of active ingredients without production of larger particles. Suitable for combination of two or more active agents within the same unit, in any ratio. It produces spherical particles with high bulk density, low hygrscopicity, narrow particle size distribution and smoother surface.

Question 72

List the disadvantage of Extrusion-Spheronization Granulation

Answer 72

Time consuming process having requirement of more labour. Moisture sensitive and thermo-labile materials are not suitable candidates for it.

Question 73

Explain the process of Fluidized Bed Granulation

Answer 73

It is an air suspension technique in which binder solution is sprayed on to the fluidized powder bed in order to get finer, free flowing and homogenous granules. This fluidized bed processor contains air handling unit, product container, air distributor, spay nozzle, disengagement area, process filters, exhaust blower/fan, control system, and solution delivery systems. The particle formation in fluidized bed granulation is influenced by numerous parameters like moisture content in solids, liquid spray flow rate, airflow rates, and atomization pressure. Granulation in fluidized state can be achieved either by batch process or continuous process. For granulation in batch process, the dry starting product is placed in the product container, where it is mixed vigorously in the heated gas stream, held in the suspension and granulated by spraying with a suitable bonding material. The product is finally dried to the required end moisture content.

Question 74

Explain the process of Spray Drying Granulation

Answer 74

This process is used to produce microcapsules, food ingredients, flavors and various biotechnological preparations. Dry granular product is obtained by feeding a solution of active agent along with excipients into the drying system, where the feed is atomized and dried with a heated gas stream followed by separation of granular product from the gas stream. This process differs from other methods in that it is a continuous process in which a dry granular product is made from a solution or a suspension rather than initially dried the primary powder particles.

Question 75

What are the steps involved in Spray Drying Granulation

Answer 75

 Liquid feed’s atomization into fine droplets  Mixing of sprays droplets with a heated gas stream, for liquid evaporation.  Separation of the dried powder from the gas stream.

Question 76

What are the advantages of Spray Drying Granulation

Answer 76

 It is a rapid and continuous process  It reduces overall cost by eliminating labor intensive drying and granulation steps.  Less exposure to dust.  Heat sensitive product are suitable candidates.

Question 77

Explain the process of Steam Granulation

Answer 77

This process is simply a modification of conventional wet granulation method. In this technique, water steam is used as binder.  Pure form of steam is transparent gas, and it provides a higher diffusion rate into the powder and a more favorable thermal balance during the drying step.  At standard temperature and pressure, pure steam (unmixed with air, but in equilibrium with liquid water) occupies about 1,600 times the volume of an equal mass of liquid water. After condensation of the steam, water forms a hot thin film on the powder particles, requiring only a small amount of extra energy for its elimination, and evaporates more easily.

Question 78

What are the advantages of Steam Granulation

Answer 78

 Results in more spherical granule formation  Higher diffusion rate  Environment friendly, safe for working operator.  Maintain sterility

Question 79

What are the disadvantages of Steam Granulation

Answer 79

 There is need of special equipment for steam generation and transportation.  Need of high energy inputs  Not suitable for thermo labile materials.

Question 80

Explain the process of thermal adhesion granulation

Answer 80

This technique involves granulation of the blend by addition of very less amount of water or solvents. This technique is quite simple and convenient with low moisture and binder contents in a closed system for preparing highly compressible materials or for modifying the poor characteristics of excipients.  In this process the binder is first moisturized by spraying water or ethanol, and then this blend is transferred into a pre warmed glass bottle and sealed.  It is then heated properly by an infrared lamp to raise surface temperature of the vessel to 90oC-105oC in case of water and 70oC-90oC in case of ethanol, and mixed under tumble rotation for 3-20 minutes until the granules are formed.  Thermal adhesion granulation process is performed under low moisture content or low content of pharmaceutically acceptable solvent by subjecting a mixture of excipients to heating. This method utilizes less water or solvent when compared to conventional wet granulation technique.

Question 81

What are the advantages of thermal adhesion

Answer 81

 Utilizes less amount of water or solvent.  Granules with good flow properties and binding capacity were obtained even with substances having poor tableting properties.  Minimizes the dust generation during powder processing.

Question 82

Explain the process of pneumatic dry granulation

Answer 82

This method involves production of granules from powder particles by initially applying mild compaction force by roller compactor to produce a compacted mass comprising a mixture of fine particles and granules.  To separate the granules and to recycle the rejected fraction, a newly innovated fractionating device is employed. Granules pass through the fractioning chamber to be compressed into tablets.  Pneumatic dry granulation is suitable for automatic or semi-automatic production of granules.

Question 83

What are the advantages of pneumatic dry granulation

Answer 83

 High drug loading is possible.  Faster development (within weeks).  Suitable for thermo-labile and moisture sensitive drugs. d. Improved stability with increased shelf-life.  Compatible with other technologies like coating, sustained release.  Produce soft and porous granules with improved flow property and compressibility.  Taste masking can be achieved.  Sterile products and toxic materials can be handled.  Reduces cost of final product by minimizing waste through recycling and production cost.

Question 84

What are the effects of Effects of Granule Properties on Tablets

Answer 84

as granules size increases, there will be respective increase in tablet weight variation, decreased hardness and increased friability