Micronisation process in pharmaceutical
and chemical application from R&D to
production scale
Presented by
Stefano Butti
Technical Sales Manager
Mobile: +39 331 6819414
F.P.S. Food and Pharma Systems Srl
Via Vandelli 20
I-22100 Como (Italy)
e-mail: [email protected]
website: www.foodpharmasystems.com
Presentation Summary
1.
Milling and Micronisation Introduction
2.
A short history
3.
Key Components
4.
Product range
5.
Safety Issues
Spiral Jet Mill Systems
1. Milling and Micronisation
introduction
Process Introduction
Pharmaceutical need for size reduction
 Specific Surface increase
 Pharmaceutical research is creating API with very limited
solubility in water (<100mg/ml)
 Access to inhalation therapy
 Reduced systemic toxicity
 Quick availability of API
 High concentration in lungs
 Acceleration of dissolution rate due to crystal structure
change
 Product amorphization
 Top-down particle size dimension control
 Crystallization
molecules
may
be
difficult
for
large/complex
Process Introduction
Available Milling system
50 cm
Crusher
 Crushers
ConeMill
 50cm below to 2 cm
 Mechanical mills
Pin/Hammer mills
 5 cm below to 30 microns




Oscillating mills below to 150 mm
Cone mills below to 100 mm
Hammer mills below to 50 mm
Pin Mill below to 40 mm
Loop/ QMills
 JetMills
 1-2 mm below to 3 microns
 Loop Mills (Qmills) below to 10 mm
 Spiral JetMills below to 3 mm
3 mm
Spiral Jetmills
Process Introduction
Basic Notes
 Micronization is an high energy milling process
 Particle size reduction occurs without mechanical components
intervention, but using a pressurized gas to impart high speeds to
particles and determining high energy impacts between particles.
 The micronisation process allows to reduce the particle size of a
substance in powder form down to micro-meter size (10-6m),
increasing the exposed product surface.
 Particle size reduction is obtained thank to particle-to-particle
collisions inside the micronisation chamber.
Process Introduction
Pro/Cons Vs. Mechanical Milling
With reference to jet milling:
Advantages
• No mechanical moving parts
 no lubrication required
 reduced metal contamination
• Easy components cleaning
 reduction of X-contamination
• Temperature approx. constant
 product characteristics preserv.
 mill heat sensitive products
• Very fine particle dimensions
obtained
 D90 down to 3mm are possible
Dis-Advantages
• Lower productivity
 e.g. 50kg/h with large units
• Large equipment size
 large foot print
 large installation rooms
• High process gas flow
 safety when using nitrogen
 expensive
Process Introduction
Some applications
Typical industrial applications:
• Pharmaceutical industry
 Aerosols
 poor soluble drugs
 increasing bio-availability
• Cosmetic industry
 Compact powders, lipstick, eye-shadows
 Silky touch
• Ceramic industry
 pigment distribution
• Aeronautic industry
 solid fuels
Process Introduction
Still poorly known…
Micronization process is often
considered as a black box:
- coarse particles enter the system
- fine powder exit the system
By adjusting the grinding pressure
and the product feed rate into the
system it is possible to get the
desired result, without much
knowledge of the process.
New molecules development, a better process
control (PSD, amorphous content, specific surface
value) and the requests from pharmaceutical
authorities ask for a different process approach.
Process Introduction
Micronisation process approach
The spiral jet milling process is not governed only by the jet
mill itself. It is a process involving different machines and
components which need to be properly integrated and
controlled.
Spiral Jet Mill Systems
2. Short History for Fluid Energy Mills
Micronization Equipment History
Introduction
There are a number of different micronization systems that
are widely used.
They differ one from the other for the way they use the
pressurised gas to reduce the particle size.





Fluid impact mills
Opposed jet mills
Fluidized bed opposed jet mills
Oval chamber Mills (loop mills or Qmills)
Spiral (pancake) jet mills
Micronization Equipment History
Fluid impact mills
First jet mill introduced in 1882





Particle-to-target collision
No classifier
Target high wear
Low throughput
Lab use for particle fracture analysis
Micronization Equipment History
Opposed jet mills
Introduced in 1917




High product density required
Particle-to-particle collision
Dynamic or static classifier
High wear due to gas-particle flow in nozzles
Micronization Equipment History
Fluidised bed opposed jet mills
Evolution of opposed jet mill




High product density required
Particle-to-particle collision
Dynamic classifier
Sharp cut in top PSD curve
Micronization Equipment History
Oval chamber mills (Loop mills or QMills)
Introduced in 1941





Particle-to-particle and particle-to-target collisions
Static classifier
No moving parts
High throughputs
FPS alternative to Mechanical Pin Mills
Micronization Equipment History
Spiral (pancake) jet mills
Introduced in 1934




Particle-to-particle collisions
Static classifier
No moving parts
FPS preferred choice
Micronization Equipment History
Spiral (pancake) jet mills - A short history
Historical development of jet mill chamber
shape:
 Rectangular section (’40s)
–
–
–

Octagonal section (’70s)
–
–

Easy to manufacture
Very high parasite turbulence
Blow-back
Discontinuity lines still inside the
chamber
High parasite turbulence
Elliptical section (FPS - 2003)
–
–
–
High parasite turbulence reduction
Fluid-dynamic optimization
Lower gas consumption
Jet Mill Systems
3. Key Components
Key Components production equipment
Final extraction and filtration unit
Key Components Pilot equipment
Feeding unit
Cyclone filter
JetMill
Key Components
Feeding unit
Different dosing systems may be adopted:

Vibrating channel:

Single screw feeder:
 Screw speed control
 Various screws geometries
 Problems with poor flowing products

Twin screw feeder
 Screw speed control
 Various screws geometries
 Good with poor flowing products
Key Components
Feeding unit
The feeding unit has typically the following components:
Product hopper:
 Size depending on batch
 Various shapes
 Screw filler (agitator):
 Two flights
 Dosing screws:
 Open / close profile
 Small / Large pitch
 Motor and controller:
 gearbox ratios

Key Components
Feeding unit
The feeding unit can have the following
configurations:

Volumetric / Gravimetric:
 Speed set at fixed value
 Various shapes

Bowl / flat bottom:
 Two flights

Separation plate:
 For isolator / sterile applications
 Technical parts separated from
process ones
Key Components
Piping
Piping required in a micronization system are:
 product transport line
–
–
–

pressure compensation line
–
–
–

Transfer micronized product to cyclone
Needs to be short
Few bends
Closes the process
Less noise
Reduced dust
control manifold
–
–
Regulation valves (manual / automatic)
instrumentations
Key Components
The Jet Mill
The jet mill is composed of many elements:
the injection line
 the Venturi nozzles
 the top plate
 the bottom plate
the expansion nozzles
 the classifier
the pressurized area

Key Components
The separation cyclone
Different gas-solid separation system
may be considered:

Bottom discharge for the jet mill

Separation cyclone

Cyclone with filtering cartridges

Cyclone with filter sleeve
Key Components
The separation cyclone
The separation cyclone with filtering sleeve is
composed of :
 an antistatic PE filter sleeve:
–
–
–
single bag
octopus type
single/octopus with cone
a cylindrical body
 a lower cone, with tangential inlet
 a shaking system
 a process gas exhaust
 a discharge chute

Key component
Final filtration unit
The exhaust gas exiting the cyclone separator is not HEPA filtered,
so final filtration unit is necessary prior to gas exhaust final espulsion
to atmosphere:

Filtration unit is including :
–Pre filtration stage
–Final HEPA H14 filter
–Extraction fan for process automatic
pressure control
Key Components
Instrumentation
Typical instruments required in a
micronization system are:
Pressure gauge for injection line
 Pressure gauge for grinding line
 Thermometer for process gas
 Differential pressure transmitter to detect the clogging
of the filter sleeve
 Differential pressure transmitter to detect the pressure
of the separation cyclone

Sometimes in production units are
considered also:
scale for gravimetric feeding unit
on-line PSD analyser, for full process control and
feed-back

Jet Mill Systems
4. Product range
Full product range
from R&D to production
Innovations in API micronization
R&D jet mills
PilotMill-Zero
Worldwide smallest jet mill for early
R&D
Verification of possibility to micronize the
molecule at an early stage
 Milling possibility, to increase product
solubility thanks to smaller PSD
 Batch size: 10mg-200mg
 Tested product recovery higher than 75%

with very interesting yields*:

7.5 mg out of 10 mg (75%)

16.4 mg out of 20 mg (82%)
190 mg out of 200 mg (95%)
*above mentionned results are referred to internal trials
performed using Lactose

Innovations in API micronization
R&D jet mills
LaboMill
Adopted for development phases
Batch size: 200mg-100g
 Tested product recovery higher than 85%
 Configuration with liners
(AISI316L/Ceramic/PTFE)
 Feeding possibility
 Bottom or top discharge

Test unit is available in RUSSIA to test it
with your own products
Innovations in API micronization
Pilot jet mills

Pilot jetmills :
–
Utilised in first phases of development or preproduction phases
–
Several dimensions available 2”, 3”, 4”, 5”, 6”
High yields up to 99.9%
–
–
All dimensions available with top-discharge
configuration
–
ATEX certification available
–
Containment systems for HPAPI
–
Rental units available
–
Possibilities of scale-up studies for
production units
Innovations in API micronization
Pilot Multi-Milling station
Multi Milling station complete with
interchangeable milling head :
–
–
–
–
–
Cone Mill
Hammer Mill
Pin Mill
Qmill
Spiral Jetmill
All in one single portable unit suitable for
batch sizes from 50 g up to 30 kg
PSD from 1cm below to 3 mm
–
–
–
–
Explosion proof version (ATEX)
Cryo configuration below to -130°C
Containment systems for HPAPI
Possibilities of scale-up studies for
production units
Innovations in API micronization
Pilot Multi-Milling station with containment
Multi Milling station complete with
OEB 5 containment system:
–
–
–
–
–
Cone Mill
Hammer Mill
Pin Mill
Qmill
Spiral Jetmill
Innovations in API micronization
Production jet mills

Production jetmills :
–
Utilised production phases
–
Several dimensions available 8”, 10”,
12”, 16”, 20”
High yields up to 99.9%
–
–
All dimensions available with topdischarge configuration
–
ATEX certification available
–
Containment systems for HPAPI
Innovations in API micronization
Production jet mills with containment
charging
Production jetmills :
OEB5 high contained
integrated spiral Jetmill:
 Charging system
with Vacuum
Transport Systems
(VTS)
 Discharging and
weighting system
with dedicated
isolator
 ATEX 2GD IIB T4
 Fully cleanable in
place
discharging
Innovations in API micronization
R&D test centre
FPS company has its own R&D test laboratory where it is possible to execute
technical tests for milling andmicronization optimization according specific
needs.
The lab is complete with:
Mechanical mills
jet mills, spiral and QMill:
–
R&D
–
Pilot
–
Production
 Nitrogen as process gas
 Many geometrical
configurations for
jet mills
 Temp. control down to –100°C
 PSD instruments:
–
Microscope
–
Laser analyzer
Innovations in API micronization
R&D test centre: comparison
Below are summarized the trial parameters on PinMill-100:
Mill
feed rate
Trial No.
adopting
(kg/h)
PinMill
PinMill
PinMill
Trial 1 PinMill
1
2
3
3
3
3
RPM
5000
10000
15000
time trial
(min)
5
5
5
PSD (µm)
Malvern
D10
3.25
3.08
1.92
D50
33.2
26.7
15.9
D90
79.89
59.5
40.41
Trial 3 PinMill
Innovations in API micronization
R&D test centre: comparison
Raw Material
Trial 1 spiral Jetmill
Below are summarized the trial parameters comparison between Spiral Jetmill and QMill:
Mill
feed rate
Trial No.
adopting
(kg/h)
ProMill
ProMill
ProMill
1
2
3
Mill
Trial No.
adopting
QMill
4
5
10
10
feed
rate
(kg/h)
5
pressure (barg)
injection
6
6
11
ring
6
6
11
pressure (barg)
injection
6
ring
6
time trial
(min)
10
5
4
time trial
(min)
10
PSD (µm)
FPS Beckman Coulter
LS100Q analyser
D50
3.14
3.82
3.47
D90
5.41
6.94
6.52
PSD (µm)
FPS Beckman Coulter
LS100Q analyser
D50
7.6
D90
17.21
Trial 4 QMill
Innovations in API micronization
R&D test centre: comparison
Trial 1 spiral Jetmill
Below are summarized the trial parameters on PilotMill-2:
Mill
feed rate pressure (barg)
Trial No.
adopting
(g/h)
injection
ring
PilotMill
1
100
9
8
PilotMill
2
170
9
8
Trial 1 spiral Jetmill
time trial
(min)
5
5
PSD (µm)
Malvern
D10
0.96
1.03
D50
1.80
2.19
D90
3.16
4.27
Spiral Jet Mill Systems
6. Safety Issues
Safety Issues
Introduction
All process machines poses some safety issues.
For micronization in a pharmaceutical industry, we
need to consider:
1.
2.
3.
4.
5.
process gas
fine powder generation
dust explosion
pressurized elements
noise
Safety Issues
Process gas
Whenever a gas different from air is
adopted as process gas, depending on
the size of the equipment, it is
fundamental to remember that the
environment saturation may lead to
asphyxia.
Oxygen level inside the working room
has to be above 20% at any time.
Adoption of:

oxygen detectors in the jet mill installation room

a close system (with compensation line)

an exhaust fan unit allows proper control of the risk
Safety Issues
Fine Powder Generation
Aim of micronization is to obtain a very fine powder.
This needs to be properly contained to prevent operator from breathing it.
Fine powder risk is addressed:

closing the equipment
By adopting the pressure compensation line,
the only two open points of the system are:
– Feeder Hopper
– Cyclone discharge

enclosing the equipment
In case of very active or toxic API, the jet mill
is required to be installed within a barrier
isolator
Safety Issues
Dust Explosion
An explosion occurs in specific circumstances:

presence of oxidizer
Typical oxidizer in jet milling is air:
– Used as process gas
– Entering the system through the Venturi funnel

presence of fuel
Most pharmaceutical powders are explosive in powder form.
Explosion characteristics depends on API and its PSD

an ignition source
Electrostatic discharge is quite common in API jet milling
Safety Issues
Dust Explosion
In order to protect people/environment against explosion:

Eliminate the oxidizer
–
–

Vent the explosion
–
–
–

Determine a preferred path through which a possible explosion may be vented
Cyclone needs to be pressure rated (typ. 2barg)
Suitable valves required
Contain the explosion
–
–

Nitrogen used as process gas
Closure of the equipment (compensation line)
Cyclone needs to be pressure rated (typ. 10barg)
Suitable valves required
Suppress the explosion
–
–
–
Install systems detecting and suppressing the explosion
Cyclone needs to be pressure rated (typ. 2barg)
Suitable valves required
Safety Issues
Pressurized components
We need a pressurized gas in a jet mill, so
we can not avoid this risk.
 pressurized elements are limited
– Venturi line
– Grinding line
Jet mill chamber pressure is very low
tri-clamps with nuts are preferred on
pressurized lines

– minimum torque requested in nuts fixing
– if not adopted for specific reasons (access,
cleaning, …) operator attention is necessary.
Safety Issues
Noise
A jet mill works thanks to a gas expansion, that is a noise
generation process.
Noise level may be particularly high especially when the jet
mill is operated with no powder.
Possible actions:

Close the system
– pressure compensation line

Enclosure

Ear protections
Thank you very much for you attention !
Presented by
Stefano Butti
Technical Sales Manager
Mobile: +39 331 6819414
F.P.S. Food and Pharma Systems Srl
Via Vandelli 20
I-22100 Como (Italy)
e-mail: [email protected]
website: www.foodpharmasystems.com