1
Q
what is granulation
A
size enlargement process during which (in the presence of a binder liquid or compressive forces) fine powders or particulate are bound together to produce physically larger aggregates of sufficient integrity but the original constituents can still be identifies
2
Q
why do we granulate
A
- improve flowability
- reduce segregation tendency
- improve compactability
- reduce dust
3
Q
methods of granulation
A
- direct compression
- thermoplastic granulation
- wet granulation
- dry granulation
4
Q
direct compression
A
- most efficient method to prepare free flowing powders for tableting, mix and blend, without additional step to increase particle size
- suitable for materials with suitable flow, narrow size distribution, minimal segregation and good compressibility
5
Q
dry granulation
A
- aka slugging, which produce ‘poor quality’ tablets, showing wide variability in weight and hardness due to poor flow of pre mix into dies
- powdered tableting pre-mix are blended well and compressed into large tablets or slugs of 25mm or larger, using heavy duty compaction machines (4-6 ton)
6
Q
roller compaction
A
- efficient dry granulation process capable of continuous production
- homogenously mixed powder blend passed between two counter-rotating rollers and the compact (flake/ribbon/briquette) formed can be milled into granules
7
Q
advantage of roller compaction
A
- fewer unit processes, thus lower COP
2. suitable for heat/water sensi materials
8
Q
bonding mechanism in dry granulations
A
- particle rearrangement: occurs initially as powder movement begins filling voids, displacing air, increasing powder density (as compression forces increase, deformation increases leading to fracture or bonding)
- particle fragmentation: second stage- higher compression loads, fragmentation of particle leads to new surfaces, increased point of contacts, increasing potential bonding sites
- particle bonding: @ molecular level- van der waals
9
Q
factor affecting compacting strength
A
- applied pressure
- extend of air entrapment (use of vacuum system)
- roll dwell time
- powder void fraction (space into which air is compacted)
- particle size of component and density
- type of binders included
- moisture content of material
10
Q
wet granulation
A
- most widely used, possible for almost any powder/ mixture provided they are stable to moisture/heat
- hardness and solubility controlled by using suitable binders and granulating agents
11
Q
purpose of wet granulation
A
- improve flow properties
- reduce bulk volume, densification
- improve compression properties
- improve distribution of minor constituent (eg. low dose drug, binder, colorant)
- prevent components from segregating
- reduce dust
- minimise or mitigate adverse properties of API (hydrophobicity, bad taste, poor stability)
12
Q
disadvantage of wet granulation
A
- additional processing steps, add complexity, cost, extra validation work
- additional time and space needed
- unsuitable for moisture-sensitive or thermolabile drug
- material loss due to additional processing steps
13
Q
how does small scale wet granulation work?
A
- blend aPI and excipients
- add granulating liquid to moisten the mass
- pass mixture through screen forming extrudates
- dry at 60 degrees
- re-granulating through screen to mill it down to reasonable sized granules
- compacting to form tablets
14
Q
agglomerate growth
A
during wet granulation, with agitation, an eqm exists between crushing and coalescence
- stronger agglomerate coalesce in collision to form bigger ones
- weaker agglomerates are often crushed- fragments or fines which either re-enter cycle of nucleation coalescence or be picked up by bigger agglomerats by layering
TLDR: if eqm favours (with impact force/ addition of liquid) the coalescence (forming) mechanism, the agglomerate grows
15
Q
liquid saturation
A
ratio of pore volume occupied by liquid to the total pores within the agglomerate
16
Q
unsaturated granule
A
3 phase system
17
Q
saturated granule
A
2 phase system
18
Q
effect of densification
A
can increase the liquid saturation and surface plasticity which will promote agglomerate growth by coalescence
- as agglomerate becomes denser, it becomes more resistant to breakdown due to attrition
19
Q
change in states of liquid bridging saturation caused by densification of agglomerate
A
- pendular
- funicular
- capillary
- droplet
20
Q
why does smaller particles require higher amount of binder liquid
A
- smaller particles are usually more difficult to densify due to higher packing density
- with agglomerate size being kept constant, total primary particles surface area is larger when formed by smaller particles
21
Q
how does particle shape affect packing properties
A
- irregular shape will create interlocking among particles and thus increase agglomerate strength
- whereas a rounder particles reduce the strength
- possibility to compensate for the raw materials with unsuitable properties with the one with good granulation properties
22
Q
important factor for granule formulation
A
- particle size
- size distribution
23
Q
requirement for successful granulation:
A
- dissolution of solids into the granulating liquid, then on drying, solute forms crystalline bridges
- dissolved binder in the granulating liquid may also be responsible for the formation of solid bridges
- solid bridges formed the binding structures between dried particles
- if solid bridges are absent, granules will revert back to the original powder
24
Q
bonding mechanism for agglomerate
A
- adhesion and cohesion forces immobile liquid film hold particles tgt for secondary bonding mechanisms
- interfacial forces and capillary pressure of mobile liquid, prerequisite to solid bridges
- solid bridges, formed by chemical reaction, crystallization of solutes, deposition of solidification of binders
- attractive forces between solid particles brought together very close (by pressure) form closed or interlocking bonds by mechnical folding or interlocking of bulky particles (fibres)
25
agglomerate growth mechanism
1. nucleation: start granulation, begins around droplets of binder, primary particles are drawn together to form 3-phase air-water-solid nuclei
2. coalescence: formation of larger agglomerates by successful collisions (must be surface moisture imparting plasticity, enable partial deformation, enable coalescence)
3. layering: successive addition of fines on larger agglomerate (like coating)
4. abrasion transfer: mass transfer between two colliding agglomerates resulting in abraded material from one agglomerate deposited onto another
5. ball growth/ snow balling growth: rapid growth into large, spherical granules, rapid coalescence continue, producing an unstable system, often associated with over-wetted mass
26
high shear granulation (mixer granulator)
- widely used in pharma industry as mixer and granulator
- blending wet massing operations are accomplished through strong mechanical agitation by an impeller and de-lumping by a chopper
27
steps of granulation by high shear mixer
1. mixing of dry powder at high impeller speed (2-5min)
2. addition of liquid binders, lower speeds, 1-2 min
3. wet massing, high speed, 1-5min (note temp increment)
4. wet sieving of granules, usually using cone mill
5. drying usually by fluid bed dryer
6. re-granulation by cone mill
28
advantage of HSM granulation
- short process time
- less binder needed (shorter drying time)
- suitable for cohesive material as well as dense products
- less sensitive to raw material physical attributes than fluid bed granulation
- closed system: Good manufacturing practice, possibility for vacuum, microwave drying
- easy to clean, clean-in-place possible
29
issues with HSM granulation
- mechanical degradation of weak powders and granules
- some heat generation, unsuitable for thermolabile products
- risk of over wetting leading to uncontrolled growth
30
process variables
- impeller rotation speed (tip speed)
- chopper rotation speed
- load
- liquid addition method
- liquid addition rate
- wet massing time
31
role of chopper in high shear granulation
- no effect upon the granule size distribution
- function to disturb uniform flow pattern of mass
- also chop up oversized aggregates if present
32
fluidisation
produced by creasing a pressure drop across a material bed or product layer
- air is passed through material bed at speed high enough to set particles in motion without exceeding particles' terminal velocity
33
movement of air through product layer for
1. granulation
2. drying
3. coating
34
characteristics of fluid bed granules
- open structure
- bulk density similar to raw materials
- good distribution of binder on surface
- uniform and narrow particle size distribution
- good texture
35
hot melt extrusion
the process of applying heat and pressure to melt polymer and force it through an orifice in a continuous process to form extrudates
- mixing API with polymers can enhance the API bioavailability or prepare precursors for thermoplastic drug eluting devices such as subcut or intraocular implants and intravag rings
- popular for solubility enhancement of poorly water soluble API
36
how is hot melt extrusion HME carried out
using extruder with a heat-jacketed barrel containing one or two rotating screws
37
four sections for extruders of HME
1. feeder for material entry, continuously supplied to in a controlled manner
2. conveying process barrel with screws for material
transport, melting, mixing and granulation
3. orifice (die) for shaping the material as it leaves extruder
4. downstream auxiliary equipment for cooling, cutting and or collecting finished product
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