Post on 27-Nov-2021
Agglomeration = particle size enlargement
1) Purpose: - improve flow properties - improve dispersion/dissolution properties - ensure composition uniformity (segregation) - reduce dustiness - improve visual appeal - dosage uniformity
2) Mechanisms: - “Dry” agglomeration (compaction) - “Wet” agglomeration
3) Equipment
4) Population balance model
Mechanical agglomeration
(tabletting, roll compaction, pelletisation, briquetting…)
Elastic deformation
Plastic deformation
Brittle failure
before after during
Single particle
Force
Phenomena: - Particle rearrangement - Elastic deformation - Plastic deformation and/or viscous flow - Particle bonding (adhesion bonding, diffusion bonding) - Brittle failure - Elastic recovery
Strain (Δx/x0)
Stress (Force/Area)
Heckel model (1st order):
ln(1/1-D)=P/Py+A
D… relative density ρ/ρ0 P… applied pressure A… particle rearrangement Py… yield pressure (material property)
Low Py … soft/plastic materials (5-50 MPa) High Py … hard/brittle materials (100-1000 MPa)
Tabletting
Cyclic operation:
- Feed
- Pre-compact
- De-aerate
- Final compaction
- Eject
Need to use lubricants (e.g. magnesium stearate) to avoid sticking to punch or die walls and reduce wear.
Problems: capping, de-lamination
Wet Granulation
Principle: contact powder with a liquid binder, wet powder particles become cohesive, agglomeration occurs during particle collisions, binder sets to form mechanically stable granules.
Binder types: - melt binders ~ melts, solidify upon cooling (e.g. PEG) - aqueous binders ~ solutions, solidify upon drying (e.g. PVP) - water ~ partial dissolution and recrystallisation of ingredient(s)
Binder application: - spray (liquid atomisation) for low-shear processes - mechanical dispersion in high-shear processes
Granulation processes: - fluid bed granulation - high-shear mixer granulation
Mechanically agitated granulators - continuous
Single-shaft (plough shear)
Twin-shaft (paddle mixers)
Growth regime map (Iveson & Litster, AIChE J 44, 1510, 1998)
€
Stdef =ρgUc
2
2Yg
€
smax =wρs(1− εmin )
ρlεmin
Liquid distribution in a wet granule:
Image © Ullmann’s Encyclopedia of Industrial Chemistry
A) pendular
B) funicular
C) capillary
D) droplet
Extrusion-spheronisation
Principle of operation: - Prepare a paste from API, excipients, binder, water - Extrude paste through screen to form “noodles” - Contact extrudates with a high-speed rotating disk - Dry resulting spherical pellets
…but it is also possible to carry out spheronisation after wet granulation
Population balance of agglomeration
ck … volumetric concentration of granules consisting of k primary particles (single granule mass mk= km1)
€
dckdt
=12
βijcic j −i=1, j=k− i
k−1
∑ βikcicki=1
N
∑ +1τ(ck
in − ck )
βij .. agglomeration kernel (rate constant)
€
βij = β0ψ ijgeomψ ij
phys β0 ... collision frequency
Ψij ... success factors
si ... surface coverage
€
ψ ijgeom =1− (1− si)(1− s j )
Conditions for agglomeration of wet patricles
Criteria for coating vs. agglomeration:
⎟⎟⎠
⎞⎜⎜⎝
⎛=≤=
avv h
StDumSt λ
πµln2~3
~8 *20
: viscous Stokes number : reduced particle mass : reduced particle diameter : velocity of collision
: binder viscosity : thickness of binder layer : particle surface roughness
vStm~
D~
0u
µ
λ
ah