Scale-Up with Lonza MicroReactors for Pharma · PDF fileScale-Up with Lonza MicroReactors for...

Scale-Up with Lonza MicroReactorsfor Pharma Manufacturing

M. Eyholzer, M. Gottsponer, N. Kockmann, D.M. Roberge / Lonza AG / September 23rd, 2010

Siegfried-Symposium

Joe Pont, Chemistry Today 2009 (June) 8

Oct-10

Lonza Ltd., Visp Switzerland

Leading-edge Technologies� Chemical and biotechnological

Life science company� Nutrition, health care, pharmaceuticals, ...

Fine chemistry in Visp� cracker for C2 supply

� continuously operating production units: Niacin, ...

� Large fermentation units

� R&D, process development, small scale production, andfine chemical complex FCCfor pharma production

Lonza Overview

Oct-10

MRT at Lonza - Brief History Since 1992: “microreactors” for cryogenic organometallic reactionMicroreactor team started February 2003� 3 Dedicated laboratories� Connected with the kg-lab to produce kg-quantities

� 2 Integrated production units (c-SSP, R01)� Own reactor development and collaborations with others

� More than 10 Chemical patent applications (wide-ranging)� Process, Nitration, Oxidation, Reduction, and Organometallic reactions.

� 4 Technical patent applications� 3 Microreactors, 1 lab system

� several publications (CET, Angewandte Chemie, OrgProcR&D, …)� two monographs on microreactor technology� several peer reviewed articles and invited talks� Citations in Nature, Chemical & Engineering News…

Oct-10

Agenda

IntroductionMicroreactor Technology – Lonza MicroReactors� Reaction classes� Reactor design� Scale-up Concept

Chemistry in Flow using Microreactors� 5 chemical examples� Chemistry meets engineering: organo-lithium in ton quantity

Future Perspective

Oct-10

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 1inlet fluid 2

outlet product

inlet cooling

outlet cooling

mixing

delay loop

1 – 600 mL/min

Microreactor Technology @ Lonza

Lonza MicroReactor A6

Oct-10

When do we use MicroReactors ...

Observations indicating the feasibility of MRT� Fast reaction kinetics < 10min� Mixing sensitive reactions

� Long dosing time or dosing controlled� 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 concentration

� High activity of reagent, catalyst, or solvent� Undesired by-product formation� Large production volume expected / to be realized

Oct-10

Reaction Classification & Microreactor Technology Advantages

A

B

C

� Type A reactions� Very fast (< 1s)� Controlled by the mixing process� Increase yield through better mixing/heat exchange

� Type B reactions� Rapid reaction (few seconds to 10min)� Predominantly kinetically controlled

� Avoid overcooking and increase yield

� Type C reactions� Slow reaction (> 10min)� Batch processes with thermal hazard� Enhance safety

� Need intensification

Oct-10

Shifting reactions to suit MicroReactors

Reactions can be designed to suit MicroReactor Technology� Increased concentration

� Harsher reaction conditions� Fast reactions

� Increased temperature� Hazardous reagents

and intermediates� Efficient use of expensive

solvent and catalysts� Controlled educt quality, filtering,

avoid impurities and particles

TypeA

TypeC

TypeB

Roberge et al. Chem. Eng. & Technol. 2005 (28) 318

21% 23%

6%

Oct-10

Industrial Reactors

Module ARapid fluids contacting,Multi-injection reactor toavoid hot spot formation

Module B

Module C

Multi-scale reactor designGain volume

and limit pressure drop

Conventional flow technology and advanced design

Static mixer /mini-heat exchanger

costs efficientMiprowa Ehrfeld Mikrotechnik BTS

Oct-10

Lonza MicroReactors

Development Reactor� View the chemistry� Reaction at tiny flow rates

� Test different channel geometries

Production Reactor� Design as key ingredient to

scale-up� Avoids total parallelization� Multi-purpose and modular

Plate Size: A6 Plate Size: A5LabPlate Channel structure

Oct-10

Convective flow in microchannels

Flow structures� straight laminar Re<10� vortex generation

� transient flow regime

� chaotic flow� turbulent flow

Two phase flow� Taylor bubble flow� Dispersed flow

T600x300x300, Re = 300; f = 440 Hz

100 µm

CO2-water flow in tangential mixing elements

5 mm

Oct-10

Lonza concept of plate dimensions

Channel and plate size� single channel approach and step-wise scale-up� channel diameter and plate size correlate

2.01.41.00.70.5

0.350.2

diameter

plate size Lab-Plate A6 A5 A4

Oct-10

Scale up for microreactor production

Lonza approach for continuous flowproduction with microreactors� laboratory feasibility study� process development in lab� kg-production in lab

� ton-production in pilot plant

concentration

cross section

pressure

operation time

more reactors

campaign size

lab scale small scale production large scaleproduction

100x

2-n x

101 kg 100 1 t 10 100 t10 g 100

2-6x

2x

4-10x flow rate

Oct-10

Scale-up Concept with MicroReactor in Plant

Concept

LabPlate A6 A5 A4

Laboratory SystemMicroReactors &conventional technology

Small-ScaleMicroReactors &conventional technology,cGMP, EX environment

Large-Scale MicroReactors &conventional technology,cGMP, EX environment

1-50 g/minsample production

30-200 g/min2-10 kg campaigns200-600 g/min0.1-2 t campaigns

0.6- 5 kg/min50 t + campaigns

Pre-clinical phase

Process researchProcess development

Phase 1, 2, 3 Commercial Products

Oct-10

Lonza’s Project Approach

Phase 1: Proof of Concept

Phase 2: Optimization Study� Design of experiments (DOE) or complete kinetic analysis

Phase 3: Long Run Study� 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� Own CAPEX assessment for dedicated plant

time &

complexity

Oct-10

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

LiR1R3

O

R2R1 R3

OH

R2+

R1 X

OR2 Mg X

O

R1 R2+

R O

O

R

ODibal-H

Ar X Li Ar Li+

Oct-10

Example 1: Hazardous Reactions even Solvent-Free Well under Control

Nitration of Phenol as Type C reaction with large accumulation

� Efficient heat exchange: the reaction is autocatalytic with adiabatic temperature rise of more than 200°C � reach nitro-decomposition temperature

� Rapid radical propagation in a confined volume: auto-catalytic reaction

OH

ON

OH

OOH2

OH

NO O

OH

NO

O

+ ++

PhenolMW 94.11

Nitric AcidMW 63.01

4-NitrophenolMW 139.11

2-NitrophenolMW 139.11

Ducry and Roberge, Angewandte Chemie International Edition 2005 (44) 7972

Oct-10

� Reaction is auto-catalytic.� Auto-catalytic reactions are

the cause of most chemical hazards.

� Semi-batch process is for nitrophenol impracticable under the actual conditions.

0 20 40 60 80 1000

50

100

Hea

t flu

x [W

]

0 20 40 60 80 100-20

0

20

40

60

80

Tem

pera

ture

[°C

]

0 20 40 60 80 1000

0.2

0.4

0.6

Reaction duration [min]

Rea

ctor

mas

s [k

g]

1 2

1. Dosage of 40 g nitric acid in 10 min 2. Dosage of 120 g nitric acid in 30 min

Autocatalysis with Runaway when Performed Semi-Batch Wise

Oct-10

Reaction is well under control in the microreactor with T variation < 10°C

� Control of the auto-catalysis in the microreactor

� At higher temperatures the auto-catalysis starts right away; at lower temperatures the auto-catalysis does not start or extinguishes.

� Same observation for the stoichiometry.

-1 0 1 2 3 4 5 625

30

35

40

45

50Thermal fluid-in (cyan), Thermal fluid-out (blue), Reaction-out (red)

Tem

pera

ture

[°C

]

-1 0 1 2 3 4 5 60

5

10

15Phenol (green), Nitric acid (pink)

Time on stream [min]

Add

ition

rat

e [g

/min

]

Start autocatalysis

Oct-10

Example 2: Design of New Industrial Processes

Formation of Aldehydes by Direct Synthesis Using Esters

� Perfect control of micro-mixing: control access to the aldehyde by the control of a Type A reaction

� Environmental benign: route via the alcohol oxidation may request strong oxidizing agents (e.g. MnO2, or CrO3) or relatively expensive conditions (e.g. Swern-Moffat)

O

O

AlH

AlH

OHO

- MeOH

+H2 from +H2 from

Methyl ButyrateMW 102.13

DIBAL-HMW 142.22

ButyraldehydeMW 72.11

ButanolMW 74.12

Stop the reaction here

Ducry and Roberge, Organic Process Research & Development 2008 (12) 163

Oct-10

Batch Results are not scalable and Required very Low Temperatures

0

10

20

30

40

50

60

70

80

90

100

-80 -60 -40 -20 0 20 40Temperature [°C]

But

yral

dehy

de (

3) [a

rea%

]

Microreactor

Batch

Oct-10

Example 3: Microreactors at Their Thermal Limits

Grignard Reaction as a highly exothermic Type A reaction

� Efficient heat exchange: but even a microreactor is not a perfect reactor and will come to its limits

� Exact control of residence time: once reacted the quench reaction show follow directly

Roberge et al., Chem. Eng. Technol. 2008 (31) 1155

OO

O

O

MgCl

O

O

O

O

OH

O

O Mg Cl

Dimethyl oxalateCN 16543

MW 118.09

Ethylmagnesium chlorideCN 38038MW 88.82 2-MOB

CN 32182MW 116.12

+

2-MOB_enolCN 32759

MW 116.12RRT 1.17

+

Oct-10

Multi-Injection Principle

Multi-injection zone 4



IM1 IM2 IM3 IM4

A

B

Q

Q/4 Q/4 Q/4 Q/4

2Q

B B B


time

T°C

Batch

Multi injection From Corning

Oct-10

Influence of injection, Concentration, and Temperature

40%

45%

50%

55%

60%

65%

70%

75%

80%

85%

90%

-20 -15 -10 -5 0 5 10

Temperature [°C]

Yie

ld in

are

a%

1-injection, Feed-1 = 10 wt%



4-injections, Feed-1 = 10 wt%

4-injections, Feed-1 = 15 wt%

4-Injections, Feed-1 = 20 wt%

Glass MR namelyCorning mono-injectionCorning multi-injectionreactors at 40 g/min

Oct-10

Reactor Material

50%

60%

70%

80%

90%

25 35 45 55 65 75Flow Rate [g/min]

Yie

ld [a

rea%

]

Plate 315, Hastelloy, 0.5 mm

Plate Corning, glass, 0.5 mm

Plate 350, SiC, 0.9 mm

Plate 215, Hastelloy, 0.8 mmall at -15°C

Oct-10

Example 4: Control of OrganometallicReactions based on HexLi/BuLi

3-Feeds setup via 2 reactions in series

2-Feeds setup via 1 single reaction� the so-called In Situ Quench Method

� Exact control of residence time: Li intermediates are short living � s to min reactions

� Good control of micro-mixing: Bromo compound reacts faster than the quench reagent (borylation agent) � ms reactions

Schwalbe, T. et al. EP1500649A1 2004, now to Lonza AG.

Br

R

Li

BO O

R

+ Borylationagent +

Rozada Sanchez et al. CHISA 2010, Prague.

In collaboration

with Astra Zeneca

H (acidic)R1 Li LiR1+ +

LiR1R2

O

R3 R2R1

OLiR3+ +

Oct-10

Example 4: Insitu Quench with HexLi

2-Feeds setup via 1 single reaction� the so-called In Situ Quench Method

� Perfect control of micro-mixing: Bromo compound reacts faster than the quench reagent (borylation agent) � ms reactions

� Drivers to go continuous:� Operational difficulties from low temperature transfer of reagents� Lithiation is exothermic (∆HR ~ 200 kJ/ mol SM, ∆Tad ~ 25ºC)

� Addition rate controlled process in batch� Increased local concentration of lithiation reagent, favouring

formation of the di-lithiated species.


Br

R

Li

BO O

R

+ Borylationagent +

Oct-10

Example 4: HexLiEquipment setup for 2 feeds


Starting MaterialBorylation Reagent

Lithiation Reagent

Product

Borylated intermediate

Oct-10

Example 4: HexLiEquipment setup for 3 feeds


Starting Material

Lithiation reagent

Borylated reagentProduct

Lithiated intermediate

Borylated intermediate

Oct-10

Example 4: HexLiResults for 3-feed setup


Severe plugging issues after few minutes� precipitation of side product(s)

� other results:� lithiation reag. 2.1eq., boronation reag. 1.3 equ.� lithiation finished <1sec, borylation >20sec

Oct-10

Example 4: HexLi2kg production in lab with 2-feed setup


No plugging issues over 1.5 days� 15 batches in total� simpler chemistry and

process setup� increased reaction temperature

of more than 30°C

but:� throughput is limited by solubility

of starting material and intermdiates

� scale-up difficult due to formationof precipitates

� low production amount

Oct-10

Example 5:Monolithium Acetylide Reaction

Chemical route

HH LiH

LiSi Cl

SiH

Acetylen

BuLi

Monolithiumacetylide

TMSCl

SilanETM

Quench

By-products� Dilithium acetylide, irreversible if T > -25°C

� TMS Butane

Li Si Cl Si Li Cl

BuLi

TMSCl

+

TMS butane

Li-chlorid

+

Oct-10

Monolithium Acetylide Reaction: Initial feasibility

Batch reaction

� Literature [Midland, J.Org.Chem, 1975]

� Yield: > 90%

� Experiment� Temperature: -75°C� Time: 2 h� Yield > 93 %

X =93.5 %S =99.5 %

� Reaction work well at lab scale

1. BuLi

2. TMSCl

R01100 ml glass

T = -75°C

Vent

AcetyleneV4

03

N2

B11C11

Gas washer

PI11

V1

V2 V3

V5

02

01

04

V6

QI01

TI11

V6

FI11

N2

Oct-10

Monolithium Acetylide Reaction: 3-Feed setup

Heterogeneous reaction in MR

� Three feeds� Acetylene� THF� BuLi 15 % in hexane

� Parameters� Reactor temperature� Flow rates � Stoichiometry

� Acetylene limitation� p max = 1.5 barg� ∆p reactor < 1 bar

TMSCl

Oct-10

Monolithium Acetylide Reaction: Optimisation

Investigations in microstructured plate 400:� Acetylene dissolution in THF� Reactor plugging

� Reaction with BuLi

Conditions and apparatus � Cooling temperature: -50°C� MFC: 0…1000 mlN/min N2� Coil for THF: H1 (10m)

� Coil for BuLi: H2 + H5 (~10 m)

Acetylene

THF (BuLi)

(BuLi)

exit

Oct-10

Monolithium Acetylide Reaction: Optimization

Acetylene dissolution in THF at -30°C

Acetylene = 615 mlN/minTHF = 25 ml/min

N2 = 50 mlN/minTHF = 25 ml/min

Acetylene

THF

N2

THF

Oct-10


Reactor plugging

Plugging at BuLi entry

Reasons ?

• Hot spot: Dilithium acetylide salt

• Water trace: reacts with BuLi

� LiOH formation

Solutions

• Heat transfer enhancement

• Remove water in THFBuLi

Acetylene

THF

Oct-10

Monolithium Acetylide Reaction: Plate reactor

Reactor � Lonza MicroReactor� Multi-Injection plate 240

Results� Ymax= 97 %� Tr = -50°C

� CBuLi = 0.5 M

Observations� Acetylene dissolution before reaction� CBuLi: negative effect� Temperature: no big impact if T < -40°C

� Residence time: fast reaction� Problem: Reactor plugging if T > -30°C

Lonza MicroReactor

Multi-Injection Reactor Plate

THF

Acetylene BuLi Exit

Oct-10


Effect of BuLi concentration

Constant parameter:� THF = 26.5 g/min� Acetylene/BuLi ratio = 1.15� T reactor = -50°C

Selectivity decreases when CBuLi is higher than 0.5 M !� Same result has in literature for batch reactions

monolithium acetylide stabilisation by THF decreases if CBuLi > 0.5 M� Further explanation: hot spot formation for CBuLi > 0.5 M� Great limitation !

70%

75%

80%

85%

90%

95%

100%

0,35 0,40 0,45 0,50 0,55 0,60 0,65 0,70 0,75

BuLi concentration [mol/l]

Yie

ld,

Con

vers

ion

Yield

Conversion

Oct-10

Chemistry Meets Engineering ��

Organometallic Reactions with HexLi

On clear disadvantage:� Plugging� Lonza patent pending

Ultrasonic De-plugging System

H (acidic)R1 Li LiR1+ +

LiR1R2

O

R3 R2R1

OLiR3+ +

First reaction: Type A, highly exothermic (∆Tad > 75°C)

� Various reactors studied

Second reaction: Type B, exothermic (∆Tad < 25°C)

� Use of a static mixer under adiabatic conditions

2-Step Synthesis: Lithiation and Coupling

Oct-10

MRT Leads to Drastic Process Intensifications

� Lower reactor investment� Less manpower� Higher flexibility� Enhance safety� Faster change-over

“Factory of the Future”

Manufacturing gain up to 30%. Process intensification to enable inherently safer processes leading to a production paradigm

250 L

Oct-10

Flow Process in a Production Environment – from kg to tons

3-Feed setup with� MicroReactor for cryogenic reaction� Static mixer for 2nd reaction

� Controlled residence time

Oct-10

Scale-up Results and Thermal Safety

Chemical Project� More than 2 tons of isolated

material have been produced in one single campaign (4 weeks)

� More than 20 m3 of processed reaction volume

Lonza Universal Reactor Technology

� MicroReactor platform that supports rapid process development; it is also robust, multi-purpose, and scalable

� Clear path from laboratory chemistries to large-scale manufacturing processes

� completely avoids the parallelization / numbering-up strategies

880.3933Static mixer 3/8“

841.641148Static mixer 3/8“

860.4-1433Glass MR

883.215148Glass MR

874.5-16237Lonza MR-A5

893.0-19187Lonza MR-A5

882.0-21150Lonza MR-A5

908.8-16140Lonza MR-A6

890.9-2233Lonza MR-A6

YieldP [bar]

Tout[°C]

F MR [g/min]

Reactor

Oct-10

In the past conventional means all batch processes

Currently the MR is used to increase reaction yield & safety

Future will lead to fully integrated flow processes: MR and more…

The Future of Flow Processes will be theFull Integration of MRT in Production Units

Oct-10

� Microreactor for flash reactions

� Mixers-settlers/acid neutralization

� Distillation� Reactor cascade (CSTR)� Liquid-liquid extraction � Fully automated system

Throughput� More than 10 kg/day of Product

Mini-Plant concept to enable New Processes and extend the design space of how we perform chemistry

Mini-Plant Technology at the Center of Flow Processes

Oct-10

Conclusions

Flow technologies are the forefront of a quantum leap in pharmaceutical manufacturing leading to greener processes at lower costs

� Design new chemical routes

Lonza is a leading manufacturer of chemicals using flow processes and advanced technologies

� The heart of the process is the microreactor

Acknowledgments� W. Quittmann, N. Bieler, R. Forbert (Siemens), L. Ducry,

F. Rainone, M. Thalmann, W. Brieden, B. Zimmermann,M. Mathier, A. Brunner

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