Powders and Granulation

Question 1

(a) State the primary bonding mechanisms by which the individual powder components form wet granules.

Answer 1

Adhesive and cohesive forces in the mobile liquid film;
Interfacial forces in the mobile liquid film within granules

Question 2

Describe a suitable piece of granulating equipment?

Answer 2

Shear granulator, high-speed mixer/granulator, fluidised-bed granulator.

Question 3

Discuss the critical nature of the absolute amount of water used in terms of the rheological properties of the wet granulation and the effect of extrudate quality.

Answer 3

If too dry, the cohesive and adhesive forces will be weak and formation
of extrudate impossible from the partially wetted powders. The granulation will not exhibit the plastic flow necessary for successful extrusion and densification. Spheronisation will result in a fragmented powder. If too wet, extrusion will be easy but spheronisation will produce large
spheres.

Question 4

Following spheronisation, the water content of the spheronised
pellets is measured at 30 %(w/w) and the total quantity of pellets
is 250 g prior to drying.
(a) Give a reason for the reduced amount of water measured in the
spheronised pellets compared with the wet granulation prior to
extrusion.

Answer 4

Frictional processes during extrusion and spheronisation produce heat
which causes granulating fluid to evaporate and exposure to the
environment causes further desorption of water

Question 5

Following spheronisation, the water content of the spheronised pellets is measured at 30 %(w/w) and the total quantity of pellets is 250 g prior to drying.
Based on the absolute quantity of water measured in the pellets prior to drying, calculate the minimum amount of heat energy required to reduce the water content to 3 %(w/w). The specific
heat capacity of water is 4.18 J.g-1.K-1
, the latent heat of vapourisation is 2256 J.g-1 and room-temperature is 20C.

Answer 5

Quantity of water in pellets prior to drying = 250 g  30% = 75 g
Sensible heating from 20-100C (i.e. T = 80K) = Q1 = mcT
Evaporation of water (30% to 3% = 27%) = Q2 = mL
 Total heat = Q1 + Q2
= (75 g  4.18 J.g-1.K-1  80K) + (27% of 250 g  2256 J.g-1
= 25,080 J + 152,280 J
= 177,360 J (177.36 kJ)

Question 6

Describe a method for determining the final water content of the
pellets.

Answer 6

One from thermogravimetric analysis (TGA or heated balance),
Karl-Fischer potentiometric titration or dynamic vapour sorption (DVS).

Question 7

Whats a powder?

Answer 7

a solid substance in the form of tiny loose particles.

powder (when used to describe a dosage form) describes a formulation in which a drug powder has normally been mixed with other powdered excipients to produce the final product.

Question 8

What is an example of Powder mixes for Internal use only?

Answer 8

Oral powder - e.g. oral antibiotic syrup (amoxicillin oral suspension)

Question 9

What is an example for powder mixes for external use only?

Answer 9

Dusting powder e.g antifungal powder (clotrimazole powder)

Question 10

How do you measure powder properties?

Answer 10

Angle of repose, Bulk density ( tap density), Critical orifice diameter

Question 11

What is a granule?

Answer 11

a small grain.

granules (when used as a dosage form) consist of
powder particles that have been aggregated to form
a larger particle.

Question 12

How do you form a segregated powder, granules and monosized granules

Answer 12

Powder then overmixing forms segregated powder

Powder then granulation forms granules and then sieving forms monosized granules

Question 13

Why do we require to granulate powder?

Answer 13

To prevent segregation
To improve the flow properties
To improve the compaction properties and other reasons in aultons pharmaceutics

Question 14

State the two methods of granulation

Answer 14

Dry granulation and wet granulation

Question 15

What is dry granulation?

Answer 15

Powders are mixed and compressed to form a slug
Slugs are then milled and sieved
Can be used for APIs that do not compress well after wet granulation or are sensitive to granulation fluids (mainly water).

Question 16

What is a wet granulation?

Answer 16

Powders are dry blended and a granulating fluid (normally containing an adhesive binder) is added.

Wet granules are screened, sieved and dried

Individual granules contain bonded powder components

Question 17

What are the five granulation mechanisms?

Answer 17

Powder particles within granules are bound together by

Adhesive and cohesive forces in the immobile liquid film.

Interfacial forces in the mobile liquid film within granules.

Solid bridges after solvent evaporation.

Attractive forces (adhesive and cohesive) between solid particles.

Mechanical interlocking.

Need to describe each of the five bonding mechanisms in more detail

Question 18

What is an adhesive and cohesive force?

Answer 18

Interparticular distances will be reduced causing increased particle attraction due to Van der Waals forces (cohesive).

The presence of a sufficient amount of liquid in a powder will result in a very thin, immobile layer (adhesive force).

Question 19

How do particles get a mobile film around them?

Answer 19

Addition of increasing amounts of granulating fluid (mainly water) will produce a mobile film around all the particles.
dry state - pendular - fenicular - capillary

Question 20

What are solid bridges?

Answer 20

Partial melting, hardening binders and crystallisation of dissolved substances

Question 21

What are the attractive forces between solid particles?

Answer 21

In the absence of a granulating fluid, two attractive forces operate: electrostatic and van der waals

Question 22

What is mechanical interlocking?

Answer 22

Particle size and shape will determine the degree of interlocking

Question 23

What granulation equipment are there?

Answer 23

SHEAR GRANULATOR
powders placed in a planetary mixer
granulation fluid added during agitation
largely redundant in the pharma industry

HIGH-SPEED mixer/ granulator
mixers with three-bladed impeller and an auxilliary chopper
powders are mixed in a bowl by the impeller
granulating fluid is added via a port,
chopper is switched on once the moist mass is formed to break up the mass into granules

FLUIDISED-BED GRANULATOR
heated air is blown up through the powder
to produce a fluidised-bed,
granulation fluid is sprayed onto the bed
to produce granules that are subsequently
dried in the hot air.

Question 24

What is a common application of wet granulation?

Answer 24

Multiparticulates (pellets or beads)
Small size – typically 0.7 – 2.0 mm,
Spherical shape gives good flowability,
Narrow particle size distribution,
Low friability reduces dust formation,
Distributed throughout the GI tract (c/f tablets),
High surface area/volume ratio
- ideal surface for coating
- maximises drug dissolution.

Question 25

What is the process for extrusion and spheronisation?

Answer 25

Wet granulation - extrusion - spheronisation - drying - coating then either capsule filling or tablets are formed

Question 26

What are the advantages of pellets in the GI tract?

Answer 26

Less irregular passage
through the GI tract than
single unit dosage forms
less irregular dosing.
Less chance of ulcerative
damage often experienced
with single unit dosage
forms (esp. NSAIDs).
Failure of individual
pellets will not result
in dose dumping.
Can contain high levels of active ingredient without using excessively large particles (ie minimises excipient content).

Question 27

What are the advanatages of pellets?

Answer 27

• immediate release or controlled release possible,
  
  • can be filled into hard gelatine capsules or
    compacted into tablets to form unit dosage forms,
  • can contain two or more active ingredients,
  • incompatible actives can be manufactured
    as separate pellets (and mixed for capsule filling),
  • can be coated at different ‘coat-weights’
    (in sub-batches) to produce a range of release
    rates (eg immediate, fast or slow release).

Question 28

Advantages of pellets in processing?

Answer 28

• increased bulk density,
  • improved flow properties,
  • reduced dust production (low friability),
  • increased strength,
  • smooth surface (for coating)
  • regular shape for packing (capsules, tablets)

Question 29

What are the disadvantages of pellets in processing?

Answer 29

• manufacture is more labour/energy intensive
  than other granulation methods mainly due to
  the high levels of solvent (water) required.

Question 30

What is the manufactoring process

Answer 30

Dry blending - Wet granulation - Extrusion - Spheronisation - Drying and then screening

Question 31

What does Dry blending involve?

Answer 31

uses normal powder mixing
equipment eg Y-cone, rotating tube

Question 32

What does Wet Granulation involve?

Answer 32

uses normal wet granulation equipment eg shear mixers, high-speed or fluidised-bed

Question 33

What does Extrusion produce?

Answer 33

forms rod-shaped particles of uniform diameter

Question 34

What does spheronisation produce?

Answer 34

forms spherical particles from rod-shaped particles

Question 35

Why is drying used?

Answer 35

to achieve the desired final water content

Question 36

What is screening used for?

Answer 36

to achieve the desired narrow size distribution

Question 37

How does water content affect pellet quality?

Answer 37

• can range between a lower and upper limit and still produce pellets of an acceptable quality.

If LESS water - lots of dust formed during spheronisation producing a large yield of fines,

IF MORE WATER - over-wetted mass results in agglomeration of individual pellets (large spheres result).

Question 38

How does composition affect pellet quality?

Answer 38

different grades of the same excipient,
- solubility of excipients and drug/s,
- particle size of starting materials,
- amount and type of granulation fluid used

Composition of the wet mass is critical in determining
the properties of the particles produced,

ie the physical properties of the specific excipient used, on their own and in combination with the other excipients/drug, will determine the amount of granulating fluid required for optimum extrusion/spheronisation properties.

Question 39

What are the formulation variables?

Answer 39

Composition of the wet mass is critical in determining
the properties of the particles produced,
ie the physical properties of the specific excipients used, on their own and in combination with the other excipients/drug, will determine the amount of granulating fluid required for optimum extrusion/spheronisation properties.

The absolute level of granulating fluid used is arguably the single most influential factor for successful processing

The wet mass must be plastic enough to deform when extruded and to break-off to form uniformly sized cylindrical particles that can be readily spheronised.

Question 40

What types of extruders do you get?

Answer 40

Screw extruders - axial and radial
Roll extruders (gravity fed) cylinder and gear

Question 41

Factors affecting pellet quality are?

Answer 41

Extruder type - axial/radial screw extruder give different extrudate densities; differences in ‘work done’ produces temperature variations. variations in shear stress/shear rate of different extruders and the specific rheological properties of the wet mass.

Extrusion speed - surface ‘roughness’ and ‘shark-skinning’ may (or may not!) become more pronounced with increased speeds (use of lubricants inhibits this).

Extrusion temperature - increased temperatures causes evaporation of granulation fluid (a screw extruder can be fitted with an external cooling jacket)

Extrusion screen - diameter of perforations effects pellet size, screen thickness effects densification of mass

Question 42

What are the process variables for spheronisation?

Answer 42

Feed rate of the wet mass - dependent on the plasticity and cohesivenes of the wet mass.

Diameter of the die and length of the die all affect the final size of pellets

Water content - if too high, extrudate/pellets aggregate forming large spheres during spheronisation
if too low, extrusion is difficult (can damage equipment) and much powder is produced in spheroniser

Question 43

What are the factors affecting pellet quality - spheronisation

Answer 43

Spheronisation speed - affects the particle size of pellets. Some researchers report increased quantities of small pellets and fines,
others report decreased fines and larger mean pellet diameters!!
- pellet hardness, roundness, porosity, bulk and tapped densities friability, flow properties and surface structure are all affected.
- ‘optimum speed’ should be discerned (generally >400 rpm).

Spheronisation time - no clear correlations exists.
(2-10 mins is normal).
Spheroniser load - no clear correlations exist
(best to avoid overloading).

Question 44

What is the 3rd line?

Answer 44

COX-2 inhibitors (‘coxibs’):
NSAIDs that directly target COX-2, reducing the risk of peptic ulceration.
Higher risk of cardiovascular adverse effects due to inhibition of COX-2 in blood vessels, leading to a decrease of production of prostacyclin which may cause clot formation and hypertension.
Balance cardiovascular vs. GI risk.