Post on 12-Feb-2017
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: butti@foodpharmasystems.com
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 may be difficult for large/complex
molecules
Process Introduction Available Milling system
Crushers 50cm below to 2 cm
Mechanical 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
JetMills 1-2 mm below to 3 microns
Loop Mills (Qmills) below to 10 mm Spiral JetMills below to 3 mm
50 cm
3 mm
Crusher
ConeMill
Pin/Hammer mills
Loop/ QMills
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.
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
With reference to jet milling:
Process Introduction Pro/Cons Vs. Mechanical Milling
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
• 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
Typical industrial applications:
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)
– Easy to manufacture
– Very high parasite turbulence
– Blow-back
Octagonal section (’70s)
– 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
JetMill
Cyclone filter
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 – Transfer micronized product to cyclone
– Needs to be short
– Few bends
pressure compensation line – 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
Pilot jetmills :
– Utilised in first phases of development or pre-production 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 jet mills
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
Multi Milling station complete with OEB 5 containment system:
– Cone Mill
– Hammer Mill
– Pin Mill
– Qmill
– Spiral Jetmill
Innovations in API micronization Pilot Multi-Milling station with containment
Production jetmills :
– Utilised production phases
– Several dimensions available 8”, 10”, 12”, 16”, 20”
– High yields up to 99.9%
– All dimensions available with top-discharge configuration
– ATEX certification available
– Containment systems for HPAPI
Innovations in API micronization Production jet mills
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
Innovations in API micronization Production jet mills with containment
charging
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 adopting
Trial No. feed rate
(kg/h) RPM
time trial
(min)
PSD (µm) Malvern
D10 D50 D90
PinMill 1 3 5000 5 3.25 33.2 79.89
PinMill 2 3 10000 5 3.08 26.7 59.5
PinMill 3 3 15000 5 1.92 15.9 40.41
Trial 1 PinMill Trial 3 PinMill
Innovations in API micronization R&D test centre: comparison
Raw Material Trial 1 spiral Jetmill
Trial 4 QMill
Below are summarized the trial parameters comparison between Spiral Jetmill and QMill:
Mill adopting
Trial No. feed rate
(kg/h)
pressure (barg) time trial (min)
PSD (µm) FPS Beckman Coulter
LS100Q analyser
injection ring D50 D90
ProMill 1 5 6 6 10 3.14 5.41
ProMill 2 10 6 6 5 3.82 6.94
ProMill 3 10 11 11 4 3.47 6.52
Mill adopting
Trial No. feed rate
(kg/h)
pressure (barg) time trial (min)
PSD (µm) FPS Beckman Coulter
LS100Q analyser
injection ring D50 D90
QMill 4 5 6 6 10 7.6 17.21
Innovations in API micronization R&D test centre: comparison
Below are summarized the trial parameters on PilotMill-2:
Mill adopting
Trial No. feed rate
(g/h)
pressure (barg) time trial (min)
PSD (µm) Malvern
injection ring D10 D50 D90
PilotMill 1 100 9 8 5 0.96 1.80 3.16
PilotMill 2 170 9 8 5 1.03 2.19 4.27
Trial 1 spiral Jetmill
Trial 1 spiral Jetmill
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. process gas
2. fine powder generation
3. dust explosion
4. pressurized elements
5. 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 – Nitrogen used as process gas
– Closure of the equipment (compensation line)
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 – 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: butti@foodpharmasystems.com
website: www.foodpharmasystems.com