(pancake) jet mills

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

mailto:[email protected]

http://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.


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


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


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


– 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


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


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)


PSD (µm) FPS Beckman Coulter

LS100Q analyser

injection ring D50 D90

QMill 4 5 6 6 10 7.6 17.21


Below are summarized the trial parameters on PilotMill-2:

Mill adopting

Trial No. feed rate

(g/h)


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


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)


Suppress the explosion – Install systems detecting and suppressing the explosion

– Cyclone needs to be pressure rated (typ. 2barg)


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

mailto:[email protected]

http://www.foodpharmasystems.com/

(pancake) jet mills

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