Narendra B. Ambhaikar, Ph.D.

Seeking Green Chemistry via Process

Research

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

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

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)

Contribution of Synthetic Chemistry in Pharmaceutical Research and Development

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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

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

API Life Cycle – A Chemistry Prospective

Innovator

Generic

10-15 Years

>20 Years

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

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

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

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

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)

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

Route Scouting / Process Research Work Flow

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

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

Technology

•Chemocatalysisi. Organometallicsii. Organocatalysis•Biocatalysisi. Recombinant enzyme based

• Discovering new greeneralternatives to non-greentransformations

• Molecular Modeling• Reaction Kinetics

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

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.

Innovative R&D Practices

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)

Some Examples of GCbD

Keck, G. E.; Krishnamurthy, D. Org. Synth, 1997, 75, 12.

Wilstӓtter

Lewis Acid

Some Examples of GCbD

Baran, P. S.; Ambhaikar, N. B. et. al. J. Am. Chem. Soc. 2006, 128, 8678.

Some Examples of GCbD

Process research to remove ozonolysis

Some Examples of GCbD

Ambhaikar, et. al. US Patent No: 8,461,352

• Low yielding process with long reaction times

Some Examples of GCbD

Keck, G. E., Li, X-Y., Krishnamurthy D. J. Org. Chem., 1995, 60, 5998

BASF Process, 1914Lefort, 1931

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

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

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

Green Chemistry, Process Research and Profitability

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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

Present and Future Challenges

•Awareness•Education•Incentivization•Branding•Setting up a market regulation•Increased R&D Investment

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.

THANK YOU!