microreactor technology at lonza

Microreactor Technology at Lonza

Location, 14 June 2009

Name / Lonza / Date

28-Oct-11

Agenda

Reaction classes and chemical examples

Lonza Universal Reactor Technology

Scale-up strategy and production units

Lonza proposal

Joe Pont, Chemistry Today, June 2009

Adapt as a function of your needs

28-Oct-11

Lonza has been working closely with

microreactor technology for some time

1992: “Microreactors” for cryogenic organometallic reaction

Microreactor Team Formed in 2003

Two dedicated laboratories

Connected with the kg-lab to produce kg-quantities

Two Integrated production units (Launch Plant, Visp)

Own reactor development and collaborations with others

Seven chemical patent applications (wide-ranging)

process, nitration, and organometallic reactions

Three technical patent applications

Two microreactors, one lab system

Several publications (CET, Angewandte Chemie, OrgProcR&D)

Citations in Nature, Chemical & Engineering News, etc.

28-Oct-11

Microreactor Technology

It enables Continuous Processes based on plug flow reactors with

minimal volume of reagents, rapid dynamic responses and

robustness, good temperature control,

efficient mixing, etc.

inlet cooling

outlet cooling

inlet fluid 1

inlet fluid 2

outlet product

inlet cooling

outlet cooling delay

loop

28-Oct-11

Batch

Process

Synthesis Design

Continuous

Batch

Protection Li exchange Coupling Hydrolysis Extraction Distillation

DryerCentrifuge

Protection Hydrolysis Extraction Distillation

DryerCentrifugeCoupling

Microreactor

Li exchange

Microreactor

Value-added

in terms of Yield

Extraction Distillation

dryerCentrifugeCoupling

Microreactor

Li exchange

Microreactor

Value-added

in terms of Yield

Protection

Microreactor

Hydrolysis

Microreactor

Conventional

Current

Future

The Toolbox Approach:

Integration into Production

28-Oct-11

Reaction Classification & Advantages

Type A reactions

very fast (< 1s)

controlled by the mixing process

Increase Yield through better mixing/heat exchange

Type B reactions

rapid reaction (10 s to 20 min)

predominantly kinetically controlled

Avoid overcooking and increase Yield

Type C reactions

slow reaction (> 10 min)

Batch processes with thermal hazard

Enhance safety

Need intensification

28-Oct-11

Reactions at Lonza

D.M. Roberge et al., CE&T 2005 (28) 318

Big circle based on kinetics only

Inner circle based on kinetics and phases

81%

21%

23%

6%

50%

8%9%

2%

Type A reactions

Type B reactions

Type C reactions

Remaining

Organometallic reactions

Diketene reactions

Autocatalytic nitrations

28-Oct-11

Shifting reactions to suit Microreactors

Reactions can be designed to suit

microreactor technology:

Increased concentration

harsher reaction conditions

fast reactions

Increased temperature

Adjusted residence time RT

Hazardous reagents and intermediates

Expensive, but more effective solvent and catalysts

Controlled educt quality, filtering,

avoid impurities and particles

Type A

Type C

Type B

28-Oct-11

Chemical examples

Organolithium exchange, Dibal-H, and Grignard reactions [Type A]

Organolithium coupling reaction [Type B]

Nitration as hazardous reactions [Type C]

Ar H Ar NO2HNO3+ Ducry & Roberge Angew. Chem. IE 2005 (44) 7972

Ducry & Roberge OrgProc R&D 2008 (12) 163

Roberge et al. PharmaChem 2006 (June) 14

Roberge et al. CE&T 2008 (31) 1155

Roberge et al. OrgProc R&D 2008 (12) 905 R X Li Ar Li+

R1 X

O

R2 Mg X

O

R1 R2+

R O

O

R

ODibal-H

LiR1

R3

O

R2

R1 R3

OH

R2

+

28-Oct-11

Industrial Reactors

Module A Multi-injection reactor to avoid hot spot formation

Module B

Module C

Multi-scale reactor design

Gain volume and limit pressure drop

Conventional technology

Static mixer / mini-heat exchanger

costs efficient

Corning S.A.S. Fontainebleau Research Center

Lonza design

For example Exergy

28-Oct-11

Lonza Microreactor as Universal Modules

Modular, robust, pressure over 100 bar

Hastelloy plates: process fluid

Aluminum plates: thermal fluid

Compactness, ease of adaptation

Each plate = one specific design

1 Plate for Gas-liquid reactions

2 Plate for multi-injection

2 2

28-Oct-11

All Lonza Microreactors

Lonza development reactor

A6 A5

View the chemistry

Reaction at tiny flow rates

Test different mixing structures

Lonza production reactor

Design as key ingredient to scale-up

Avoids totally parallelization

Multi-purpose

Lab-Plate

channel structure

28-Oct-11

Basic Flow Rates

For Type A reactions (Multi-injection)

Ensure sufficient cooling between the plates or mixing points

Provide maximum mixing capacity → large ΔP

For Type B reactions (Multi-scale design)

Scale-up issues are avoided if the same area to volume ratio is

maintained

Optimize mixing quality → ΔP as low as possible

Isolated product

per campaign

Lab Plate = 1-10 mL/min development tool, few grams

A6 = (10) 50-150 mL/min 0.1 - 300 kg

A5 = 100-300 mL/min 300 - 900 kg

A4 = 200-600 mL/min 900 - 2500 kg

28-Oct-11

Lonza has an extensive track record

with continuous flow processes

Type A

reactions

Type B

reactions

Type C

reactions

Continuous flow

benefits

Grignard

reaction

Simmons-Smith

reaction

Nitrations (many

examples)

saponification

organolithium

reaction

Wittig reaction amination hydrogenation

alkylation Diketene reactions methylation dehydrogenation

bromination Coupling of unstable

intermediates

oxonolysis

chlorination oxidation Emulsion reaction

nitrosation BOC-protection

Reduction

(DIBAL)

28-Oct-11

Straightforward Scale-up Approach

Simple numbering-up / device parallelization is limited

Control issue

Chemical systems are in general meta-stable

Not acceptable cleaning capacity

How can I insure all channels are cleaned

No pressure driven system

Always ensure stoichiometry

Operation time

Reactor design

High pressure pump

Cross section

More reactors

campaign size

lab scale small scale production large scale production

100x

2-6x

4x

4-6x

10 1 kg 100 1 t 10 100 t 10 g 100

28-Oct-11

Scale-up concept with MR in Plant - MiP

laboratory system

Microreactors & conventional technology

30-200 g/min 2-10 kg campaigns

1-50 g/min sample production

Pre-clinical phase, Process research, Process development

MiP-SSP

Microreactors & conventional technology, cGMP, EX environment

200-1000 g/min 0.1-2 t campaigns

Clinical phase I, II, III

MiP-LSP

Microreactors & conventional technology, cGMP, EX environment

10 times

1- 5 kg/min 50 t + campaigns

Commercial Products

10 times

Under

Development

Lab-Plate A6 A5 A4

28-Oct-11

Case Study Scale-up

2-step Serial Reaction

Various reactors are studied

Feed-1: Substrate (15 wt%)

Feed-2: Reagent 1 (30 wt%)

Feed-3: Reagent 2 (17 wt%)

Stoichiometric reaction, two temperature levels

First reaction is of Type A highly exothermic (ΔTad > 75°C)

Various reactors are studied

Second reaction is of Type B and exothermic (ΔTad < 25°C)

Use of a static mixer under adiabatic conditions

H (acidic)R1 Li LiR1+ +

LiR1

R2

O

R3 R2R1

O

LiR3+ +

28-Oct-11

Flow Diagram

Feed-1

Feed-2

Feed-3

Pump-1

Pump-2

Pump-3

Reactor XX

Quench tank

T

P

F MR

F Total

Static mixer

Thermal fluid

large excess

cryogenic

Outlet

adiabatic

28-Oct-11

Scale-Up Results

Reactor F Total

[g/min]

F MR

[g/min]

T

[°C]

P

[bar]

Yield

Glass MR 100 33 -14 0.4 86

Glass MR 440 148 15 3.2 88

Static mixer 100 33 9 0.3 88

Static mixer 440 148 41 1.6 84

Lonza MR-A6 100 33 -22 0.9 89

Lonza MR-A6 420 140 -16 8.8 90

Lonza MR-A5 450 150 -21 2.0 88

Lonza MR-A5 562 187 -19 3.0 89

Lonza MR-A5 614 204 -18 3.4 88

Lonza MR-A5 711 237 -16 4.5 87

28-Oct-11

Chemical project

Multiple-tons of isolated material have been produced

All product within specifications

More than 20 m3 of processed reaction volume

Lonza Universal Reactor Technology

Clear path from laboratory chemistries to large-scale

manufacturing processes

Completely avoids the parallelization / numbering-up strategies

Microreactor platform that supports rapid process development;

It is also robust, multi-purpose and scalable

Was tested for several customer products

Conclusions for Scale-up

28-Oct-11

Pilot Plant Microreactor Technology

Key Features

Multi-purpose system

Modular

Hastelloy

T = -80 to +180°C

ATEX standards

Qualifiable for cGMP

production

Track record

organolithium exchange

organolithium coupling

nitration reaction

3 dosage lines

1 - 6 bar

5 - 300 g/min (per line)

28-Oct-11

Continuous Production in Launch Plant

Key Features

Multi-purpose system

Capacity in the range of

150 kg/h

Campaigns were performed

with in-between cleaning

Track record

Simmons-Smith reaction

organolithium coupling

Based on conventional technology

Static mixers

Mini-heat exchangers

28-Oct-11

Continuous Ozonolysis (Gas-liquid)

Key Features

Only for gasses with low

solubility and large volume

fraction such as ozonolysis

Gas-liquid mass transfer

intensification

Scale-up: predictable mass

and heat transfer (Kla)

Fully automated system

Track record

Several ozonolysis projects Kg-scale lab system with Sulzer

SMV mixing elements

Ton-scale system with Sulzer SMV

mixing elements in the launch

plant for industrial production

28-Oct-11

Continuous work-up steps

Key Features

2-step bi-phasic reaction and

quench with following phase

separation

complete continuous flow

miniplant

Scale-up: adjust residence time

and temperature

Fully automated system

Track record

nitration

saponification phase separation

solvent distillation in falling film

solvent extraction in Karr column

28-Oct-11

Conclusions

Lonza is a leading player in microreactor technology

The lab development is solely made in the microreactor

Lonza has developed own microreactor concept

Different sizes of microreactors are in operation

Microreactor setup and chemical production

Reaction classification based on reaction kinetics

Scale-up to large scale and microreactor applications

Manufacture under cGMP conditions

28-Oct-11

Back-up

28-Oct-11

Lonza’s Proprietary Microreactor Technology

WO2007/045509: Mass flow rate control system

WO2007/087816: Nitration of activated aromatics in MRs

WO2007/112945: Micro-reactor system

WO2008/006420: Swern oxidation

WO2008/009378: Method for Grignard Type Reactions in MRs

WO2008/095646: Method for Lithium Exchange Reactions

WO2009/003661: Process for the preparation of Aldehydes

WO2009/046992: Method for the preparation of organic nitrates

EP1500649A1: In-situ quench method

Others pending

28-Oct-11

Lonza Proposal

Phase 1: Proof of Concept (2 weeks)

Phase 2: Optimization Study (2-4 weeks)

Design of experiments (DOE) or complete kinetic analysis

Phase 3: Long Run Study (3 weeks)

kg-Lab production from 1–20 kg

Phase 4: Pilot Production & Commercial Manufacturing

From 20 kg to 2.5 tons of product for pilot production

Ton quantities for commercial manufacturing

CAPEX assessment

time &

co

mp

lexity

28-Oct-11

Phase 1: Proof of Concept

Activities

Safety assessment (if

required)

Determine maximum feed

solubility at different

temperatures

Solvent screening

Determine reaction class

(Type A, B, and C)

Flow rate versus residence

time

Ascertain optimal reactor

Requirements

Lab batch protocol, RC-1 data

Supply of raw materials

Analytical method with product

sample for calibration

Deliverables

Statement on process

compatibility with MRT for

operability and plugging

Solution yield, including

impurity profiling

Basic PowerPoint report for

go/no-go decision

28-Oct-11

Phase 2: Optimization Study

Activities

Factors analysis using DOE

→ Type A Reactions

Temperature, stoichiometry,

concentration,

additives/stabilizers, multi-

injection..

Kinetic analysis including

activation energy → Type B

Reactions

Obtain highest Yield and

optimal operability

Requirements

See Proof of Concept &

detailed product

specifications

Deliverables

Isolated product, including

yield and purity

Firmed process description

for application in

Microreactor Technology

PowerPoint report on most

optimal process conditions

with MRT

28-Oct-11

Phase 3: Long Run Study (1/2)

Activities

Process Synthesis Design (if required)

Scalability

Perform a long run with the smallest MRT structure

Use various proprietary de-plugging methods

Perform reaction at high flow rate for a short period

xx g for yield assessment and impurity profiling

Kg-lab production campaign

Preparation (short risk assessment), production, cleaning

GMP: Qualify start-up and termination phases

28-Oct-11

Phase 3: Long Run Study (2/2)

Requirements

See Proof of Concept & Optimization Study

Deliverables

Statement on readiness of process for Pilot Production or Commercial Manufacturing

Requested kg-quantity of materials

28-Oct-11

Phase 4: Pilot Production &

Commercial Manufacturing

Activities

20 kg to 2.5 tons of product

for Pilot Production

Tons quantities for on a case

by case analysis for

Commercial Manufacturing

Including CAPEX

assessment

GMP manufacturing

On going optimization

Requirements

Supply agreement

Deliverables

Product

Documentation

Final evaluation of the project and production report

28-Oct-11

We have observed a wide range of

applications for microreactor technology

Fast Kinetics

Less than 10 min

Mixing Sensitivity

Long dosing time

High stirrer speed, selectivity depends on stirrer speed

Temperature Sensitive

Selectivity is lower in larger vessels/beakers (heat transfer)

Strong exothermic reaction

Autocatalytic, reaction rate depends on product

High Activity

Reagent, catalyst, or solvent

Undesired By-product Formation

28-Oct-11

Reactions Can be Designed for Microreactor Technology

Increased concentration

harsher reaction conditions

fast reactions

Increased temperature

Hazardous reagents and intermediates

Expensive, but more effective solvent and catalysts

Controlled educt quality, filtering,

avoid impurities and particles

We are able to shift reactions to suit

microreactor technology

28-Oct-11

Microreactors have a wide range of

benefits over conventional reactors

Mixing Controlled Reactions

Mixing time shorter than

reaction time

Energy dissipation

determines mixing time

Temperature-Sensitive

Reactions

Avoid hot spots by high

heat transfer and multi-

injection

Higher process

temperatures are possible

Volume Minimization

Autocatalytic reactions are

controllable

Unstable intermediates can

be intercepted

New Process Windows

Higher educt concentrations

or temperatures

Highly efficient solvents and

catalysts

But, Limitations Exist

Slow reactions, solid forming,

polymerization, etc.

28-Oct-11 D.M. Roberge et al, WO2007112945, to Lonza AG

Types of Microreactors:

Lonza

Key Features

Design by Lonza

Aimed at maximizing heat

transfer and mixing but

allowing a residence unit

Material: Hastelloy C, SiC

Minimize pressure drop

Modular, ease of adaptation

Excellent mixing performance, can

also be used for Type A

Modular residence time up to 1 min.

Pressure up to 100 bar

Various partners for the reaction plates

28-Oct-11

© hiTran CalGavin

Types of Microreactors:

Static Mixer Technology Modules

Key Features

Conventional modules based

on standard heat exchangers

and static mixers with high

flexibility example are from

BHR (Flex reactor), Sulzer

(SMR reactor), or Fluitec.

Engineer and construct

appropriate residence time

modules (RT-module)

© Exergy © Sulzer

© Fluitec

microreactor technology at lonza

Documents