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Granulation Flashcards

1
Q

what is granulation?

A
  • size enlargement process
  • the use of a binding liquid (wet) or compressive forces (direct compression/dry)
  • original constituents can still be identified
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2
Q

advantages of granulation

A

improves flowability

reduce segregation tendency

improve compactability

reduce dust

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3
Q

4 different methods of granulation

A
  • direct compression
  • dry granulation
  • wet granulation
  • thermoplastic granulation

(bet wet and thermoplastic: continuous wet granulation using twin screw extrusion)

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4
Q

material characteristics required for direct compression

A
  • suitable flow
  • narrow size distribution
  • minimal segregation
  • and have good compressibility
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5
Q

when is direct compression used

A

to prepare free flowing powders for tableting, mix and blend, wo the additional step to increase particles size

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6
Q

what are the tablet (slug) characteristics at the end of dry granulation - slugging method

A
  • poor quality tablet
  • wide variability in weight and hardness
  • poor flow of pre-mix
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7
Q

what to do to convert slugs into granules?

A
  • milled and sieved into suitable size fractions
  • collected as granules for tableting
  • fines may be slugged again
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8
Q

what is dry granulation - slugging?

A

powdered tableting where pre-mix are compressed in large tablets/slugs of 25mm or larger, using heavy-duty compaction machines

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9
Q

what is dry granulation - roll compaction

A

mixed powder blend passed bet 2 counter-rotating rollers and the compact is formed, which is milled into granules

compacts = flake, ribbon, briquette

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10
Q

why is the roll surface in compaction roll important

A

establishes the friction required bet product and roll surface

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11
Q

adv and disadv of smooth compacts

A

adv: force applied was even
disadv: material can slip between the roll, thus no ribbon may be formed

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12
Q

adv and disadv of serrated/textured compacts

A

adv: provide better grip
disadv: pressure at top and bottom (peak and valley is different)

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13
Q

advantages of roller compaction

A
  • fewer unit processes, thus lower production cost
  • suitable for heat/water sensitive materials
  • process used to prepare control release products
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14
Q

bonding mechanism in dry granulation

A

step 1: particle rearrangement
~ powder moves to fill spaces, thus displaces air –> increase powder density
~ particles start to deform as compression forces increase, more contact points bet particles –> more bonding happens where plastic deformation happens

step 2: particle fragmentation
~ at higher compression: second stage of bond formation
~ fragmented particles create new surfaces, increase contact, thus increase bonding sites

step 3: particle bonding
~ occurs at molecular level, by vdW forces

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15
Q

factors affecting compact strength for dry granulation

A
  • applied pressure
  • extend of air entrapment
  • roll dwell time
  • powder void fraction (how much air is compacted instead of powder)
  • particle size of component and density
  • type of binder used
  • moisture content of material
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16
Q

why is wet granulation preferred over dry

A
  • hardness and solubility can be controlled by using suitable binder and granulating agents
  • improves flow properties
  • reduce bulk volume, densification
  • improve compression properties
    ~ dry granules are pre-compressed and thus lose their compressibility –> tablet strength is lower
    ~thus wet granules can prevent this
  • improves distribution of minor constituents (e.g. low dose drug, binder/colorant used minimally)
  • prevent segregation of component
  • reduce dust
  • minimise adverse properties of API (hydrophobicity, bad taste, poor stability)
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17
Q

wet granulation can use two types of solvent. but which is more preferred

A
  • aq solvent (water) = easy to dispose

- non-aq solvent for water sensitive material = factory has to be explosion-proof

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18
Q

disadvantages of wet granulation

A
  • additional processing step
    ~ more complex, cost, validation work
  • additional time and space
  • unsuitable for moisture-sensitive or thermolabile drugs
  • material loss due to additional processing step
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19
Q

steps for a small scale wet granulation

A
  • API + excipient + granulating liquid –> moistened mass
  • moistened mass pass through screen –> extrudates
  • extrudates are then dried at 60c
  • dried extrudates are re-granulated through a screen
  • the now formed granules + lubricant (e.g. MgSt) undergo compacting to become tablets
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20
Q

when does agglomerate growth happens?

A

when the eq between crushing and coalescence, and when the eq FAVOURS the coalescence mechanism

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21
Q

3 ways agglomerate growth happens

A

(1) stronger agglomerates coalesce by collision with other agglomerates to form bigger ones
(2) weaker agglomerates are crushed, where the fragments/fines re-enter into the cycle of nucleation-coalescence
(3) or the fragment/fines picked up by bigger agglomerates by layering process

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22
Q

what is liquid saturation?

A

ratio of pore volume occupied by liquid to the total volume of pores within agglomerate

can have:
3-phase = air, liquid, solid (unsaturated)
2-phase = liquid, solid (saturated)

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23
Q

why does densification promote agglomerate growth by coalescence

A

densification increases liquid saturation and surface plasticity –> promote agglomerate growth by coalescence

  • as agglomerate becomes denser, more resistant to breakdown via attrition, therefore, growth takes place
24
Q

4 different states of during densification of agglomerate and the trend seen with agglomerates becoming denser

A

(1) pendular
(2) funicular
(3) capillary
(4) droplet (has surface plasticity, agglomerate growth occurs)

when agglomerates becomes denser, more resistant to breakdown due to attrition

25
Q

2 ways liquid can be distributed to make granule more surface plastic and liquid saturation and promote agglomerate growth
(states of liquid distribution caused by…)

A

(1) liquid addition

2) densification (particles come together

26
Q

granulation examples for liquid addition and densification

A

(1) liquid addition = fluid bed granulation
(2) densification = high shear granulation

both granule growth allows the final product form which is the tablet to have good compressibility and makes stronger tablets

27
Q

why small size primary particles can be a hassle in the granulation process, but makes tablets (i.e. the final product) to have very good compressibility, and stronger as compared to using larger particles

A

hassle: smaller particles more difficult to densify due to high packing density (as they trap more air, need more effort to densify) - require more binder liquid than larger particles

but and adv: total small size primary particle surface area is larger = make more bonds = stronger tablets

28
Q

what particle shape is preferred to make stronger tablets (end product)

A
  • irregular particle shape = interlocking among particles –> increase agglomerate strength
  • rounder particles = reduce strength
29
Q

why is particle shape impt

A

affects the packing properties; and thus the surface property of the end product

30
Q

important factors for forming granules

A

(1)

  • wide size distribution
  • Low mean particle size
  • -> high strength granule is formed via nucleation and coalescence
  • need for fines/fragments

(2) not preferred
- narrow size distribution
- large mean particle size
- -> low strength granule even with broken particles that can increase contact
- -> via nucleation and layering

31
Q

what is required to form successful granules (final fate of granules in wet granulation)?

A

solid bridges have to be formed bet the dried particles

if no solid bridges formed: granules revert back to original powder

32
Q

process of a successful granulation (final fate of granules in wet granulation)?

A

(1) dissolution of solids/particles into granulating liquid –> drying –> the solute (aq/non-aq) forms crystalline bridges
- ESP for drugs that are water soluble (no need for binder)

(2) the dissolved binder in the granulating liquid may also be responsible for the formation of solid bridges
- ESP FOR drugs that are NOT water soluble
- example of binder: PVP, starch, lactose

33
Q

5 agglomerate growth mechanisms

A

(1) nucleation
- primary particles drawn to droplets of binder to form 3 phase (air-water-solid) nuclei
~ pendular liquid bridges are formed
~mass & number of nuclei changes over time

(2) coalescence:
- forming larger agglomerates by successful collisions
~ for coalescence: surface plasticity required (for partial deformation)
~ for surface plasticity: surface moisture required

(3) layering
- addition of fines/fragments onto larger agglomerate
- slow process, like a coating process
- fines from: abraded materials
- (3) seen in solution/suspension/powder layering (methods written in pelletization)

(4) abrasion transfer
- mass transfer bet 2 colliding agglomerates
- where abraded material from one agglomerate deposited onto another

(5) ball/ snow balling growth
- rapid coalescence happens, producing an unstable system
- due to over-wetted mass (excess moisture)

34
Q

What are some bonding mechanism for agglomeration?

how are the solid bridges formed during agglomeration

A
  • adhesion and cohesion forces by immobilize liquid film holds particles via secondary bonding mechanism
  • interfacial forces and capillary pressure of mobile liquid required for solid bridges to form
    ~ attractive forces (e.g. short range vwD, electrostatic, magnetic) bet solid particles
    ~ brought together via pressure
  • solid bridges formed by chemical rxn, crystallisation of solutes, deposition or solidification of binders
    ~ interlocking bonds by mechanical folding or interlocking bulky particles (e.g. fibres)
35
Q

how are agglomerates FORMED

not talking about agglomerate growth

A

by distributive mechanism:

solid + binder –> distribution – coalescence

36
Q

what is a high shear mixer (HSM) granulator?

A
  • used in pharma industry, as a mixer and granulator
37
Q

how does the HSM granulator works?

A

(1) blending and wet massing through strong mechanical agitation by an impeller and de-lumping by a chopper
(2) mixing, densification, agglomeration of wetted materials done through shearing and compaction forces exerted by impeller, tip speed (5-15m/s)

(3) chopper (small agitator)
~ 1500-400rpm
~ function: breaks lumps into smaller fragments

38
Q

process steps of doing granulation by HSM

A

(1) mixing dry powder at high impeller speed for 2-5 min
(2) add the liquid binders; at lower speed 1-2min
(3) wet massing, high speed (1-5min)
(4) wet sieve the granules, usually using a cone mill
(5) drying, by a fluid bed dryer
(6) re-granulation, by cone mill

39
Q

different types of HSM

A

(1) top-drive (impeller and chopper at top)
(2) bottom-drive (impeller and chopper at the bottom)
(3) hybrid model: bottom- drive is impeller, top-drive is chopper

40
Q

advantages of HSM granulation

A
  • short process time
  • less binder needed, thus shorter drying time
  • suitable for cohesive materials as well as dense products
  • less sensitive to raw material physical attributes than fluid bed granulation
  • close system: GMP, can have vacuum, microwave drying
  • easy to clean, clean-in-place (CIP) possible
41
Q

disadvantages/ problems of HSM granulation

A

~mechanical degradation of weak powders and granules

~ some generate heat, unsuitable for thermolabile products

~risk of over-wetting = leading to uncontrolled growth

42
Q

what can vary in the HSM granulation

A

~ impeller rotation speed (aka tip speed)

~ chopper rotation speed (usually kep fixed)

~ load

~ liquid additional method (spray/pour)

~liquid addition rate

~ wet massing time

43
Q

what’s the role of the chopper in HSM granulation

A

~ size and speed of chopper has NO EFFECT on granule size distribution

function

  • disturb uniform flow pattern of the mass
  • chop up oversized aggregates, if present
44
Q

how does the fluid bed granulation work?

A
  • using theory of fluidization
    ~ fluidization occurs when a pressure drop is created across the bed
    ~ in fluidization: air is passed through a material bed at a high speed to set particles in motion WITHOUT exceeding the particles terminal velocity
45
Q

whats the purpose of air in the fluid bed processing?

A
  • movement of air through product layer for:
    ~ granulation
    ~ drying
    ~ coating

(the air is being pulled by vacuum and not being pushed)

46
Q

whats the purpose of spray addition

A
  • spray addition
    ~ ensure constant inlet air temp/humidity
    ~varies air flow
    ~ binder/wetting agent: varies addition rate & varies atomising pressure
47
Q

how do we know when fluid bed granulation has completed?

A
  • endpoint
    ~ look at exhaust temp = increases and plateaus
  • product moisture
    ~ no more water
48
Q

what affects granule formation and growth for HSM granulator and fluid bed granulation

A
  • choice of binder and conc play an impt role

- concentration and viscosity

49
Q

the mechanism for fluid bed granulation?

A

droplet formation

evaporation

sticky droplets contact powder particles

open lattice snowflake type granule
~ good binder distribution
~ good compressibility

50
Q

how is surface plasticity achieved in HSM granulation and fluid bed granulation?

A

HSM granulation: densification

Fluid bed granulation: adding more liquid

51
Q

characteristics of the fluid bed granules

A
  • open structure
  • bulk density similar to raw materials
    ~(products are highly compressible (got a lot of space) - make stronger tablets)
  • good distribution of binder on surface
    ~ these granules are good to distribute LOW DOSE DRUG
  • uniform and narrow particle size distribution
  • good texture
52
Q

adv and disadv of fluid bed granulation

A

Adv:
- produce good quality granules, free-flowing, compressible

Disadv:
- feed materials and processing variables need good control to achieve desired end product attribute

  • various equipment design variations = contribute to differences in operation and final pdt attributes
53
Q

describe the thermoplastic granulation by hot melt extrusion (HME)

one method of thermoplastic granulation = HME

A
  • apply heat and pressure -> melt polymer –> force through orifice to form extrudates
  • API’s bioavailability can be enhance by mixing API with polymer
  • form precursors for thermoplastic drug eluting devices (SC/intraocular implants, intravaginal rings)
54
Q

HME popular for what process?

A

solubility enhancement of poorly water soluble API

55
Q

what is the process steps for HME?

A
  • extruder with heat-jacketed barrel containing 1/2 rotating screw

(1) feeder
(2) conveying barrel w screw for material transport, melting, mixing, and granulation
(3) orifice for shaping material as it leaves the extruder
(4) cooling, cutting, collecting finish product

56
Q

use of twin screw extrusion technology (continuous manufacturing)

A
  • thermoplastic and wet granulation system = allows for continuous manufacturing

(hybrid method bet wet and thermoplastic granulation)

Solid (16 decks)

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