Continuous Micro Reactor Technology for Drug Substance Synthesis:

Continuous Micro
Reactor Technology for
Drug Substance
Synthesis:
Brian J. Marquardt Ph.D.
Wesley Thompson, Thomas Dearing, Michael Roberto
Applied Physics Laboratory
University of Washington
Seattle, WA 98105
marquardt@apl.uw.edu

Analytical Sampling for Online Applications

Why Use Advanced Flow Reactors
High Throughput Experimentation For…
Discovery and screening
Process development
Process optimization
Process control
Production
• Eliminate chemical engineering production
problems related to scaling up batch systems
• Increase production through use of many parallel
microreactors to achieve volume

Intensity
Esterification Reaction Monitored by
Example: Esterification of Methanol
Raman Spectroscopy
20000
15000
Acetic Acid + + Methanol
ROI
H +
H +
Heat
Methyl Acetate + H 2 O
Standard Raman spectra
Acetic Acid
Methanol
Methyl Acetate
10000
5000
0
400 600 800 1000 1200 1400 1600 1800
Raman Shift (cm -1 )

Relative Intensity
Batch Runs at Different Temperatures
250
200
150
65º
55º 45º
35º
25º
15º
100
5º
50
• PCA analysis of the formation of acetate monitored
by Raman spectroscopy – reaction time 1.5 hours
0
0 30 60
Reaction Time (min.)
Total experiment time ~ 1 week (includes charging reactors, cleaning, …)
90

Continuous Rxn. with Temp. Step
Temp 40°C
Temp 25°C
• with residence time module
• flow rate: 10.56 ml/min
(residence time ~ 2.5 min)
(25°C – 40°C)
methyl
acetate
acetic
acid
• With control of flow reactor parameters and analytics, fast optimization is possible

Product Yield vs. Temperature
PCA Analysis on data after mixing:
1 st PCA scores Increase in reaction yield
after each temperature step
Range = 30-60°C
• without residence time module
• flow rate: 0.89 ml/min
(residence time ~ 5 min)
• 1 week of batch data reproduced in less than three hours by continuous flow

Result: Estimated Response Surfaces

Challenges To Using AF Reactors
• EDUCATION!!!!!!
• Sampling and screening
• Analytical characterization
• Data handling
Sensor fusing
Multi-sensor modeling
• Process modeling and feed back control
(particularly if they are used for production)
• Process optimization – move toward feed
forward control

Demonstrating QbD - Phase 1
‣ Goal: to improve reaction development and
optimization through the use of continuous glass flow
reactors, NeSSI and analytics
‣ Funded by the FDA to demonstrate the benefits of
improved reactor design, effective sampling and
online analytics to increase process understanding
(QbD)
‣ Partners: FDA, Corning, CPAC, Kaiser, Parker
‣ QbD Project began November 2008
‣ Process Reactions – June 2009

AF Reactor and Raman Analyzer
• 4 channel, 785 nm Kaiser Optical Systems Rxn2 probes placed at different reactor zones

Chloroformate Chemistry
Organic Acid Chloride
Organic Carbonate + dimer
O
O
OH
pyridine
Cl + O
HO
toluène
O
O
OH
+
N
.HCl
2-ethylhexyl chloroformate butane-1,2-diol 2-ethylhexyl 2-hydroxybutyl carbonate
OH
O
Cl
+ O O
O
O O O
O
O
O
O
2-ethylhexyl chloroformate
2-ethylhexyl 2-hydroxybutyl carbonate
dimmer dimer
• Carbonate and dimer formation

Design of Experiments Information
• 31 Experiments total
Temperature steps
Reaction with no toluene
Changes in butanediol ratio
Changes in pyridine ratio
Propanediol instead of butanediol
Simulated Reactor problems
• Pump failure
• Less heat exchange
• Poor dilution of chloroformate

Raman Analysis of AF Reactor
1
2
3 4
• Monitor reaction with 4 channel 785 nm Raman system
• NeSSI sampling systems (1-4) equipped with Raman ballprobes
• Online GC also used as post quench online analyzer (4)

NeSSI Ballprobe - Raman/NIR/UV
Ballprobe Specs.
•Hastalloy c-276
Ti, SS, Monel
•Sapphire optic
•Std. temp range:
-40 – 350° C
•Pressure:
0-350 Barr
Matrix Solutions: www.ballprobe.com

What is NeSSI
• Industry-driven effort to
define and promote a new
standardized alternative to
sample conditioning systems
for analyzers and sensors
• Standard fluidic interface for
modular surface-mount
components
• ISA SP76
• Standard wiring and
communications interfaces
• Standard platform for
micro analytics

What does NeSSI Provide
• Simple “Lego-like” assembly
Easy to re-configure
No special tools or skills required
• Standardized flow components
“Mix-and-match” compatibility between vendors
Growing list of components
• Standardized electrical and communication (Gen II)
“Plug-and-play” integration of multiple devices
Simplified interface for programmatic I/O and control
• Advanced analytics (Gen III)
Micro-analyzers
Integrated analysis or “smart” systems
Provides platform for coupling analytics to flowing systems

NeSSI Sampling System for Reactor
Raman Probe
monitor
clean
bypass

NeSSI and Raman Probe Images

Raman Peaks of Interest for Rxn.
Chloroformate
Toluene
Carbonate
Dimer
Toluene

3D Plot of Raman Reaction Data (Low cm -1 )
GC Results (%)
Test R-OH 2EHCF R-Cl Carbonate Dimer
1 1.17 0.00 0.26 96.17 2.40
2 2.16 45.84 0.32 51.42 0.59
Ch. 1
Toluene
Chloroformate
Toluene

DoE Run1 Channel 1 Data (Reactor)
0.18
0.12
Run1Ch1LowPCA
Density 1
Density 2
Density 3
0.16
Run1Ch1LowPCA
Feed 1
Feed 2
Feed 3
0.1
0.14
0.12
0.08
0.1
0.06
0.08
0.04
0.06
0.04
0.02
0.02
0
20 40 60 80 100 120
0
20 40 60 80 100 120
0.14 Run1Ch1LowPCA
Pressure 1
Pressure 2
Pressure 3
0.12
0.12
0.1
Run1Ch1LowPCA
Ambient Temp.
Quench Temp.
Reactor Temp.
0.1
0.08
0.08
0.06
0.06
0.04
0.04
0.02
0.02
0
20 40 60 80 100 120
0
20 40 60 80 100 120

Normalized Signal Intensity
Normalized Signal Intensity
Reaction Profiles for 2 DoE Steps
0.8
0.7
0.6
GC Results (%)
Test R-OH 2EHCF R-Cl Carbonate Dimer
1 1.17 0.00 0.26 96.17 2.40
2 2.16 45.84 0.32 51.42 0.59
1
0.8
0.5
0.4
Test 1
0.6
0.3
0.2
0.1
Test 2
---- Carbonate
---- Chloroformate
0.2
0
0 10 20 30 40 50 60 0
Sample Number
0.4

Project Summary and Future Directions
• Data collected and organized
17 days in Toulouse France
• Analysis and Modeling
Evaluation of various modeling
protocols
• PCA, MCR, ALS
Calibrate to GC results (PLS)
• Phase 2 of project
Acquire reactor at CPAC
Focus on reactor control
Implement more sensors
Scale-up vs. scale-out
Real-time product work-up
• Implement Models for Process
Feedback Control

FDA Project - Phase 2
Nov. 2010 – Oct. 2011
• Process Scale Up and Control
Chemistry
• Determine, evaluate and test reactions in CF reactors
Pharmaceutical industry relevant chemistry
Emphasis on processing not specific chemistry
• Determine CRF (Critical Response Factors) and Levels
Sampling & DoE
• Coupling analytics at mL and mL scales
• Scalability
Reaction monitoring w/online analytics
• Reaction/Data Modeling
Determine Control Mechanisms
Initiation of Process Control

Chemtrix - Labtrix
• Reaction optimization
Features
• Syringe pumps
• Automated sample collection and
control
• Tests at pressures of 25 bar and
temperatures of -15 to 195°C
• Standard interchangeable reactors
• Catalyst reactors:
Courtesy Paul Watts, University of Hull, UK
• Labtrix platform will be the low volume reactor platform for our Phase II FDA project

Corning ® Advanced-Flow TM LF
Low-Flow Capability (1-10 mL/min)
Corning has introduced a reduced
flow-rate reactor that retains the
outstanding mixing and heat
exchange performance of its
Advance-Flow TM glass reactors
while providing:
• Low internal volume (2 mL flow)
• High flexibility
• Metal-free reaction path
• Scalability
• Compatibility with analytics
• T, Flow and Pumping control
• LF platform will be the larger reactor platform for our Phase II FDA project

Reactor with NeSSI and Analytics at CPAC

Esterification of Benzoic Acid and
Subsequent Hydrolysis

Swern Oxidation – 3 step rxn

Phase 2 – QbD Envisioned
• Process Optimization
Scale Up Versus Scale Out
• Transfer chemistry from mL scale to mL scale
• Full DoE at small scale and transfer for fast optimization at larger
scale
Development of Generic Strategy
• define selection of the best analytical tools, processing methods,
and model designs in a short time frame
• Speed optimization of new chemistry with CF reaction methods
• Continuous Process Control
Initiate control protocols utilizing analytics for improved product quality
Evaluate continuous post-reaction workup steps – Phase 3
• Purification
• Desolvation
• Separation

Mettler Toledo - React-IR,

Thermo/C2V Fast Micro-GC
http://www.c2v.nl/ as well as http://www.thermo.com

Conclusions and Projections
• The initial demonstration phase of the QbD project successfully
demonstrated the capability of effective sampling coupled with
higher order analytics to provide a real-time view of a chemical
process
• The second phase builds on the sampling and analytical methods
developed in phase 1 and models the sensor data in real-time to
perform fast and efficient optimization of new chemistries using DoE
and low volume continuous reactors (Chemtrix system)
• Once the chemistry has been optimized and validated at the
microliter scale, that chemistry will be scaled up to the mL scale
(Corning LF system) and optimized using an optimal DoE
• The final aspect of phase 2 will be to integrate the real-time analytics
into a control algorithm for continuous feedback control of the
system for consistent and validated quality production

Thanks
• U.S. Food and Drug
Administration
Moheb Nasr
Christine Moore
Sharmista Chatterjee
David Morley
• Corning Glass
• Parker
• Kaiser Optical Systems
• CPAC
• University of Washington
• Applied Physics Lab
• La Maison Européenne des
Procédés Innovants (MEPI )
U.S. Food and
Drug Administration
MEPI