research - industrial green chemistry · 2018-03-26 · green chemistry by design (gcbd) in...
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Narendra B. Ambhaikar, Ph.D.
Seeking Green Chemistry via Process
Research
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Outline
• Introduction – Green Chemistry by Design (GCbD), Process Research,and Innovation
• API Life Cycle – A Green Chemistry Prospective
• Alignment and Relationships between Process Research, GC Principles and Cost Savings
• Current Challenges in Designing the Greener Synthetic Routes (GCbD)
• Strategies to Achieve GCbD through Effective Process Research
• Future Challenges and Opportunities
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Process Research
Definition:
Investigative activities that a business chooses to conduct with the intentionof making a discovery that can either lead to the development of newproducts (new synthetic route) or procedures or improvement of existingproduct (synthetic route) or procedures
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Green Chemistry by Design (GCbD) inPharmaceutical or Related Chemical R & D
Any synthetic route that incorporates maximum number of Green Chemistryprinciples (GCbD)
GCbD can be achieved by conducting effective Process Research at Route Scouting stage using 12 GC Principles
Obviously, all the natural biological processes are perfect examples of GCbD
There are couple of citations in the literature for Green Chemistry by Design(1) Used for Green Products(2) Used for synthetic processes that uses enzymes (Roger A. Sheldon, Fundamental of Green Chemistry:
efficiency in reaction design)
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Contribution of Synthetic Chemistry in Pharmaceutical Research and Development
09 January 2014 5
Discovery
Synthesis
Process
Research/
Route Scouting
New
Route
(Cost, EI, Speed)
Final Process
Production
Process
Development
and Pilot
Plant
Medicinal
Chemistry
Process Research and Development/Pilot PlantDiscovery Production
Process Research: Design a scalable, atom-efficient, cost-effective, technically robust, and environmentally considerate route for APIGCbD
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09 January 2014 6
Process Research / Process Chemistry and Green Chemistry
Process Research in Chemical Industries can also be defined as Innovation in Process Chemistry
Innovation = Invention + Impact (time, economics, and environment)
Therefore, in order to innovate, Process Research must use Green Chemistry
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API Life Cycle – A Chemistry Prospective
Innovator
Generic
10-15 Years
>20 Years
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Alignment of API Economicswith Greener Route (GCbD)
1. Overall yield, Convergence and number of Steps
2. Chemo, Regio and Stereo Selective routes
3. Throughput (function of plant related operation and process constraints)Process Constraints:a. Chemical Yieldb. Cycle time c. Number of Chemical Steps and Convergenced. Use of higher molecular weight protecting group and reagentse. Number of energy consuming operations
Indirect Cost: Cost related to overcoming poor quality, safety and removal or recycling costs for waste
Characteristics of Cost Effective Route go hand in hand with GCbD
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Process Research versus Green Chemistry
Parameters Process chemistry consideration
Environmental consideration
Use a minimal number of synthetic steps
Efficiency (most important) Less energy and waste
Easy isolation, no SiO2 Scalability, throughput Less waste (solvents)
Avoid cryogenic conditions
Scalability, robust, lower cost Less energy
High selectivity (chemo, stereo and regio)
Efficiency/easy purification Less waste
Avoid hazardous reagents and reactions
Safety, scalability Safety, less pollution
Inexpensive, available raw materials
Cost, lead time Know-how for waste management
Minimize oxidation state adjustments
Efficiency Less waste, potential pollution (metals)
Minimize the use of protecting groups
Efficiency, atom economy Less waste
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Why Process Research is Important?
Effective Process Research helps Cost, Quality, Safety and Environmental Impact achieve GCbD, which builds the foundation for API
Process Development coupled with engineering excellence further improves the API Cost, Quality, Safety and Environmental Impact
In general, it is not a good practice to develop a non-green route (the route not designed by Process Research) to production because the organization has to spend enormous amount resources to deal with the cost, Quality, safety and environmental issues
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Why Process Research is Important?
Many Critical parameters can only be controlled at Process Research stage of development
All of them have Cost, Quality, and the Green elements
• Convergent synthetic route and number of steps
• Use of any protection/deprotection, resolution and non recyclablechiral auxiliaries
• Use of potentially toxic intermediates (in particular geno toxic intermediates) orthe reagents that can generate toxic impurities
• Selection of KSMs and designing a new economical route if necessary
• Chemo, Regio and Stereo selectivities of organic reactions
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Process Research, Green Chemistry and API Cost
Almost all of the Green Chemistry principles can be implemented at the process researchStage of development of an API or related molecules
Therefore, Green Chemistry by Design (GCbD) is very critical for a selected synthetic route
Process Research/Route scouting stage contributes maximum to cost, quality and EI for the API
In order to design the greener route, process research in the pharmaceutical industry needs to be scientifically driven with the intent of commercialization
Ideally, during process research stage process research chemists should think like academic scientists and should completely understand the environmental and scale up issues and therefore they can maximize their ability to design “Greener” synthetic routes
Process research scientists also need to ensure all the basic raw materials are obtained fromrenewable feed stock and not from petroleum based products (this will be a challenge due tocost effective technologies are not completely in place)
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Current Challenges in API Route Selection Process(both at Innovator and Generic)
timely demonstration of PoC of a selected route
route must be cost effective to meet the organizational budget requirements (during development stage) and to meet market needs (during commercialization)
route should minimize environmental impact
route should be amenable to scale-up as needed
route and intermediates must possess freedom to operation (free of any IP issues)
processes must have a good control for GTI and other impurities
need to operate utilizing minimum resources
right-first-time approach for route selection
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Route Scouting / Process Research Work Flow
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Functional Excellence in GCbD in Process R & D
New R&D Practices
Academic Collaboration
Human Capital(Internal or External)
Technology(Internal or External)
GCbD
Instrument
HumanCapital
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Present and Future R & D Directions toward the Greener Route Selection
Route selection process can begin early enough to achieve higher levelof GCbD (need to be applied case by case to mitigate potential businessrisk)
Flexible capability building with both in house team and with partners
Potential Partners can be either CROs are productive academicinstitutions (for accessing special human capitol and certain highthroughput instruments for screening studies)
Take advantage of vast scientific literature data which was not availableto innovators
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Technology
•Chemocatalysisi. Organometallicsii. Organocatalysis•Biocatalysisi. Recombinant enzyme based
• Discovering new greeneralternatives to non-greentransformations
• Molecular Modeling• Reaction Kinetics
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18 09.01.2014
Develop catalysts libraries to screen a wide range of catalytic reactions and secure IP position
Screen, and identify novel reactions for practical synthetic routes
Research and identify new automation equipment expertise / tools to promote efficiency
DOE Reaction
Analysis DataMining
High throughput Screening and Automation
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High throughput Screening and Automation
• Conducting 100s of reactions in parallel for a given transformation (feasibility stage)
• Automation of weighing, quenching and analysis
Advantages:• In a short period of time (1 week) identification of economical, IP free and green reagent is possible for a given transformation
• Human error can be eliminated and additional analysis time can be reduced with automation.
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Innovative R&D Practices
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External Partnership in Process “Research” & “Development”
Process Research(GCbD)
Process Development
Involves academic mindset with a focus on IP, safety, economy, environment,
quality and delivery
(Emerging)
Involves execution viaoptimization of disclosed
procedure focused on manufacturing and delivery
(Matured)
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Some Examples of GCbD
Keck, G. E.; Krishnamurthy, D. Org. Synth, 1997, 75, 12.
Wilstӓtter
Lewis Acid
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Some Examples of GCbD
Baran, P. S.; Ambhaikar, N. B. et. al. J. Am. Chem. Soc. 2006, 128, 8678.
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Some Examples of GCbD
Process research to remove ozonolysis
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Some Examples of GCbD
Ambhaikar, et. al. US Patent No: 8,461,352
• Low yielding process with long reaction times
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Some Examples of GCbD
Keck, G. E., Li, X-Y., Krishnamurthy D. J. Org. Chem., 1995, 60, 5998
BASF Process, 1914Lefort, 1931
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Responsibilities of Process ResearchScientists
Designing the route that fulfills following criteria
Safety – Process Safety and Substance Safety
Environmental - Minimize the use of natural resources and harmful substances
Legal – Free of IP issues and Regulations that control use of reagents and intermediates
Control – Control of quality parameters
Throughput – Cycle time
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Key Skill Sets for Process Research Scientists for executing GCbD Highly Innovative
Should have drive to gain a detailed scientific understanding of chemistry
Should have ambition to discover and develop the shortest and most efficient synthesis (GCbD)
Should pay attention to detail during experimentation and good experimentation skills
Highly motivated towards interacting with academics, reading day to day literature and discussions with colleagues and piers
Should have an academic mind set with business understanding
Should able to understand the environmental issues and therefore chemists maximize his ability to design the greener synthetic process
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Fundamentals of Route Scouting/Process Research Organization
Consists of Process Research Scientists with desired skill sets
Highly motivated environment with encouragement for openness to discuss their ideas among colleagues and peers
Encouragement from management for risk taking from scientists and reduce the fear failure as long as project time lines are met.
Certain level of high throughput/automation support with analytical scientists for short method development
Encouragement of scientists to continues interacting with academics, participation in the conferences and publishing in the peer reviewed journals as long as the IP is protected.
In a scientifically matured organization the process research group may merge with process development group
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Green Chemistry, Process Research and Profitability
PR $$$$
GC
PR $$$
GC
PR
GC
$$$
$
$
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Way Forward
• Involvement of scientists• Knowledge sharing
• Learning• Publication
• Conferences• Collaborations
Ideation &
Learning
Ideation, Learning & Application
Ideation, Learning, Application & Institutionalization
IncreasedSustainability
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Present and Future Challenges
•Awareness•Education•Incentivization•Branding•Setting up a market regulation•Increased R&D Investment
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For Further Reading
1. Sheldon, R. A. Chem. Soc. Rev. 2011, ASAP.
2. Butters, M. et al. Chem. Rev. 2006, 106, 3002-3027.
3. Song, J, Frutos, R, Tampone, T, Dhileep Krishnamurthy,Senanayake, C. H. Comprehensive Chirality, 2011.
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THANK YOU!