Pfizer

Siegfried Symposium: New Methods in Process Chemistry
Everything Old is New Again

Developing a New Paradigm for
Process Research Through Application
of New Technologies
Van Martin
Pfizer Global Research & Development
Siegfried Symposium 2004
Institute of Organic Chemistry, University of Zurich
14th October 2004, Zurich, Switzerland
Purpose of this Presentation

To catalyze discussion concerning the way Process
Chemical R&D is Performed
To discuss the on-going development of a New
Paradigm for the practice of Chemical Process R&D
To show how Classical Physical Organic Chemistry
and New Technologies are combined as a part of this
New Paradigm
To propose actions to hasten the development and
implementation of this New Paradigm
14 October 2004; Van Martin
Pfizer Global Research & Development-La Jolla: CRD Technologies
What is Chemical Process R&D?

(an Operational-Compilation)
Pre-Candidate Enabling
New Route Development
Screening
Route Scouting
Optimization
Safety Testing
Robustness Testing
Critical Process
Parameterization
Scale-up
Validation
Technology Transfer
Impurity / Isomer Preparation

Metabolite Preparation
Competitor Compound
Synthesis
Salt Screening
Polymorph Screening
Synthesis of Material for
Toxicology Testing
Synthesis of Material for
Formulation Development
Clinical Material Synthesis

(a Workflow Definition)
New Route Development
Screening
Optimization
Characterization
Long-Term
Process
Safety
Robustness
Critical Process
Parameters
Scaleup
and
Validation
Discovery
Enabling
Chemistry
Development
Manufacturing
Safety
Scaleup
Optimization
Partial
Characterization
Immediate Material Preparation

Material
Preparation
Short-Term
Process

(A Strategic Definition)
At the strategic level, CP R&D is the production of
information that is needed to move a product
candidate from Discovery to Manufacturing
The material produced by CP R&D (for both internal
and external use) is only used to generate information
CP R&D is Essentially the Search for Information
(i.e. exploration of Chemical Development Information
Space)
and conversion of that information to an appropriate form
What is it We do to Obtain Information?

(How do we explore Information Space)
Experimentation
Enter Here
Cogitation
& Planning
CP R&D
ScientificData Collection
Information Cycle
Enter Here
Data Analysis
This describes all aspects of scientific research in CP R&D

and is the basic process for information acquisition
What is the Current Paradigm, for the Average

Process Research Chemist, for doing CP R&D?
How do we explore information space?
Typically only a few reactions are run simultaneously
Amount of data gathered per reaction is low
Data logging is performed manually
In situ monitoring of reactions is rare
Except for temperature monitoring
Automated sampling of reactions is rare
Techniques for running reactions are not optimal

Poor control of addition of reagents via dropping funnels
Poor agitation and mixing
A stir bar in a round bottom flask is about a bad as you can get
Exploration of Chemical Space is unsophisticated

Standard Paradigm for Performing CP R&D

In much, or even most, of their work the average
Chemist is performing Experimental Organic
Chemistry essentially the same way it was done 50
(or even 75) years ago
The Major Exceptions are
Use of NMR, HPLC, and Computerized Literature Searching
Just About Everything Else We Do on a Regular

Basis Was Done, or Could Have Been Done, in 1950
Knowledge has Changed; the Techniques Used (for
the most part) have Not
Where Have the Major Changes Occurred in the

CPR&D Work-Cycle?
Relatively unchanged over last 50 years
And, not that much change over last 75 years
Experimentation
Cogitation
& Planning
Data Collection
Data Analysis
the majority of the

improvements in the way
we do chemistry have
occurred here
New Technologies / Improvements in Data

Collection and Analysis
pH Meters in regular use: late 1930s / early 1940s
Beckman Model G pH Meter (1936)
UV-Vis Spectroscopy in regular use: 1940s

Beckman DU UV-Vis Spectrophotometer (1941)
Mass Spectrometry in regular use late 1940s

Model 21-101 Mass Spectrometer (1942)
IR Spectroscopy in regular use: 1950s

PE Model 21 Dual Beam IR Spectrometer (1950)
GC in regular use: early 1960s

First commercial instruments: mid-1950s
TLC (as we know it) in regular use: 1960s

Developed in late 1950s / early 1960s
Not an instrument, but an important analytical tool
NMR in regular use: 1960s

Varian A60 NMR (1961)
New Technologies / Improvements in Data

Collection and Analysis (cont.)
The melding of computers with instruments: 1980s
IBM PC Introduced (1981)
The move from analog data acquisition/storage/manipulation, to digital
FT IR in regular use: 1980s

Nicolet 5MX FTIR Spectrophotometer (1982); FTIR for the masses
FT NMR / Super Conducting Magnets in regular use: 1980s

First routine C13 analysis (1972)
High Field Strength Magnets (late 1970s early 1980s)
HPLC in regular use: 1980s

First commercial HPLCs (1970s)
CP R&D achieves one HPLC per chemist (1990s)
Routine use of Hyphenated Methods: 1990s 2000s

e.g. HPLC-MS (and NMR)
New Technologies / Improvements

in Experimentation
Parr Shakers in regular use: 1930s
Basic design 1922; Offered commercially by Parr about 1926
Heating Mantles in regular use: 1940s

First commercial heating mantle; Glas-Col 1939
Ground Glass Joints in regular use: late 1940s

Basic concept, Quickfit and Quartz Ltd (1934)
Magnetic Stirring in regular use: 1950s

Invented in 1940s (perhaps earlier): Stir bars required inert, soft coating
Rotary Evaporators in regular use: 1960s

First Commercial Rotary Evaporator: Buchi 1957
Electronic Balances in regular use: 1970s

Automatic Temperature Control in regular use: 1990s
I2R THERM-O-WATCH 1957; although not uncommon, not widely used earlier
Summary of Development of New Technologies for

the Chemical Process R&D Research Cycle
Analytics and Data Analysis
Massive changes from 1920s to near present
Experimentation
Very little change over same time period
The advent of the personal computer has had little or no effect on
the way reactions are run
Nothing the average chemist uses in their day-to-day work is more
complicated than Microsoft Word or ChemDraw
Thinking and Planning (about Exploration of

Information Space)
Essentially no changes in last 50 years
Why do We Need a New Paradigm for Performing

Chemical Process R&D?
Industry is under enormous pressure to to shorten
timelines and decrease costs
We need more information in less time
The old paradigm does not provide for efficient
searching of Chemical Development Information
Space
The Goal of a new paradigm should be more efficient
exploration of Information Space
But the Old Way Works Just Fine!
We still need to be faster and more efficient

Under an improved paradigm,
Simple problems become even simpler
Difficult problems are solved faster
Very difficult problems become doable
This is
often not
accepted,
because we
typically
work on
open-ended
problems
We are not doing CP R&D only for fun

this is business
What is the Focus on in Developing a New

Paradigm for Chemical Process R&D?
Operational Level (experimentation at the bench)
Change the techniques and improve the tools we use
Implement New Technologies
This takes money and a change in behavior
Strategy Level
Change the way we work and improve efficiency
More efficient ways of exploring Information Space
This only requires training and a change in behavior
What is New Technology?

Technology
A scientific method of achieving a practical purpose *

the practical application of knowledge **
the specialized aspects of a particular field of endeavor **
It is that which allows us to do what we need to do;
it is the tools that allow us to search information space ***
New Technology (a situational definition)

Any technology, from any source, that allows us to search
information space more effectively, and that is not utilized or
is underutilized in Chemical Process R&D ***
* The Merriam-Webster Dictionary (1974)
** Merriam-Websters Collegiate Dictionary, 10th ed. (2002)
*** Me, (2004)
Examples of New Technologies

(Instruments)
Computer Controlled Reactor Systems
Mettler LabMax; Argonaut ASI 4100; HEL AutoLab
Parallel Reactor Systems

Mettler Multimax; Argonaut Endeavor; Argonaut ASI 2410
In Situ Monitoring
IR (e.g. Mettler ReactIR)
Raman (e.g. Kaiser Optical Systems RamanRxn)
Particle Sizing (Mettler Lasentec FBRM and PVM)
High Throughput Screening

Zinsser SOPHAS / CRISSY; Tecan
Calorimeters
Mettler RC1; HEL Simular; OmniCal Super CRC
Reaction Blocks
Radleys Carousel Blocks, Stem Blocks, etc.
What Else is New Technology?

New technologies are more than just instrumentation
The way in which you approach a problem is also
Technology
Technology is also in the strategies you take to
explore information space
New Technologies include the use of:
Classical Physical Organic Chemistry
Design of Experiments / Statistical Optimization
Computational Chemistry
What is Physical Organic Chemistry?
Physical Organic Chemistry

the study of the underlying principles and rationale
of organic reactions
Neil Isaacs, Physical Organic Chemistry, 2nd ed., 1995
Classical Physical Organic Chemistry

Application of standard kinetic reaction analysis to
the elucidation of organic reaction mechanisms
Along with thermodynamics, catalysis, structure reactivity
relationships, etc.
Physical Organic Chemistry

as a New Technology
Physical Organic Chemistry is a set of tools for

exploring Chemical Information Space
Physical Organic Chemistry is essentially a
New Technology in that it is currently
underutilized in Chemical Process R&D
More about this later
How Do We Optimize Reactions?
Screen for Critical Reaction Parameters

Run a Set of Experiments Varying those Parameters
Build a Mental Model
Use the Model to Suggest the Next Set of
Experiments
Repeat as Needed
How are Reactions Optimized Using DoE?
Screen for Critical Reaction Parameters (guided by

DoE theory and Software)
Run a Set of Experiments Varying those Parameters
Build a Computer Model
Use the Model to Suggest the Next Set of
Experiments
Repeat as Needed
Whats the Difference Between the Usual Way and

Using Statistical Optimization / DoE?
The usual way is often less efficient
A drunkards walk through reaction space
One reaction and one variable at a time
DoE forces you to do what you should have been

doing anyway
i.e. systematic exploration of a portion of information space
DoE often allows you to run less experiments

Several variables can be varied simultaneously
DoE takes into account the effects of linked variables

Most reactions contain critical reaction parameters that are
linked
DoE is more likely to lead to counter-intuitive

solutions to problems
The Basis of a New CP R&D Paradigm

What do New Instrument Technologies, Statistical
Optimization/DoE, and Physical Organic Chemistry all
have in common?
They are under utilized by the average process
chemist
They all allow us to either
Search Chemical Development Space more efficiently
Access new areas of Chemical Development space
Or, examine them in a clearer and more controlled fashion
When used together, they provide the foundation for a

New Paradigm in CP R&D
What Does This New Paradigm Look Like?

It includes combining New Technologies, Physical
Organic Chemistry, Statistical Optimization, and
Computational Chemistry, to more efficiently search
Chemical Development Information Space
It involves a two-pronged approach
Specialty Groups for use of the more complex
instrumentation and technologies
Wider application of New Technologies by Process
Research Generalists
What Does This New Paradigm Look Like?

Organic Chemists and Chemical Engineers working
more closely with one another
Improved Experimentation (i.e. running reactions)
involving
Running more quality reactions per unit time

Greater instrumental control of reaction conditions
Gathering more data per reaction
Automated data logging
A more sophisticated and efficient exploration of Chemical
Information Space
What is the General State of the Pharmaceutical

Industry vis--vis this Paradigm
Specialty Groups are beginning to adopt it, across the
industry (essentially innovators and early adopters)
High Throughput Screening
Hydrogenation Catalysts
Polymorphs
Salt Selection
In Situ Reaction Monitoring

Control of particle size
Control of polymorphs
Reaction Profiling and Kinetics
Use of DoE and Physical Organic Chemistry
Process Research Generalists are interested, but are

slow to / dont want to adopt a New Paradigm
Why is Industry Slow in Development and

Implementation of a New Paradigm?
What is slowing us down
1) New Technologies, be they new instruments or
different ways of thinking and working, almost
always face significant barriers to adoption
2) Classical Physical Organic Chemistry is in a decline
and has, in general, become disconnected from the
standard practice of Organic Synthesis and
Reaction Optimization
3) Organic Chemists have seldom been exposed to
the techniques of Statistical Optimization
The Process of Technology

Adoption & Dissemination
In marketing terms, Moore describes this barrier in the
progression of the technology adoption cycle as a chasm*
* G. A. Moore, Crossing the
Chasm: Marketing and Selling
High-Tech Products to Mainstream
Customers, 1999 (rev. ed.)
Once this chasm is jumped

the adoption cycle may
accelerate rapidly
The Chasm
Innovators
Early
Adopters
10%
1-5 years
Early
Majority
Late
Majority
40%
40%
10-15 years
Laggards
10%
? (maybe never)
In General, Where Do We Stand,

With Respect To Technology Adoption
The vast majority of new technologies, especially in the area
of experimentation, have yet to cross the chasm
HTS, DoE,
POC
ALRs; React IR, DoE
Simple reaction blocks

rudimentary temperature controllers
HPLC, NMR, Desktop Literature Searching
Innovators
Early
Adopters
The
Chasm
Early
Majority
Late
Majority
Laggards
Where has Physical Organic Chemistry Gone?

When the average Process Research Chemist
encounters a problem, they typically try to solve it by
changing reaction conditions, changing reagents, or
changing solvents, without really trying to understand
or investigate the underlying cause of the problem
The approach, although guided by intellect, is similar to the
game Battleships
The relative proportion of chemists trained in the

techniques of Physical Organic Chemistry has
steadily declined over the last three decades

(continued)
Those chemists with the inclination to do POC are
going into other related areas
Computational Chemistry
Materials Science
Molecular Biology / Physical Biochemistry
Organometallic Chemistry
Because of its general utility, Physical Organic

Chemistry has been dispersed over a wide variety of
sub-disciplines
In the process, many of the classical techniques have
become lost to synthetic organic chemists

(continued)
it is becoming generally recognized that organic

chemistry cannot be treated satisfactorily without
reference to those questions of physical chemistry
which it involves
Nevil Vincent Sidgwick
The Organic Chemistry of Nitrogen; 1910
Why is Physical Organic Chemistry in Decline?

In the 1940s Physical Organic Chemistry became
strongly connected with Organic Synthesis
Before this time chemists were taught that mechanism had
nothing to contribute to real chemistry
See Barton p. 25 Grappling with Woodward
During the 1960s/1970s Physical Organic Chemistry

started becoming disconnected from synthesis again
Too much effort spent on non-classical carbonium problem?
See Streitwieser p. 62 for interesting discussion
Less perceived need by Synthesis Chemists?

Wider range of available reagents
Increasing complexity of Physical Organic Chemistry?

Change in the nature of scientific funding
e.g. in the US, the dominance of the National Institutes of Health has
skewed the pattern of funding for chemical research

(continued)
The Pharmaceutical Industry has inadvertently
contributed to the decline in Physical Organic
Chemistry
big pharma has not , in general, sought a variety of
backgrounds, viewpoints, and approaches in the
chemists it hires.
Jack E. Baldwin (University of Oxford)
Chemical & Engineering News, 2004, 82(26), 37-41

(continued)
the industry is known to strongly favor hiring of
synthetic chemists instead of people trained more
broadly in other chemistry subdisciplines
Charting Better Routes to Drugs; Stu Borman
Chemical & Engineering News, 2004, 82(26), 37-41
Ironically, most candidates we interview are over

trained in Synthesis Theory, Methodology and
Operational Technology and under trained in the
fundamental concepts of Physical Organic Chemistry
and Basic Experimentation
Kim Albizati
Executive Director; Pfizer Chemical R&D La Jolla
(former tenured Professor with Wayne State University)
This Decline has also Contributed

to Other Problems
The current gap between chemistry and chemical
engineering is due to the decline in classical physical
organic chemistry
Donna Blackmond
Professor of Chemistry and Chemical Engineering
Imperial College London
(personal discussion)
What Other Factors do We Face in Trying to

Apply New Technologies to CP R&D?
Cost of Instrumentation
Complexity of User Interfaces
Stage of Development of New Instrumental
Technologies
Most really new technologies are not ready to be widely
distributed
But, changing the way people work only partly involves new
technologies
Human Factors
Lack of Proper Training
Barriers to Adoption
What Needs to be Done to Change the Way

Chemical Process R&D is Done?
Industry needs to:
Take a broader approach towards the types of
scientists it hires
Work more closely with Academia
Play a stronger role in distribution of funding
Make its needs known to funding agencies
Have individuals participate more in funding decisions
Fund more fundamental research
A Pharmaceutical Research Fund (akin to the Petroleum Research
Fund)?
Put more effort into dealing with the Human Factors

Change the way it works
Stop doing process chemistry like medicinal chemistry

Technology Vendors and Innovators need to:
Solicit greater Industry involvement and participation
in instrument design
Develop more robust instruments
Develop simpler user interfaces
Work more closely with Academia, to make new
instruments available, so that students will have
greater familiarity with New Technologies

Academia needs to:
Provide to students more and better training in
The practical aspects of Physical Organic Chemistry
Including practical kinetics and computer aided curve fitting
The use of Statistical Optimization

Especially using the new simplified software
General Chemical Process R&D
Work more closely with Industry
General References
General Changes in Chemical Research over the last 60 years
Istvan Hargittai Candid Science: Conversations with Famous
Chemists Imperial College Press, London, 2003
Istvan Hargittai Candid Science III: More Conversations with Famous
Chemists Imperial College Press, London, 2000
Also see the series Profiles, Pathways, and Dreams: Autobiographies of
Eminent Chemists, Jeffrey I. Seeman, Series Editor, American
Chemical Society, Washington DC
Two volumes that were particularly useful are:
Derek H. R. Barton, Some Recollections of Gap Jumping, Profiles,
Pathways, and Dreams: Autobiographies of Eminent Chemists, Jeffrey
I. Seeman, Series Editor, American Chemical Society, Washington DC,
1991
Andrew Streitwieser, A Lifetime of Synergy with Theory and
Experiment, Profiles, Pathways, and Dreams: Autobiographies of
Eminent Chemists, Jeffrey I. Seeman, Series Editor, American Chemical
Society, Washington DC, 1996
General References
Human Factors and Barriers to Technology Adoption
G. A. Moore, Crossing the Chasm: Marketing and Selling High-Tech
Products to Mainstream Customers, 1999 (rev. ed.)
V. Martin, Automation and New Technologies in Chemical R&D:
Challenges to Industry, Academia, and Technical Innovators, Scientific
Update 6th International Symposium on Laboratory Automation & New
Technologies in Chemical Process R&D, London, UK, 2003
http://www.scientificupdate.co.uk/confs/index.htm (past events)
V. Martin, New Technologies in Chemical Process R&D: An Historical

Overview and a Look to the Future, Mettler-Toledo AutoChem Users
Forum, 12th 15th September 2004; Cambridge MD, USA
V. Martin Theory and Philosophy of Process R&D: The Intersection of
Philosophy, Scientists, and New Technology, Scientific Update 7th
International Symposium on Laboratory Automation and New
Technologies in Chemical Process R&D, Boston, MD, September 2324, 2004
General References
For the the general status of New Technologies (and
the New Paradigm) in the Pharmaceutical Industry
See the conference proceedings for the last several years of the
Scientific Update International Symposia on Laboratory Automation and
New Technologies in Chemical Process R&D
Chester, UK, 2001
Boston, MD, 2002
London, UK, 2003
Boston, MD, 2004
Acknowledgements
Discussion partners, and some of the individuals off whom I
have bounced individual ideas over the last several years
Kim Albizati Pfizer Chemical R&D; La Jolla, USA

Joel Hawkins Pfizer Chemical R&D; Groton, USA
Paul Higginson Pfizer Chemical R&D; Sandwich, UK
Robert Wade Pfizer Chemical R&D; Kalamazoo, USA
Donna Blackmond Imperial College; London, UK
David Collum Cornell University; Ithaca, USA
Trevor Laird Scientific Update; Mayfield, East Sussex, UK
Jay Siegel University of Zurich; Zurich, Switzerland
Questions and Discussion?

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Siegfried Symposium: New Methods in Process Chemistry

Everything Old is New Again

Purpose of this Presentation

Pfizer Global Research & Development-La Jolla: CRD Technologies

What is Chemical Process R&D?

Impurity / Isomer Preparation

Pfizer Global Research & Development-La Jolla: CRD Technologies

What is Chemical Process R&D?

Immediate Material Preparation

What is Chemical Process R&D?

Pfizer Global Research & Development-La Jolla: CRD Technologies

What is it We do to Obtain Information?

This describes all aspects of scientific research in CP R&D

Pfizer Global Research & Development-La Jolla: CRD Technologies

What is the Current Paradigm, for the Average

Automated sampling of reactions is rare

Techniques for running reactions are not optimal

Exploration of Chemical Space is unsophisticated

Pfizer Global Research & Development-La Jolla: CRD Technologies

Standard Paradigm for Performing CP R&D

Just About Everything Else We Do on a Regular

Pfizer Global Research & Development-La Jolla: CRD Technologies

Where Have the Major Changes Occurred in the

14 October 2004; Van Martin

the majority of the

New Technologies / Improvements in Data

UV-Vis Spectroscopy in regular use: 1940s

Mass Spectrometry in regular use late 1940s

IR Spectroscopy in regular use: 1950s

GC in regular use: early 1960s

TLC (as we know it) in regular use: 1960s

NMR in regular use: 1960s

Pfizer Global Research & Development-La Jolla: CRD Technologies

New Technologies / Improvements in Data

FT IR in regular use: 1980s

FT NMR / Super Conducting Magnets in regular use: 1980s

HPLC in regular use: 1980s

Routine use of Hyphenated Methods: 1990s 2000s

Pfizer Global Research & Development-La Jolla: CRD Technologies

New Technologies / Improvements

Heating Mantles in regular use: 1940s

Ground Glass Joints in regular use: late 1940s

Magnetic Stirring in regular use: 1950s

Rotary Evaporators in regular use: 1960s

Electronic Balances in regular use: 1970s

Pfizer Global Research & Development-La Jolla: CRD Technologies

Summary of Development of New Technologies for

Thinking and Planning (about Exploration of

Pfizer Global Research & Development-La Jolla: CRD Technologies

Why do We Need a New Paradigm for Performing

Pfizer Global Research & Development-La Jolla: CRD Technologies

But the Old Way Works Just Fine!

We still need to be faster and more efficient

We are not doing CP R&D only for fun

Pfizer Global Research & Development-La Jolla: CRD Technologies

What is the Focus on in Developing a New

14 October 2004; Van Martin

Pfizer Global Research & Development-La Jolla: CRD Technologies

What is New Technology?

A scientific method of achieving a practical purpose *

New Technology (a situational definition)

Pfizer Global Research & Development-La Jolla: CRD Technologies

Examples of New Technologies

Parallel Reactor Systems