Granulation Flashcards
what is granulation?
- size enlargement process
- the use of a binding liquid (wet) or compressive forces (direct compression/dry)
- original constituents can still be identified
advantages of granulation
improves flowability
reduce segregation tendency
improve compactability
reduce dust
4 different methods of granulation
- direct compression
- dry granulation
- wet granulation
- thermoplastic granulation
(bet wet and thermoplastic: continuous wet granulation using twin screw extrusion)
material characteristics required for direct compression
- suitable flow
- narrow size distribution
- minimal segregation
- and have good compressibility
when is direct compression used
to prepare free flowing powders for tableting, mix and blend, wo the additional step to increase particles size
what are the tablet (slug) characteristics at the end of dry granulation - slugging method
- poor quality tablet
- wide variability in weight and hardness
- poor flow of pre-mix
what to do to convert slugs into granules?
- milled and sieved into suitable size fractions
- collected as granules for tableting
- fines may be slugged again
what is dry granulation - slugging?
powdered tableting where pre-mix are compressed in large tablets/slugs of 25mm or larger, using heavy-duty compaction machines
what is dry granulation - roll compaction
mixed powder blend passed bet 2 counter-rotating rollers and the compact is formed, which is milled into granules
compacts = flake, ribbon, briquette
why is the roll surface in compaction roll important
establishes the friction required bet product and roll surface
adv and disadv of smooth compacts
adv: force applied was even
disadv: material can slip between the roll, thus no ribbon may be formed
adv and disadv of serrated/textured compacts
adv: provide better grip
disadv: pressure at top and bottom (peak and valley is different)
advantages of roller compaction
- fewer unit processes, thus lower production cost
- suitable for heat/water sensitive materials
- process used to prepare control release products
bonding mechanism in dry granulation
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
factors affecting compact strength for dry granulation
- 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
why is wet granulation preferred over dry
- 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)
wet granulation can use two types of solvent. but which is more preferred
- aq solvent (water) = easy to dispose
- non-aq solvent for water sensitive material = factory has to be explosion-proof
disadvantages of wet granulation
- 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
steps for a small scale wet granulation
- 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
when does agglomerate growth happens?
when the eq between crushing and coalescence, and when the eq FAVOURS the coalescence mechanism
3 ways agglomerate growth happens
(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
what is liquid saturation?
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)
why does densification promote agglomerate growth by coalescence
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
4 different states of during densification of agglomerate and the trend seen with agglomerates becoming denser
(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
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
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
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
what particle shape is preferred to make stronger tablets (end product)
- irregular particle shape = interlocking among particles –> increase agglomerate strength
- rounder particles = reduce strength
why is particle shape impt
affects the packing properties; and thus the surface property of the end product
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
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
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
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)
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)
how are agglomerates FORMED
not talking about agglomerate growth
by distributive mechanism:
solid + binder –> distribution – coalescence
what is a high shear mixer (HSM) granulator?
- used in pharma industry, as a mixer and granulator
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
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
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
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
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
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
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
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
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)
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
how do we know when fluid bed granulation has completed?
- endpoint
~ look at exhaust temp = increases and plateaus - product moisture
~ no more water
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
the mechanism for fluid bed granulation?
droplet formation
evaporation
sticky droplets contact powder particles
open lattice snowflake type granule
~ good binder distribution
~ good compressibility
how is surface plasticity achieved in HSM granulation and fluid bed granulation?
HSM granulation: densification
Fluid bed granulation: adding more liquid
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
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
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)
HME popular for what process?
solubility enhancement of poorly water soluble API
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
use of twin screw extrusion technology (continuous manufacturing)
- thermoplastic and wet granulation system = allows for continuous manufacturing
(hybrid method bet wet and thermoplastic granulation)
