Powder

Pellets

Tablets

Granules
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…)

Phenomena:
- Particle rearrangement
- Elastic deformation
- Plastic deformation and/or viscous flow
- Particle bonding (adhesion bonding, diffusion bonding)
- Brittle failure
- Elastic recovery Force

Single particle
Elastic deformation

Plastic deformation

Brittle failure

before during after

 Stress (Force/Area)

Strain (Δx/x0)

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)
Roll compaction
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
Tablet press
Wet granulation: principle
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
Fluid bed granulation - batch

Top spray Bottom spray

(Wurster)
Fluid bed granulation - continuous
Fluid bed granulation - continuous

https://www.youtube.com/watch?v=CICJGx0QNPs
Drum granulator

Large scale: minerals, iron ore, fertilisers…

Pan granulator
Mechanically agitated granulators - continuous

Single-shaft (plough shear)

Twin-shaft
(paddle mixers)
Batch high-shear mixer-granulator
 Growth regime map (Iveson & Litster, AIChE J 44, 1510, 1998)

ρgU c2
St def =
2Yg

€ wρs (1− ε min )

smax =
ρlε min
Liquid distribution in a wet granule:

A)  pendular
B)  funicular
C)  capillary
D)  droplet

Image © Ullmann’s Encyclopedia of Industrial Chemistry

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)

k −1 N
dc k 1 1 in
= ∑ βij c ic j −∑ βikc ic k + (c k − c k )
dt 2 i=1, j =k −i τ
i=1

βij .. agglomeration kernel (rate constant)

βij = β0ψ geom

ψ phys β0 ... collision frequency
ij ij
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:

Stv : viscous Stokes number

~u
8m ⎛λ ⎞ ~
m
µ : binder viscosity
0 * : reduced particle mass λ : thickness of
St v = ~ 2 ≤ St v = 2 ln⎜⎜ ⎟⎟ ~
D : reduced particle binder layer
3πµD ⎝ ha ⎠ diameter ha : particle surface
u0 roughness
: velocity of collision
Complete granulation plant with recycle