Design of Continuous Reactor Systems for API Production

158 Pages·2017·2.15 MB·English

Downloaded from orbit.dtu.dk on: Jan 12, 2023

Design of Continuous Reactor Systems for API Production
Pedersen, Michael Jønch
Publication date:
2014
Document Version
Publisher's PDF, also known as Version of record
Link back to DTU Orbit
Citation (APA):
Pedersen, M. J. (2014). Design of Continuous Reactor Systems for API Production. Technical University of
Denmark, Department of Chemical and Biochemical Engineering.

General rights
Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright
owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.

 Users may download and print one copy of any publication from the public portal for the purpose of private study or research.
 You may not further distribute the material or use it for any profit-making activity or commercial gain
 You may freely distribute the URL identifying the publication in the public portal

If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately
and investigate your claim.
Design of Continuous Reactor
Systems for API Production
Michael Jønch Pedersen
Ph.D. Thesis
October 2014
Design of Continuous Reactor
Systems for API Production

October 2014
PhD Thesis

Michael Jønch Pedersen

Technical University of Denmark
Department of Chemical and Biochemical Engineering

1
Michael J. Pedersen
Chemical Technology & Implementation

2
Design of Continuous Reactor
Systems for API Production

October 2014
PhD Thesis

Michael Jønch Pedersen

Technical University of Denmark
Department of Chemical and Biochemical Engineering

University Supervisors Industrial Supervisors
Professor Kim Dam-Johansen Head of Department Tommy Skovby
Associate Professor Søren Kiil Head of Department Michael J. Mealy

3
Copyright©: Michael Jønch Pedersen
October 2014
Address: Centre of Combustion and Harmful Emission Control
Department of Chemical and
Biochemical Engineering
Technical University of Denmark
Søltofts Plads, Building 229
DK-2800 Kgs. Lyngby
Denmark
Phone: [phone]
Fax: [phone]
Web: www.chec.kt.dtu.dk
Print: J&R Frydenberg A/S
København
December 2014
ISBN: 978-87-93054-53-0
4
Preface
Preface
The industrial PhD project presented within this thesis has been a joint collaboration
between H. Lundbeck A/S Department of Chemical Technology & Implementation and
the Technical University of Denmark (DTU) at the department of Chemical and
Biochemical Engineering in the Combustion and Harmful Emission Control (CHEC)
research center. The project took place in the period from August 2011 to July 2014.
Most of the laboratory work was conducted at Lundbeck, except for a six (6) month
research period at the Massachusetts Institute of Technology (MIT) at the Department of
Chemical Engineering in the Klavs Jensen research group.
The thesis is divided into several chapters and a short outline for each chapter is
given below. The chapters containing original research with experimental sections have
all been written in the appropriate manuscript format for the journals to which they are to
be submitted for publication.
Chapter 1: A brief introduction to the pharmaceutical industry, including the
motivations for a shift towards flow chemistry and the chemical
engineering aspects of continuous production.
Chapter 2: A general discussion on the different aspects of Grignard
chemistry, with a focus on flow chemistry.
Chapter 3: This chapter provides a kinetic study of a Grignard addition
reaction investigated using flow chemistry. The studied chemistry
contains consecutive-competitive reactions.
Chapter 4: The first part of the main case study, in which a flow reactor setup
has been used to perform a base liberation of an alkyl halide salt
needed for Grignard reagent formation.
Chapter 5: The second part of the main case study, in which a continuous
reactor setup has been used for the formation of a Grignard reagent.
Chapter 6: The third part of the main study, in which a Grignard addition to a
ketone has been carried out in a continuous reactor setup.
Multi-step synthesis of an active pharmaceutical ingredient is
demonstrated.
Chapter 7: This chapter demonstrates the scale-up of a laboratory continuous
reactor setup used for a Grignard addition reaction that includes
handling of solid material.
Chapter 8: This chapter combines the Grignard chemistry demonstrated in the
previous experimental chapters. It provides a methodology for
reactor design and decision-making processes related to the
development of Grignard chemistry in flow.
i
5
6
Acknowledgements
Acknowledgements
During the last three years of this PhD project I have had the pleasure of meeting
many interesting people, through both work-related relationships and those of a more
social character.
My four supervisors deserve special thanks for their contributions to this project over
the last three years. A huge thank you to my industrial supervisor, Tommy Skovby, for
his unconditional belief in my work and his constant support. Many great discussions,
both technical and social, have been shared and hopefully many more are still to come.
My other industrial supervisor, Michael J. Mealy, likewise deserves thanks, especially for
his contributions to the chemical discussions during the project. My main supervisor, Kim
Dam-Johansen at DTU, has been a good motivator for the academic parts and has also
given me the freedom to do research with a more industrially-oriented perspective. Søren
Kiil, my other supervisor at DTU, has also been a driving force for the academic part of
the project, always pointing out missing parts that could improve the work and providing
me with useful feedback, for which I am thankful.
During the project, I had the opportunity to visit Boston for a six-month research visit
to MIT, supervised by Klavs Jensen. I am deeply grateful for the time I spent there and to
Klavs for giving me the chance to be a part of his group. Many good friendships have
been made with both people from the research group and Bostonians in general.
Hopefully I will see you all from time to time, in spite of the distance.
I am grateful that Lundbeck as a company has given me the opportunity to do a PhD
on the topic of flow chemistry and there are many colleagues I need to thank. Steen
Søgaard, for his interest in continuous production and his belief in me. The people in the
workshop, for always being open-minded towards my crazy ideas and for engineering
their technical solutions. The factory staff, for sharing their knowledge on production and
for providing me with chemicals to use in the laboratory. Thank you to my colleagues at
CTI and POL for their interest in my project and for always being ready to help, for
which I am deeply grateful. I look forward to more good teamwork.
I would like to thank my friends and family, especially the close friends I have made
during my time at DTU, where many of us are now coming to an end and finishing up our
studies, but I am sure that we will keep finding reasons to meet. To my friends outside of
DTU and to my family, thanks for being there whenever I needed you and for knowing
that I am doing “chemistry stuff”. And last but not least, Jen, thanks for putting a smile on
my face and for making me happy.
Cheers,
Michael
iii
7
8