AiCHE 2012 Pittsburgh PA

Enhanced Development and Control of

Continuous Processes Using Real Time in

Situ FTIR Analytics

Dom Hebrault, Ph.D.

2012 AIChE Annual Meeting

October 31st 2012

Continuous Flow Chemistry - Analysis Challenges

ATR-FTIR In Situ Spectroscopy with ReactIR™

Case studies:

- Safer Use and Monitoring of Hazardous Substances: Development of Continuous

Process for Alkene Ozonolysis

- A Visual, Efficient, Method to Optimize Reaction Conditions, and Enhance Process

and Product Quality: Case study on a Doebner Modification

Today’s Agenda

Continuous Chemistry - Analysis Challenges

Chemical information

- Continuous reaction monitoring superior to traditional sampling for offline

analysis (TLC, LCMS, UV, etc.)

→ Stability of reactive intermediates

→ Rapid optimization procedures

Technical knowledge

- Dispersion and diffusion: Side effects of continuous flow – must be

characterized

Today: Limited availability of convenient,

specific, in-line monitoring techniques

In-Line IR Monitoring

Monitor Chemistry In Situ, Under Reaction Conditions

- Non-destructive

- Hazardous, air sensitive or unstable reaction species (ozonolysis, azides etc.)

- Extremes in temperature or pressure

- No interference from bubbles, solid, color,…

Attenuated Total Reflectance (ATR)

Spectroscopy


Real-Time Analysis, “Movie” of the Reaction

- Track instantaneous concentration changes (trends, endpoint, conversion)

- Minimize time delay in receiving analytical results


Determine Reaction Kinetics, Mechanism and Pathway

- Monitor key species as a function of reaction parameters

- Track changes in structure and functional groups

ReactIRTM Flow Cell: An Analytical Accessory

for Continuous Flow Chemical Processing

Carter, C. F.; Lange, H.; Ley, S. V.; Baxendale, I. R.; Goode, J. G.; Gaunt, N. L.; Wittkamp, B. Org. Res. Proc. Dev. 2010, 14, 393-404

In-Line FTIR Micro Flow Cell in the Laboratory

Internal volume: 10 & 50 ml

Up to 50 bar (725 psi)

-40 → 120 ºC

Wetted parts: HC276, Diamond/Silicon & Gold

Multiplexing

Spectral range 600-4000 cm-1

FlowIR: Flow chemistry and beyond…

Internal volume: 10 & 50 ml

Up to 50 bar (725 psi)

-40 → 120 ºC

Spectral range 600-4000 cm-1

FlowIRTM: A New Plug-and-Play

Instrument for Flow Chemistry and

Beyond

9-bounce ATR sensor

(SiComp, DiComp) and head

Small size, no purge, no

alignment, no liquid N2

The Development of Continuous Process

for Alkene Ozonolysis Based on

Combined in Situ FTIR, Calorimetry, and

Computational Chemistry

Introduction

Continuous reaction setup for ozonolysis

reactions

Instantaneous “view” of the chemistry

using in situ FTIR

Investigation resulted in 2.7kg production

of API intermediate in 2 weeks

In Situ Monitoring for Continuous Manufacturing of APIs

Ayman D. Allian, Steve M. Richter, Jeffrey M. Kallemeyn, Timothy A. Robbins, and Vimal Kishore, Abbott, Process Research and Development, 1401

Sheridan Road, North Chicago, Illinois 60064, USA, Organic Process Research and Development, 2011, 15, 91-97

Understand: Steady state, rate,

intermediates, O3 efficiency, mass

transfer

Optimize: Residence time (flow rate,

reactor size)

Styrene

-50°C

In Situ Monitoring for Continuous Manufacturing of API



xxx

(37 mmol/ sec, 2L/min)

Feed rate limited

FTIR 780 cm-1

Results

Initial lab scale kinetic study in 100ml batch

Challenges

Ozonolysis highly efficient and selective

oxidation method

Hazardous and unreliable in batch

manufacturing: Exotherm, stability of

intermediates, ozone toxicity

Styrene / MeOH / DCM

-50°C




Results

100mL batch vessel retrofitted with

overflow valve → CSTR

Residence time distribution experiment

FTIR data confirmed by off-line HPLC

Results

Oxidation of an isobutylene-type API

intermediate

300g prod., 4d, 12h/d, 81% isol. yield

One week lead time

(Residence time distribution experiment)

Acetone (/heptane)

Rate is O3 feed-controlled

2L/min




Results

Jacketed bubble reactor setup

32g/h – O3 generation

Applied to styrene, isobutylene-type API

intermediate

Made 2.7kg ketone, 4d, 9h/d, rate: 80g/h

2-week lead time

Conversion 99%, O3 efficiency ≈ 85%

ReactIRTM probe

Coarse frit

17L/min

-33°C




Styrene / O3 equimolar:

Steady state 15-20% styrene




in situ FTIR allowed to

Monitor reaction progress, detect

process upsets in real time

Ensure highest degree of product quality

and yield

Eliminate need for sampling and offline

analyses → improved productivity and

safety

Outcome

Preliminary kinetic investigation in batch

Small scale CSTR for 300g production

Larger scale continuous bubble reactor

setup for 2.7kg

Optimization of a Doebner Modification of

Knoevenagel Reaction in a Continuous

Mode

Introduction

Can reaction optimization and conditions

screening be conducted inline?

How does dispersion affect fraction

collection?

Rapid Analysis of Continuous Reaction Optimization

Vapourtec – Flow Chemistry Solutions – Mettler Toledo collaboration project, U.K. 2011, White Paper

On-the-fly reaction optimization with

inline FTIR analytics

Vapourtec R2+/R4

FlowIRTM

+ CO2

Results

Reference spectra of 4 main components

3 main/unique bands

7 reaction “plugs”, on-the-fly variation of

residence time and temperature (1:1.1

benzaldehyde/malonic acid ratio)

Few hours experiment only


Malonic

Acid

(1729cm-1)

Benzaldehyde

(828cm-1)

Cinnamic acid

(772cm-1)


80°C, 10’

100°C, 10’

120°C, 20’

120°C, 10’ 100°C, 20’ 100°C, 30’

150°C, 10’

4.5 h

Results

Development of an in-situ real time assay

method

- ReactIR algorithm: iC Quant and iC IR

- Simple univariate model (trans-

cinnamic acid 772 cm-1 with 2 baseline

points)

“Proof of concept” univariate model

Limited number of datapoints

Model used to predict concentration



Trans-cinnamic acid

(772 cm-1)

(0.1-0.5M)

Results

Development of an in-situ real time assay

method:

- Application to the previous screening

- 100°C, 20’ to 30’ represent an optimum

at (1:1.1 benzaldehyde / malonic acid

ratio)



[M]

0.35

0.30

0.25

0.20

0.15

0.10

80°C, 10’

100°C, 10’

120°C, 20’

120°C, 10’ 100°C, 20’ 100°C, 30’

150°C, 10’

Variation of benzaldehyde / malonic acid:

- From 1:1.1 to 1:2 (100°C, 20’)

- No significant improvement

- Real time FTIR provides confirmation of

steady state and concentrations in the

plug

1:2

1: 1.1 1:1.5

1:1.2

1:2

Steady state

3.5 h

Conclusions

No issue with CO2 bubble

Faster, more efficient, optimization

Provides a picture of flow dispersion,

helps enhanced separation and off-line

analysis



Compared to former in-house solutions

Can be heated, cooled, pressurized

Wide spectral range and high sensitivity

Turn-key, affordable, space efficient

Acknowledgements

Abbott, Process Research and Development, USA

- Ayman D. Allian et al

Vapourtec Ltd. (U.K.)

- Chris Butters, Duncan Guthrie

Flow Chemistry Solutions (U.K.)

- Andrew Mansfield

Mettler Toledo Autochem

- Will Kowalchyk (USA), Jon Goode (U.K.)

AiCHE 2012 Pittsburgh PA

Technology

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