granulation

Question 1

what is granulation?

Answer 1

• granulation is the process of size enlargement of powders
• powder particles adhere to form larger particles
• used for production of tablets/capsules, or may be used as a dosage form themselves

Question 2

what are some of the reasons for granulation?

Answer 2

to prevent segregation in the powder mix
improve flow properties
improve compressibility
densification of powder
reduction of dust hazard
increase wettability of hydrophobic drugs

Question 3

why do you prevent segregation in the powder mix?

Answer 3

• increases uniformity of active ingredient and excipients
• powders segregate due to differences in size & density
• ideally, a granule will contain all the constituents of the mix
• don’t want segregation of the granules themselves –control size distribution

Question 4

why do you want to improbe a powders flow properties?

Answer 4

• enhance flow rate and uniformity•many powders don’t flow very well e.g. fine particles are cohesive/adhesive
• poor flow could lead to poor capsule/tablet weight uniformity i.e. non-uniform metering of volumetric dispensing
• granules are larger and often more uniform in shape
• slightly hygroscopic materials may absorb moisture, however the granule flow properties may be unaffected due to size (powders may adhere with moisture and form cake)

Question 5

why do you want to improve compressibility?

Answer 5

• some powders difficult to compress

* granules often easier to deform/fragment & produce stronger tablets

Question 6

why do you want to densify powder?

Answer 6

• granules are denser than parent powder

* occupy less volume per unit weight

Question 7

why is it beneficial to reduce hazard due to grnaulation?

Answer 7

fine powders are dust hazard – toxic and explosive

Question 8

why do you want to increase wettability of hphobic drugs?

Answer 8

• mixing drug with hydrophilic excipients

Question 9

what are the requirements for granules used in tab manufacture and capsule filing?

Answer 9

similar shape & colour
• narrow particle size distribution
• not more than 10 %w/w particle fines (i.e. below 100 μm)
• good flow
• appropriate mechanical strength
• moisture content 3-5 %w/w
• disintegration into initial powder particles

Question 10

what are the two types of granulation?

Answer 10

wet and dry granulation

Question 11

what is wet granulation?

Answer 11

• mixture of powder and binder liquid
• formation of granules
• drying
• size classification (sieving)

Question 12

what is dry gransulation?

Answer 12

• formation of slugs (on heavy duty tablet machine) or compacts (roller compaction) from dry powder
• coarse grinding
• size classification (sieving)

Question 13

what is the mechanism of granule formation?-dry granulation

Answer 13

or drygranulation, adhesion of particles due to applied pressure. Short range van der Waals forces will dominate. Large granules then milled/sieved

Question 14

what is the mechanism of granule formation for wet granulation?

Answer 14

in wetgranulation, liquid is mixed into dry powder. Granulation starts with:
•nucleation– small number of particles combine to form pendularstate, which builds into capillary state with more liquid
•then transition growth, where either single particles are added to the nuclei by pendular bridges or nuclei combine. This represents a suitable end point for granules for tablets/capsules – not too large
•if continued, get ball growth, giving large spherical granules increasing size with time. Too large

Question 15

what are the possible mechanisms of ball growth?

Answer 15

• coalescence. Two or more granules join to form a larger granule
• breakage. Granules break into fragments which adhere to other granules, forming a layer of material over the surviving granule
• layering. A powder mix is added to a bed of granules, the powder forms a layer increasing the granule size
• Abrasion Transfer. Agitation of the granule bed leads to the attrition of material from granules. This abraded material adheres to other granules

Question 16

what are mechanisms of wet granule formation?

Answer 16

• Hardening binders.When adhesive is included in the granulating solvent it forms liquid bridges. Adhesive hardens or crystallizes on drying to form solid bridges to bind the particles.
• Crystallization of dissolved substances.The solvent may partially dissolve one of the powdered ingredients. When the granules are dried, crystallization of this material acts as a hardening binder.

Question 17

give an example of a binder liquid and resultant granules/ tabs?

Answer 17

starach/ pregel starch/ gelatine

the type of binder affects the granules properties

Question 18

what are methods of wet granulation?

Answer 18

wet massing –low shear granulation

• powder mixed with binder solution in planetary mixer

Question 19

what occurs in wet massing- low shear granulation?

Answer 19

moist mass then transferred to a granulator e.g. oscillating granulator
•mass forced through a sieve screen. Mesh size determines granule size
•moist granules collected on tray and transferred to tray drying oven

Question 20

what are the disadvantages of tray dryer?

Answer 20

• long drying time
• solute migration may occur due to convective drying at surface
• aggregation of granules due to solid bridge formation

Question 21

what is a high shear mixer granulation?

Answer 21

•stainless steel mixing bowl with three-bladed impeller revolving in horizontal plane. Also, a chopper is included that revolves in horizontal plane (sometimes vertical plane) in upper regions of granulating mass

Question 22

what are the properties of a high shear mixer granulation?

Answer 22

• dry powder mixed by impeller• granulating fluid added and mixed in by impeller
• chopper switched on when moist mass formed –produces bed of fine, granular material
• granules discharged through a sieve into a bowl for fluid bed drying

Question 23

what are the advantages of a high shear mixer granulation?

Answer 23

• advantage – mixing, massing & granulation all done rapidly in same equipment.

Question 24

what are fluidized bed granulators? and how do they work?

Answer 24

• similar principle to fluidized bed dryer
• air blown through powder bed to fluidize and mix
• filter prevents escape of fine particles
• binder solution pumped through spray nozzle over particles
• temperature of air then increased

Question 25

what are the main factors that affect granule properties in a fluizied bed granulators?

Answer 25

* initial particle size distribution (no fluidization if too large (gravity) or too small (get channelling with cohesive powders) * dry powder blending time * air pressure * amount, concentration and type of binder * binder nozzle pressure * granulation time * drying time and temperature

Question 26

what are some of the advantages of fluidized bed drying?

Answer 26

* high drying rates, efficient, lower drying times than tray –good for thermolabilematerials * drying individual granules – free flowing product * good temp control – temp uniform through bed * less chance of solute migration (but if occurs may give hard outer coat (binder), or loss of ingredients due to migration the attrition)

Question 27

what are some of the disadvantages of fluidized bed drying?

Answer 27

attrition and loss of fines (collected by filters) •solute migration •static build up

Question 28

what affects the choice of granulation method?

Answer 28

batch size powder properties degreee of densification flowability

Question 29

how would batch size effect the choice of granulation method?

Answer 29

* small – low shear | * large – high shear or fluidized bed (continuous method – granules discharged and chamber refilled continuously)

Question 30

how would the granules powder properties affect its choice of granulation method?

Answer 30

* hygroscopic or moisture sensitive - use dry granulation * non-wetting, insoluble –use hydrophilic binder solution * heat sensitive –dry granulation

Question 31

how would the degree of densification affect the granulation method of choice?

Answer 31

* large – dry or high shear | * not important – fluid bed or low shear

Question 32

if the paticles have flowability what granulation method would you choose?

Answer 32

fluid bed

Question 33

what are the two types of dry granulation?

Answer 33

Roller compaction and slugging

Question 34

which of the two types of dry granulation is prefered and why?

Answer 34

Currently, roller compaction preferred because it offers greater capacity and ease of process control. Also, higher manufacturing efficiency per hour and it is a continuous process unlike slugging, which is a batch process.

Question 35

what are dry granulation methods suitable for?

Answer 35

moisture- and/or heat-sensitive compounds (no liquid or drying steps). e.g. aspirin Used for substances possessing poor flowabilityand compaction behaviour, such as paracetamoland ibuprofen. Or hygroscopic materials such as a dry herbal extract

Question 36

what is roller compaction?

Answer 36

The main principle is that compressible solids become compact when they are exposed to high stresses from applied pressure between two rolls rotating in the opposite directions

Question 37

what is the most common filler- binder excipient used?= for the roller compactor?

Answer 37

The most common filler–binder excipients used are microcrystalline cellulose (MCC), dibasic calcium phosphate (DCP), and lactose.

Question 38

what factors must be controlled with the roller compactor?

Answer 38

many factors must be controlled and optimised, e.g.roll pressure, roll speed and the feeding rate of starting materials. These factors determine the product properties density of ribbons, flowability, compressibility and tablettingability of granules, as well as the tensile strength of the finished tablets, are highly dependent on these process parameters.

Question 39

what are some of the disadvantages of the roller compaction?

Answer 39

‘loss of reworkability’. Tablets often show inferior tensile strength compared to tablets prepared by wet granulation or direct compaction. Especially with plastic substances. Need to adjusting the plastic/brittle balance of starting materials by selecting appropriate excipients is much more. Also, minimum compaction force should be used, as well as a smaller particle size of starting powder. •non-compacted powder. Because no liquid binder is used, high amounts of fines remain and less product yield is obtained versus wet granulation.

Question 40

what is slugging?

Answer 40

• conventional eccentric tablet press