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Well Mixed Reactor #2

Well Mixed Reactor #2. Insulin ester hydrolysis. Outline. Purpose of the operation Background Byproducts Rates of reaction Design Costs Suppliers. Presenters . Meghan Marshall Craig Hanna Dustin Ryan Hebba Antar. Purpose of our unit .

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Well Mixed Reactor #2

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  1. Well Mixed Reactor #2 Insulin ester hydrolysis

  2. Outline • Purpose of the operation • Background • Byproducts • Rates of reaction • Design • Costs • Suppliers

  3. Presenters • Meghan Marshall • Craig Hanna • Dustin Ryan • Hebba Antar

  4. Purpose of our unit • Removal of threonine from the insulin ester at position 30 to produce insulin Threonine

  5. Insulin ester hydrolysis Threonine 30 Reaction: Threonine is cleaved off by ester hydrolysis Threonin(30)-OR + water Threonin(30)-OH +Insulin acid

  6. Acid hydrolysis (desired reaction) • Alone, water is a weak nucleophile • Protonation turns threonine into a strong electrophile (strong acid required eg. HCl or H2SO4) • Threonine becomes a good leaving group

  7. Byproducts • Upstream: • NaOH • Undesired side reactions • Deamination –amide hydrolysis • Peptide hydrolysis • Disulphide bridge interchange • Cyclic by-products

  8. Deamination –amide hydrolysis • conformational changes in proteins due to pH change (hydrophobic/hydrophillic interactions) • Rate of reaction is reduced at ambient temperatures (need between 80oC-100oC) and less acidic conditions • Works in parallel with threonine hydrolysis

  9. Peptide hydrolysis • Scission of amino acids at extreme conditions • Reaction rate is reduced at ambient temperatures and less acidic conditions • Works in parallel with threonine hydrolysis

  10. Disulphide bridge interchange • Swap in the bridge attachment sites • Bonds have to be close together • Reduced at ambient temperatures

  11. Conditions of which reactions are most prevalent

  12. Optimizing rate of threonin hydrolysis while minimizing undesired reactions Consider: • Temperature (ambient) • pH (low) • Parallel reactions • In acidic conditions, rate of threonine hydrolysis is the fastest • Sequence and structure of the amino acids • Shielding effects • Accessibility of the ester group for cleaving • Intermolecular interactions between all components in the mixture

  13. Finding a balance… • Kinetics: Low pH desired reaction is prevalent and faster than undesired hydrolysis reactions while peptide bridge exchange is reduced • Temperature: At ambient temperatures desired reaction is a bit slower but reduces undesired hydrolysis reactions and peptide bridge exchange

  14. Reactor Choices • Batch • CSTR

  15. Batch • Advantages • Can monitor temperature and pH • Can stop operation more easily than CSTR • Disadvantages • Starts with a fairly concentrated solution (extent of reaction will not be as great) • Low productivity (down time) • Have to add a holding tank so that it is not disruptive to the downstream process (higher capital costs)

  16. CSTR • Advantages • Instantaneous mixing (good for diluting, increases extent of reaction • More efficient than batch (productivity, no turnover) • More reliable ) and constant product quality • Better control of temperature and pH (vital for desired product yield) • Disadvantage • Cannot stop system as easily if something goes wrong

  17. Design • Dilute reactor conditions • Temperature 25oC • pH 6 • First order reaction • k’=7.6x10-8 s-1(taken from hydrolysis at pH of 6.5 ofan ester polymer containing amino acid and peptide residues in the side groups)

  18. CSTR Design Equation • Calculated volume = 2080L • Design volume = 2810L • H/D = 1.5 • FAobased on annual production target • Agitator • Heating/Cooling Jacket

  19. Suppliers • Walker Equipment –custom designed or standard tanks for Pharmaceutical & Chemical Industries • Perry Videx –sell used reactors for Pharmaceutical and chemical companies • Pfaudler Inc. – Glass lined equipment: Reactors, Heat exchangers etc.

  20. Capital Costs • ChemEcon = $42600 • 5 bar • SS • Matches = $28800 • <25psi • Glass lined CS

  21. Operating Cost • Estimated Power – 6.5 kW • Annual Cost – $3,000 at 6 cents per kWh • Maintenance – $4,000 (10% of Capital Investment)

  22. References • Fogler, S. Elements of Chemical Reaction Engineering. Prentice Hall, New Jersey, 1999. • Claydon, et al. Organic Chemistry. Oxford University Press, New York, 2001. • Matches – Conceptual Cost Engineering, http://www.matche.com/EquipCost/Reactor.htm • ChemEcon, Queen’s University CHEE 470, Dave Mody

  23. Questions? • We would be happy to answer them!

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