1. The Engineering Grand Challenges and Green Engineering
MEDICINE (Pharmaceuticals)
The Engineering Grand Challenges and Green Engineering

2. Outline Why are medicines important? How do we make pharmaceuticals?
One of the most wasteful industries
In order to make them better we must make them greener
How do we make them greener?
Green solvents
Examples of use of green solvents in pharmaceuticals
Case study for ibuprofen

3. NAE. Grand Challenges for Engineering 2008
The NAE website focuses on genetic science and personalized medicines as well as drug resistant infections
Creating these medicines is a resource intensive industry
NAE. Grand Challenges for Engineering 2008

4. Pharmaceuticals industry
“As well as driving medical progress by researching, developing and bringing new medicines that improve health and quality of life for patients around the world, the research–based pharmaceutical industry is a key asset of the European economy. It is one of Europe’s top performing high–technology sectors.” (Value in million euros)
Note this figure is from the EU so the production in 2015 figure represents 225 million
Globally the global spending on pharmaceuticals is about 1.5 trillion dollars
This industry is very important and has had huge life saving impacts. For example, the number of deaths in HIV/AIDS patients has significantly fallen over the last decade
European Federation of Pharmaceuticals Industries and Associations. The Pharmaceutical Industry in Figures: Key Data 2016
EFPIA.The Pharmaceutical Industry in Figures: Key Data 2016

5. Creating pharmaceuticals is inefficient
Depends on what is termed as “waste”
Can be split into sub-categories;
Organic waste
Aqueous waste
The smaller the number, the closer to zero waste
However production of these pharmaceuticals is a very material intensive process.
The E-factor is a rough measure of the amount of waste produced in order to make 1 kg of product. In the pharma industry, E-factors are the highest compared to other chemicals production (largely in part to low volume and high cost). As such the environmental impacts associated with a process are commensurate with the waste that is produced.
Sheldon, Roger A. "The E factor: fifteen years on." Green Chemistry 9.12 (2007):
Sheldon, R. Green Chem. 2007

6. Green Engineering Research in Pharma
Key green engineering research areas
Research by GlaxoSmithKline (British Pharmaceutical Company) has looked into what are promising approaches for “greening” the pharmaceuticals industry.
Point out key industries.
By adopting some of these industries, we can significantly reduce waste, cost, and efficiency of production (example of continuous production on next slide)
Jiménez-González, Concepción, et al. "Key green engineering research areas for sustainable manufacturing: A perspective from pharmaceutical and fine chemicals manufacturers." Organic Process Research & Development 15.4 (2011): (Results of brainstorming and prioritization exercises)
Jimenez-Gonzalez, C. OPRD 2011

7. Continuous processing in process intensification
Reduce costs
Reduce the size of process equipment,
Improve product quality
Reduce energy consumption, solvent utilization
Decrease waste generation
Increase process safety
For example, continuous processing ie flow manufacturing has all of these advantages associated with process intensificiation
“Process Intensification (PI) targets dramatic improvements in manufacturing and processing by 18 rethinking existing operation schemes into ones that are both more precise and efficient than 19 existing operations. PI frequently involves combining separate unit operations such as reaction and 20 separation into a single piece of equipment resulting in a more efficient, cleaner, and economical 21 manufacturing process. “ --
Jimenez-Gonzalez, C. OPRD 2011

8. Green Engineering Principles
Principle 5: “Output-pulled” rather than “input-pushed”
Principle 1: Inherent rather than circumstantial
Principle 3: Design for separation
Principle 9: Minimize material diversity
In the following slides we will cover the remaining principles of green engineering and provide examples pertaining to the pharmaceuticals industry

9. Principle 5: “Output-pulled” vs. “input-pushed”
“Drive” a reaction or transformation to completion by adding materials or energy.
A + B  C + D
Similarly, a reaction can be “pulled” to completion by removing the product without adding materials or energy.
P5 can be thought of as utilizing le chatelier’s principle to try to drive more efficient processes. For example, in chemistry in order to make more product you could either add more starting material or you could try to remove the product to still drive the reaction progress forward.
A + B  C + D

10. Principle 5 example: Reactive distillation
A great example of this is using reactive distillation where the reaction and separation steps are combined such that while the products are being formed, they are being pulled out of the reaction section. This could improve the efficiency of the reaction but also can decrease the number of separations steps.
Taylor, Ross, and Rajamani Krishna. "Modelling reactive distillation." Chemical Engineering Science 55.22 (2000):
Taylor, R. ChemEngSci 2000

11. Unit operations in pharma synthesis
Separations
Reactions are the most frequent single unit operation
Separations processes together represent most of the processing required.
Jimenez-Gonzalez, C. OPRD 2011

12. Reactions and Separations
Materials Use: Separations contribute 40-90% of the process mass intensity of a synthesis.
Energy Use: Distillation and drying steps alone often consume >50% process energy
Time and cost: These steps are typically also process bottlenecks leading to predominant contributions to time and cost
As such focusing green engineering on these two processes can make significant impact.
One particular aspect that has a key impact on both of these is solvent use.
Jimenez-Gonzalez, C. OPRD 2011

13. Solvents Usage: Examples: isopropanol, hexane, chloroform
Dissolution
Suspension
Extraction/purification
Reaction medium
Formulation/ product delivery
Examples: isopropanol, hexane, chloroform
Strategies for solvent reduction
REDUCE, REUSE, RECYCLE
Solvents are necessary for many reaction and separation processes in pharma chemistry. They exist in many forms and have significant impact associated with them. In fact, it has been estimated that about 80% of the waste associated with pharma production is contributed by solvents.
In order to green these processes, we can try to improve solvents and their utilization.
Jimenez-Gonzalez, C. OPRD 2011

14. Principle 1: Inherent rather than circumstantial
Some traditional solvents
Diethyl ether, an explosive and extremely flammable solvent, was used for anesthesia—until doctors tired of explosions at the operating table and the resulting fatalities.
Dichloromethane, a potent environmental polluter, is another solvent of concern, especially due to its high volatility. It is often used in paint thinners, but despite its relatively low toxicity, it has caused over 50 deaths since 1980 in the US alone

15. Needs for green solvents
Metrics of a green solvent:
Toxicity, safety, hazard
Energy use, environmental metrics, life cycle metrics
Method and ease of recycling
Ease of separation
Depends on properties (ex: volatility, viscosity, stability)
Tactics: Find better existing alternatives
Neoteric alternatives
Finding a green solvent must be as benign as possible. But sometimes benign is hard to determine and quantify. We need to consider a number of different metrics in order to do this.
Jimenez-Gonzalez, C. OPRD 2011

16. Identifying green solvents
Several pharma companies have looked into green solvents for their processes and have tried to identify them based on a number of different metrics from process safety, human health, and environmental categories. These metrics are not uniform but do highlight the different exposure routes.
Soh, Lindsay, and Matthew J. Eckelman. "Green solvents in biomass processing." ACS Sustainable Chemistry & Engineering 4.11 (2016):
Soh, L. ACS Sust Chem Eng 2016

17. Life cycle inherent hazard
One must also consider life cycle impacts associated with each solvent. This includes the production and sourcing of the solvent and indicates that some seemingly green solvents may have great impacts.
Soh, L. ACS Sust Chem Eng 2016

18. Energy use for solvent production
Other life cycle metrics to consider are energy use for solvent production
Jessop, Philip G. "Searching for green solvents." Green Chemistry 13.6 (2011):
Jessop, P. Green Chem 2011

19. Solvent CO2 emissions Jessop, P. Green Chem 2011
As well as CO2 emissions – where do we draw the line?
Jessop, P. Green Chem 2011

20. Example: Pfizer green solvent guide
Alfonsi, Kim, et al. "Green chemistry tools to influence a medicinal chemistry and research chemistry based organisation." Green Chemistry 10.1 (2008):
Alfonsi, K. Green Chem 2008

21. Alternatives must be functional
Soh, Lindsay, and Matthew J. Eckelman. "Green solvents in biomass processing." ACS Sustainable Chemistry & Engineering 4.11 (2016):
Soh, L. ACS Sust Chem Eng 2016

22. GlaxoSmithKline
Solvent classification affects both utility and sustainability
Alder, Catherine M., et al. "Updating and further expanding GSK's solvent sustainability guide." Green Chemistry (2016).
Alder, C. Green Chem. 2016

23. Principle 3: Design for separation
Can solvents be designed to minimize impacts associated with separation?
Can systems be designed to allow for separation without solvents?
Capello, Christian, Ulrich Fischer, and Konrad Hungerbühler. "What is a green solvent? A comprehensive framework for the environmental assessment of solvents." Green Chemistry 9.9 (2007):
Capello, C. Green Chem 2007

24. Designing for separations
Switchable solvents are an innovative potential solution for separations without distillaition
Jessop, P. Green Chem 2011

25. Principle 9: Minimize material diversity
Allows for easier recycling and reuse
Simplifies processing

26. Supercritical fluid assisted drug delivery
Reverchon, Ernesto, et al. "Supercritical fluids processing of polymers for pharmaceutical and medical applications." The Journal of Supercritical Fluids 47.3 (2009):
No residuals
Single solvent use
Reverchon, E. J . Supercritical Fluids. 2009

27. Solvent free reactions? - Mechanochemistry
Mechanochemistry uses physical force for chemical reaction
Example of motion in a ball mill: Garay ChemSocRev
May, Preston A., and Jeffrey S. Moore. "Polymer mechanochemistry: techniques to generate molecular force via elongational flows." Chemical Society Reviews 42.18 (2013):
Garay, Ana Lazuen, Anne Pichon, and Stuart L. James. "Solvent-free synthesis of metal complexes." Chemical Society Reviews 36.6 (2007):
Šepelák, Vladimir, et al. "Mechanochemical reactions and syntheses of oxides." Chemical Society Reviews 42.18 (2013):
Example of mechanochem for polymer elongation: May 2013 ChemSocRev
Sample ball mills: Šepelák ChemSocRev

28. Case study: Sildenafil citrate
Reductions in dichloromethane and acetone. Uses greener solvents, ethyl acetate, 2-butanone, t-butanol, and cuts down on amount.
Dunn, Peter J., Stephen Galvin, and Kevin Hettenbach. "The development of an environmentally benign synthesis of sildenafil citrate (Viagra™) and its assessment by Green Chemistry metrics." Green Chemistry 6.1 (2004):
Dunn, P. Green Chem. 2004

29. Dunn, P. Green Chem. 2004

30. Reduce waste from new production process
Dunn, P. Green Chem. 2004

31. Summary
The pharmaceuticals industry currently produces much waste leading to inflated economic and environmental impacts
Green engineering principles may be applied to decrease cost and impacts
Green solvents are a growing field that can be investigated for more efficient pharmaceuticals production

32. IDEO – The Deep Dive (moodle)
Watch the posted video on Moodle and discuss with your group members:
How does the process differ from your typical thoughts on design?
How can you utilize the tactics employed for your process?
Include these thoughts in your first project update on design alternatives (due March 22)