use of real-time mid-ir analytics for enhanced development of flow chemistry
DESCRIPTION
Presentation titled Use of Real-Time Mid-IR Analytics for Enhanced Development of Flow Chemistry given at the 14th NIChE Conference on Micro Reactor Technology and Process Intensification Septemeber 21-23, 2009 at NIST in Gaithersburg, MD. Email me at [email protected] if you are interested in links to technical webinars and whitepapers on the topics of mid-FTIR in situ reaction analysis, process characterization & scale-up and reaction calorimetry.TRANSCRIPT
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Use of Real Time Mid-IR Analytics for Enhanced Development of Flow Chemistry
Paul Scholl
14th NIChE Conference
September 21 -23, 2009
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Introduction
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Combining Real Time Analytics & Process Control
Analyze Reaction Chemistry
Describe Process
Characterize Particles
Data Capture and Understanding
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- Did the reaction work?
- Understand selectivity and reactivity
- Identify intermediates or by-products
- How long did it take?
- Endpoint, initiation-point, stall-point
- Can this process be scaled-up?
- Identify key control parameters
- Understand reaction kinetics
The importance of real time reaction analysis
Introduction
- No need for a chromatography method
- Compounds can be unstable, sensitive, toxic,…
- No need for sampling at low/high temperature/pressure
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In Situ Reaction Analysis for Flow Chemistry
Current challenges- Most systems require grab sampling for analyses
Developing flow processes of novel compounds “blind”
Decreased efficiency, potential alteration of sample
- UV detection systems have limited chemical detectivity
- Increasing pressure and number of chemistries to convert to flow processes
Faster structural information in real time- Reaction mechanism/pathway
- Immediate reaction Start/End points
- Detection of transient intermediates
- Eliminates sampling
- Universal (fits with any flow system)
- Multi-stage flow capability (MultiplexIR)
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Component Spectra Component Profiles
In-situ reaction results
ConcIRT live
Peak height profiling
Quantitative model
Reaction Monitoring and Characterization
Time
Abs
orba
n ce
or
Rel
ativ
e c o
ncen
tra t
ion
Time
Abs
orba
nce
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Development of a Safe and Scalable Oxidation Process for the Preparation of 6-Hydroxybuspirone
Introduction
Active metabolite of Buspirone,
manufactured and marketed as
Buspar, employed for the treatment of
anxiety disorders and depression
Multi Kg amount needed for clinical dev.
Process lack of ruggedness and
unreliable product quality
Source: Daniel J. Watson,* Eric D. Dowdy, Jeffrey S. DePue, Atul S. Kotnis, Simon Leung, and Brian C. O’Reilly, Bristol-Myers Squibb Pharmaceutical Research Institute, NJ, USA, Organic Process Research and Development, 2004, 8, 616-623; Mettler Toledo Real Time Analytics Users’ Forum 2004, London, UK
Case Study: FTIR, PAT Tool in Pharma Development
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Challenges
Monitor deprotonation of 1 for:
-More precise determination of endpoint to minimize bis-deprotonation
-Allow for variations in the base titer, water content, and phosphite quality
Case Study: FTIR, PAT Tool in Pharma Development
KHMDS
1677cm-1
1627cm-1 Observations
-Deprotonation complete within 5’
-Enolate anion 3 stable at -25⁰C for 12h
-Addition of P(OEt)3 before addition of the base → no impact on IR signal
-Kinetics of enolate degradation
Source: Daniel J. Watson,* Eric D. Dowdy, Jeffrey S. DePue, Atul S. Kotnis, Simon Leung, and Brian C. O’Reilly, Bristol-Myers Squibb Pharmaceutical Research Institute, NJ, USA, Organic Process Research and Development, 2004, 8, 616-623; Mettler Toledo Real Time Analytics Users’ Forum 2004, London, UK
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Case Study: FTIR, PAT Tool in Pharma Development
KHMDS
Observations
-Deprotonation complete within 5’
-Enolate anion 3 stable at -25⁰C for 12h
-Addition of P(OEt)3 before addition of the base → no impact on IR signal
-Kinetics of enolate degradation
Source: Daniel J. Watson,* Eric D. Dowdy, Jeffrey S. DePue, Atul S. Kotnis, Simon Leung, and Brian C. O’Reilly, Bristol-Myers Squibb Pharmaceutical Research Institute, NJ, USA, Organic Process Research and Development, 2004, 8, 616-623; Mettler Toledo Real Time Analytics Users’ Forum 2004, London, UK
Challenges
Monitor deprotonation of 1 for:
-More precise determination of endpoint to minimize bis-deprotonation
-Allow for variations in the base titer, water content, and phosphite quality
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Case Study: FTIR, PAT Tool in Pharma Development
KHMDS Improved process
-Charged the base to 1 until complete
consumption → Stable signal (1677cm-1)
-1 / THF charged back to the vessel
until the signal increased → 1-3%
excess of the starting material
(quantified FTIR)
-Result: Impurity 8 is minimized
Source: Daniel J. Watson,* Eric D. Dowdy, Jeffrey S. DePue, Atul S. Kotnis, Simon Leung, and Brian C. O’Reilly, Bristol-Myers Squibb Pharmaceutical Research Institute, NJ, USA, Organic Process Research and Development, 2004, 8, 616-623; Mettler Toledo Real Time Analytics Users’ Forum 2004, London, UK
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Case Study: FTIR, PAT Tool in Pharma Development
Conclusion
-ReactIR™ allowed titration of the
correct amount of base, prevented
accidental overcharge due to
ambiguous concentration
- Implementation to the pilot plant (13Kg)
-69% yield and >99 area %, need for
recrystallization eliminated
-Robust, superior process &
crystallization thanks to the successful
use of PAT
Buspirone
Buspirone enolate
Source: Daniel J. Watson,* Eric D. Dowdy, Jeffrey S. DePue, Atul S. Kotnis, Simon Leung, and Brian C. O’Reilly, Bristol-Myers Squibb Pharmaceutical Research Institute, NJ, USA, Organic Process Research and Development, 2004, 8, 616-623; Mettler Toledo Real Time Analytics Users’ Forum 2004, London, UK
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Development and Scale-up of Three Consecutive Continuous Reactions for Production of 6-Hydroxybuspirone
Introduction
Control base / buspirone stoichiometry is
critical to product quality
Optimization based on offline analysis is
time consuming and wasteful
Actual feed rate adjusted based on the
feedback from inline FTIR: Flow cell
and ReactIR™ DiComp probe
Case Study: FTIR as PAT Tool for Continuous Process
Source: Thomas L. LaPorte,* Mourad Hamedi, Jeffrey S. DePue, Lifen Shen, Daniel Watson, and Daniel Hsieh, Bristol-Myers Squibb Pharmaceutical Research Institute, NJ, USA, Organic Process Research and Development, 2008, 12, 956-966; Mettler Toledo Real Time Analytics Users’ Forum 2005 - New York
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Case Study: FTIR as PAT tool for Continuous Process
Implemented startup strategy
-Start with slight undercharge of base (feed rate) to reduce diol 8
-Flow rate increased at 1% increments until no decrease of Buspirone 1 signal is observed
-Base feed rate was reduced 1-3%
-Works well because enolization fast, equilibrium reached within minutes
KHMDS
Source: Thomas L. LaPorte,* Mourad Hamedi, Jeffrey S. DePue, Lifen Shen, Daniel Watson, and Daniel Hsieh, Bristol-Myers Squibb Pharmaceutical Research Institute, NJ, USA, Organic Process Research and Development, 2008, 12, 956-966; Mettler Toledo Real Time Analytics Users’ Forum 2005 - New York
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Case Study: FTIR as PAT Tool for Continuous Process
Outcome
-Ensure product quality via proper ratio and base feed rate
-Minimize waste of starting material
-Faster reach of steady state via real-time detection of phase transitions
-FTIR also used for enolization monitoring during steady state
Scale-up
-Lab reactor: Over 40 hours at steady state
-Pilot-plant reactor: Successful implementation (3-batch, 47kg/batch)
Source: Thomas L. LaPorte,* Mourad Hamedi, Jeffrey S. DePue, Lifen Shen, Daniel Watson, and Daniel Hsieh, Bristol-Myers Squibb Pharmaceutical Research Institute, NJ, USA, Organic Process Research and Development, 2008, 12, 956-966; Mettler Toledo Real Time Analytics Users’ Forum 2005 - New York
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Technology Development: MultiplexIR & DS Series Flow Cells
Multiplexing- Monitor multi-step chemistry- Monitor up to 2 different flow systems
Built-in modularity allows enhanced usability for process development- Plug-n-play technology permits use of probe based ReactIR™ reaction monitoring
technology with the same system
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DS Series Flow Cell Schematic
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Conclusion
Organic synthesis lab at the turn of the century…
…which century?