Granulation Flashcards
Purpose of wet granulation
improve flow properties
reduce bulk volume, densification
improve compression properties
improve distribution of minor constituent
prevent components from segregating
reduce dust
minimise or mitigate adverse properties of API
Disadvantages of wet granulation
additional processing steps, adds complexity, cost, extra validation work
additional time and space needed
unsuitable for moisture-sensitive or thermolabile drugs
material loss due to additional processing steps
Why is direct compression (dry granulation) used:
most effective and efficient method to prepare free flowing powders for tableting, mix and blend, without additional step to increase particle size
no need addition of additional materials
Criteria needed for dry granulation:
suitable flow
narrow size distribution
minimal segregation
good compressibility
Steps for dry granulation:
Slugging
Roller compaction
Definition of slugging:
Powdered tableting premix blended well and compressed into large tablets/slugs of 25mm or larger
Generally poor quality tablets: wide variety in weight and harness due to poor flow of premix into dies
How are slugs processed:
milled and sieved into suitable sized fractions
collected as granules for tableting
Fines may be slugged again
Roller compaction:
efficient dry granulation process – used for continuous production
Homogenously mixed powder blend passed between two counter rotating rotating rollers and compact is formed (flake, ribbon, briquette)
Compaction roll:
patterned surface grips material better – can cause slight difference in density
if there is too much pressure, rollers will mov e slightly apart
Major advantages of roller compaction:
Fewer unit processes, lower production cost
suitable for heat and/or water sensitive materials
feasible for preparing controlled release products
Bonding mechanisms in dry granulations:
Particle rearrangement: particle shape and size are key factors
Particle fragmentation: bond formation at higher compression loads – creates multiple new surfaces and increase points of contact and thus potential bonding sites
Particle bonding: occurs at molecular level – usually by van der waal forces and hydrogen bonding
Factors affecting compact strength of granules formed by roll compaction:
Applied pressure
extent of air entrapment
roll dwell time: time where 90% of force is applied
Powder void fraction: space into which air is compacted
particle size of component and density
type of binders used
moisture content of material
Wet granulation
most widely used, possible for almost any powder/mixture produced provided they are stable to moisture/heat
How is hardness controlled in wet granulation:
Using suitable grinders and granulating agents
non aqueous liquids can be used for water sensitive materials
Purpose of wet granulation:
increase flow properties
decrease bulk volume, densification
Increase compression properties
increase distribution of minor constituents – low dose drug, binder, colorant
Prevent components from segregating
decrease dust
minimise/mitigate adverse properties of API
Disadvantages of wet granulation:
additional processing steps, add complexity, cost, extra validation work –> more regulation needed
Additional time and space needed
unsuitable for moisture sensitive/thermolabile drugs
Material loss due to additional processing steps – the more processes, the more raw materials lost – cost advantage lost
Agglomerate growth:
equilibrium exists between crushing and coalescence
- Stronger agglomerates coalease in collision to form bigger ones
- weaker agglomerates often crushed – fragments will be picked up by larger agglomerates by layering process
Liquid saturation:
ratio of pore volume occupied by liquid to total volume of pores within agglomerate – impt to study granulation process
Effects of densification:
increase liquid saturation and surface plasticity – promote agglomerate growth by coalescence
- as agglomerate becomes denser, becomes more resistant to breakdown due to attrition
Increasing liquid saturation beyond maximum will increase surface plasticity: water need to be at surface to make it surface active
Done by liquid addition/densification
Particle size of primary compounds:
Smaller particles require higher amount of binder liquid than larger particle:
- Harder to densify due to higher packing density
- constant agglomerate size, total primary particles’ surface area larger when formed by larger particles
Particle shape and binding properties:
Shape affects packing properties of materials: closely related to surface property of product
Irregular particle shape creates interlocking among particles – increase agglomerate strength – rounder particles reduce strength
Possibility to compensate for new materials with unsuitable properties with materials with good granulation properties
Size and size distribution of granules:
Low mean particle size + wide size distribution – high strength (nucleation and coalescence)
Large mean particle size+ narrow size distribution – low strength (nucleation +layering)
if too much size diff in final mix. mix will segregate easily
Requirements for successful granulation:
Dissolution of solids into granulating liquid
Dissolved binder in granulating liquid may be responsible for formulation of solid bridges
solid bridges form binding structures between dried particles – if absent, granules will revert back to original powder
Bonding and growth mechanisms:
Adhesion and cohesion forces by immobile liquid film hold particles together for secondary bonding mechanisms
Interfacial forces and capillary pressure of mobile liquid
Solid bridges formed by chemical reaction, crystallisation of solute, deposition/solidification of binders
Dissolving of some of the rough portion of particles
Bonding mechanisms for agglomeration
Attractive forces
Interlocking bonds by mechanical folding/interlocking of bulky particles
Types of attractive forces involved in agglomeration:
short range van der waals, electrostatic/magnetic forces between solid particles brought together very close
Mechanisms of growth of agglomeration:
- Nucleation
- Coalescence
- Layering
- Abrasion transfer
- Ball growth/snowballing growth
What is nucleation:
Primary particles draw together to form 3 phase air-water-solid nuclei
- Liquid bridges formed – pendular stage
- Mass and number of nuclei change as function of time
What is coalescence
formation of larger agglomerates by successful collisions
Surface plasticity needed for successful coalescences (surface moisture) – also enables partial deformation and coalescence
What is layering:
successive addition of fines on larger agglomerate – generally a much slower process
- Fines for layering much smaller than larger agglomerate
- Well-controlled and straightforward
- can also be described as coating process
What is abrasion transfer:
Mass transfer between 2 colliding agglomerates, resulting in abraded material from one agglomerate to be deposited on the other
What is ball growth/snowballing growth:
Rapid growth into large, spherical granules, rapid coalescence continue
- Produce unstable system – often associated with overwetted mass
What is the role of high shear granulators:
Mixing
Granulating
How does HSM conduct blending and wet massing operations:
Strong mechanical agitation by impeller and delumping by chopper to cut down oversized agglomerates
How does HSM achieve mixing, densification and agglomeration of wetted materials
Shearing and compaction forces exerted by impeller, tip speed of 5-15m/s
How does HSM achieve smaller fragments:
Chopper run at high rotational speed of 1500-4000 rpm
Processing steps in the HSM:
- Mixing of dry powder at high impeller speeds for 2-5 min
- Addition of liquid binders, lower speeds for 1-2 min
- Wet massing, high speeds at 1-5 mins
- Wet sieving of granules (usually cone mill)
- Drying by fluid bed dryer
- Regranulation by cone mill
Advantages of HSM granulation:
- Short process time
- Less binder needed, shorter drying time (due to use of impeller)
- Suitable for cohesive materials and dense products
- Less sensitive to raw material physical attributes than fluid bed granulation
- Closed system
- Easy to clean
Problems associated with HSM granulation:
Mechanical degradation of weak powders and granules (do at lower speeds)
some heat generation, unsuitable for thermolabile products
Risk of overwetting – uncontrolled growth of granule size
A lot of energy needed to stir ad break particles
Process variables:
- Impeller rotation speed (Tip speed)
- Chopper rotation speed (usually fixed)
- Load
- Liquid addition rate
- Liquid addition method
- Wet massing time
Theory of fluidisation
Produced by creating pressure drop across fluid bed or product layer
Definition of fluidisation
Air passed through material bed at speed high enough to set particles in motion without exceeding particles’ terminal velocity
Batch fluid bed processing:
movement of air through product layer for: granulation, drying, coating
Important to condition air and process powder
What consists of a fluid bed granulation run:
Spray addition:
- constant inlet air temp/humidity
- varying air flow
- binder/wetting agent: vary addition rate and atomising pressure
End point:
- exhaust temperature: increased to plateued
Refer to slide 48 for graph
Factors affecting spray granulation:
Choice of binder and concentration: affects granule formation and growth
Viscosity
Will have filters and blowback system to ensure powders do not escape system entirely (go look at the youtube videos in the slides)
Mechanisms of granulation in fluid bed
- Droplet formation
- evaporation
- Sticky droplet come into contact with powder particles
- Open lattice ‘snowflake’ type granule formed
- Good binder distribution
- Good compressibility
Characteristics of fluid bed granules
Open structure
Bulk density similar to raw materials
Uniform and narrow particle size distribution
Good texture
Hot melt extrusion
Process of applying heat and pressure to melt polymer and force it through orifice inn process to form extrudates
Important things to take note of for fluid bed granulation:
Feed materials and processing variables need good control to achieve desired end product attributes
Various equipment design variations can contribute significant differences in operational and final product attributes
What is hot melt extrusion usually used for:
solubility enhancement of poorly water soluble API
Different parts of a hot melt extruder:
- Feeder for material entry, continuously supplied to in controlled manner
- Conveying barrels with screws for material transport, melting, mixing and granulation
- Orifice for shaping material as it leaves extruder
- Downstream auxillary equipment for cooling, cutting and/or collecting finished product
Refer to slide 54
Why is twin screw extrusion used for both thermoplastic and wet graulation systems:
allows for continuous manufacturing
efficient pharmaceutical granulation technology
