Chemical

1
Chemical Pharmaceutical Engineering (Begun on
July 1, 2006) PSRC Review of Flagship Program
June 20, 2007
Raj Rajagopalan (Singapore) Bernhardt L. Trout
(MIT) Program Co-Chairs
2
Overview of the Flagship ProgramThree thrusts
focusing on the Pharmaceutical Industry

• Thrust A Metabolic Engineering Molecular
  Biotechnology for Engineering Targeted Biological
  Pathways
• Thrust B Chemical Catalysis Engineering
  Catalysts at the Molecular and Nanometer Scales
• Thrust C Downstream Processing Molecular
  Engineering for Separation Technology,
  Purification, and Formulation

3
Overview of the Flagship ProgramPrincipal
Professors in Each Thrust

• Thrust A Metabolic Engineering
• Saif Khan (NUS) Li Zhi (NUS)
  Greg Stephanopoulos, Too Heng-Phon (NUS)
  Danny Wang (MIT)
• Thrust B Chemical Catalysis
• Steve Buchwald (MIT), Saif Khan (NUS), Loh Teck
  Peng (NTU) Mark Saeys (NUS)
• Thrust C Downstream Processing
• T Alan Hatton (MIT), Raj Rajagopalan (NUS),
  Michael Tam (NTU), Bernhardt Trout (MIT), Miranda
  Yap (BTI, NUS)

4
Manpower

• 5 Direct PhD students entering in 2006
• 6 Direct PhD students to enter in 2007 (Another
  is pending)
• 1 Joint Post-Doc (started Feb., 2007)
• 1 Post-Doc at NUS (started in March 2007)
• 7 MIT PhD students started in 2006-2007
• 6 MIT post-docs started in 2006-2007

5
Key Accomplishments

• Thrust A Metabolic Engineering
• Initiated enzymatic synthesis on chiral chemical
  intermediate and co-factor regeneration using
  magnetic nanoclusters.  Preliminary results show
  excellent promise on this new and novel
  biocatalysis and co-factor regeneration systems
• Demonstrated taxadiene biosynthesis in
  Escherichia coli at significant amounts.
  Taxadiene is the first, most difficult step in
  the synthesis of taxol from precursors of the
  isoprenoid pathway. (Planning to submit a patent
  application)
• Thrust B Chemical Catalysis
• Developed the state of the art catalyst system
  for the carbonylation of aryl sulfonates,
  including the first system for the carbonylation
  of aryl mesylates. These (aryl tosylates) are
  less reactive than aryl halides and are
  industrially very desirable precursors to
  aromatic amides and esters.
• Set up a working microfluidics facility at NUS
  Currently fabricating microreactors for chemical
  synthesis.
• Thrust C Downstream Processing
• Demonstrated control of protein mobility
  selectively using light responsive gels, that
  certain liquid crystal mixtures can show chiral
  selectivity in solubilization of derivatized
  amino  acids, and that magnetic nanoparticles can
  be fucntionalized with chiral selectors.
• Developed initial molecular understanding of
  synthon growth of target crystals.
• Developed a molecular thermodynamic model to
  follow aggregation in the presence of excipients.

6
Industrial Interactions and Anticipated
Sponsorships

• Pfizer verbal commitment, finalizing contract
• MerLion verbal commitment, finalizing scope of
  work
• A-Bio project to be defined in 2007
• Other companies with prospective interest are
  Novartis, Merck, Schering-Plough, and SBio

7
Other Efforts in Progress

• Industry Day Workshop for Singapores
  pharmaceutical industries is planned to
  highlight CPE Programs research and educational
  activities and their relation to Singapores
  needs (e.g., Glaxo)
• (This effort will also be used to develop
  closer interactions with local pharmaceutical
  and chemical companies and the CPE Team in order
  to continually refine the program needs and
  goals.)
• Industrial tours are planned for both DM and DP
  students to local industries. One to Glaxo was
  conducted earlier this year.
• Career Planning Workshops for the students (to
  emphasize the soft skills they need) are
  planned at NUS.
• Critical Thinking Boot Camp DP students will be
  asked to enroll in the Critical Thinking Boot
  Camp, to be run by ChBE _at_ NUS, to learn how to
  read technical papers, how to develop research
  projects and proposals, etc.
• Presentation Skills Workshop Students will
  enroll in Professional Presentation Skills
  Workshop run by Prof. Bill Krantz at ChBE _at_ NUS.

8
Personnel Changes

• Prof. Michael Tam (Thrust C) has resigned from
  NTU (effective July 1, 2007) to accept a faculty
  position in Canada.
• Prof. Neal Chung (Thrust C), who has strong
  expertise and industrial collaborations in the
  area of membrane separations for pharmaceuticals,
  will join the team in July 2007.

9
Goals for Next Year

• Thrust A Metabolic Engineering
• Enzymatic synthesis of chiral intermediate will
  be investigated along with the regeneration of
  co-factor analogs.  Once these are achieved,
  patent disclosure will be filed.
• Optimization of the above pathway for maximum
  taxadiene production and initiate the
  construction of the additional 10 steps to
  complete the full taxol pathway. Also, initiation
  of the engineering of the amporphadiene pathway
  for artemisinin synthesis (antimalaria drug).
• Thrust B Chemical Catalysis
• Development of a full understanding of the
  controlling features in our new carbonylation
  system as well as extension to the preparation of
  other important functional groups such as
  carboxylic acids. Also, initiation of work on the
  carbonylation of aliphatic substrates (much more
  challenging than for aromatic substrates).
• Thrust C Downstream Processing
• Application of functionalized magnetic
  nanoparticles to continuous chiral separations
  and continued development of responsive gels for
  pharmaceutical separations and purification.
• Preliminary design and operation of
  ferrofluid-based microfluidic separation
  processes.
• Development of rational understanding of selected
  crystallization processes and formulations.

10
Summary

• Research flourishing anticipated joint
  publications in 2007-2008, potentially patent
  disclosures.
• Strong interest for industrial sponsorship.
• Needs more Direct PhD slots for industrially
  funded projects.