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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
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...)
(1) liquid addition | 2) densification (particles come together
26
granulation examples for liquid addition and densification
(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
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
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
what particle shape is preferred to make stronger tablets (end product)
- irregular particle shape = interlocking among particles --> increase agglomerate strength - rounder particles = reduce strength
29
why is particle shape impt
affects the packing properties; and thus the surface property of the end product
30
important factors for forming granules
(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
what is required to form successful granules (final fate of granules in wet granulation)?
solid bridges have to be formed bet the dried particles if no solid bridges formed: granules revert back to original powder
32
process of a successful granulation (final fate of granules in wet granulation)?
(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
5 agglomerate growth mechanisms
(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
What are some bonding mechanism for agglomeration? | how are the solid bridges formed during agglomeration
- 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
how are agglomerates FORMED | not talking about agglomerate growth
by distributive mechanism: | solid + binder --> distribution -- coalescence
36
what is a high shear mixer (HSM) granulator?
- used in pharma industry, as a mixer and granulator
37
how does the HSM granulator works?
(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
process steps of doing granulation by HSM
(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
different types of HSM
(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
advantages of HSM granulation
- 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
disadvantages/ problems of HSM granulation
~mechanical degradation of weak powders and granules ~ some generate heat, unsuitable for thermolabile products ~risk of over-wetting = leading to uncontrolled growth
42
what can vary in the HSM granulation
~ 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
what's the role of the chopper in HSM granulation
~ 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
how does the fluid bed granulation work?
- 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
whats the purpose of air in the fluid bed processing?
- movement of air through product layer for: ~ granulation ~ drying ~ coating (the air is being pulled by vacuum and not being pushed)
46
whats the purpose of spray addition
- spray addition ~ ensure constant inlet air temp/humidity ~varies air flow ~ binder/wetting agent: varies addition rate & varies atomising pressure
47
how do we know when fluid bed granulation has completed?
- endpoint ~ look at exhaust temp = increases and plateaus - product moisture ~ no more water
48
what affects granule formation and growth for HSM granulator and fluid bed granulation
- choice of binder and conc play an impt role | - concentration and viscosity
49
the mechanism for fluid bed granulation?
droplet formation evaporation sticky droplets contact powder particles open lattice *snowflake* type granule ~ good binder distribution ~ good compressibility
50
how is surface plasticity achieved in HSM granulation and fluid bed granulation?
HSM granulation: densification Fluid bed granulation: adding more liquid
51
characteristics of the fluid bed granules
- 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
adv and disadv of fluid bed granulation
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
describe the thermoplastic granulation by hot melt extrusion (HME) one method of thermoplastic granulation = HME
- 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
HME popular for what process?
solubility enhancement of *poorly water soluble API*
55
what is the process steps for HME?
- 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
use of twin screw extrusion technology (continuous manufacturing)
- thermoplastic and wet granulation system = allows for continuous manufacturing (hybrid method bet wet and thermoplastic granulation)

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