Effect of collapse on pharmaceutical protein lyophilizates [Elektronische Ressource] / Kathrin Brigitte Schersch

Kathrin Brigitte Schersch

Informations

• Publié par: ludwig-maximilians-universitat_munchen
• Publié le: 01 janvier 2009
• Nombre de lectures: 15
• Langue: English
• Poids de l'ouvrage: 10 Mo

Extrait

Dissertation zur Erlangung des Doktorgrades der
Fakultät für Chemie und Pharmazie der
Ludwig-Maximilians-Universität München




Effect of Collapse
on Pharmaceutical Protein Lyophilizates









Kathrin Brigitte Schersch
aus Kiel


München 2009
Erklärung

Diese Dissertation wurde im Sinne von § 13 Abs. 3 bzw. 4 der Promotionsordnung
vom 29. Januar 1998 von Herrn Prof. Dr. G. Winter betreut.

Ehrenwörtliche Versicherung

Diese Dissertation wurde selbständig, ohne unerlaubte Hilfe erarbeitet.




München, den 18.09.2009







……………………………………
Kathrin Schersch





Dissertation eingereicht am: 22.09.2009

1. Gutachter: Prof. Dr. G. Winter
2. Gutachter: Prof. Dr. W. Frieß

Mündliche Prüfung am: 23.10.2009 ACKNOWLEDGMENTS
The present thesis was prepared at the Department of Pharmacy, Pharmaceutical
Technology and Biopharmaceutics at the Ludwig-Maximilians-University (LMU) in Munich,
Germany under the supervision of Prof. Dr. Gerhard Winter.

First of all, I would like to express my deepest gratitude to my supervisor Prof. Dr. Gerhard
Winter for giving me the possibility to join his team and to work in this fascinating field of
research, for his professional and dedicated guidance of my work and for all his scientific and
also personal advice over the last years. Also I would like to thank him for providing
outstanding working conditions and for the opportunity to present my work at numerous
international conferences and meetings. I am deeply thankful for making possible my
research stay in the lab of Prof. Pikal.

I would like to thank Prof. Dr. Wolfgang Frieß for his continuous enthusiasm and interest in
my work, the scientific input and advice over the last years and for kindly being co-referee of
this thesis.

I would like to thank Prof. Winter and Prof. Frieß for creating an outstanding working climate
that made the preparation of this thesis a precious and exciting time.

Boehringer-Ingelheim Pharma GmbH & Co.KG is gratefully acknowledged for scientific,
financial and material support. My very special thanks go to the whole group of A BP Process
Sciences in Biberach for their very warm welcome and for their great support during this
project. Especially, I would like to thank Ortrud Betz, for her never-fading understanding and
all the support and practical help over the last years. My very special thanks are also
expressed to Dr. Silke Mühlau, Dr. Patrick Garidel and Dr. Stefan Bassarab for all their
scientific and personal contributions to the success of this exciting project and their constant
interest in this work. Thanks are extended to all other groups at Boehringer-Ingelheim that
contributed to this project during the last years.

I am deeply grateful to Prof. Dr. Michael Pikal for giving me the great opportunity to work for
three months in his lab at the University of Connecticut. I would also like to thank him for his
enthusiasm and his extremely valuable scientific input into my work. I would like to express
my profound appreciation to the entire research group at UConn for their very warm
welcome, all the help and support and also for simply having a great time. My special thanks
go to Johanna Rivera. I very much enjoyed our trips in New England. JoAnne Ronzello from the Institute of Materials Science, University of Connecticut is gratefully acknowledged for
support with the DRS measurements.
The Dr. August und Dr. Anni Lesmüller-Foundation is thanked for their generous financial
support.

Many thanks are expressed to all the colleagues from the research groups of Prof. Winter
and Prof. Frieß who shared the time with me in Munich, to Ahmed, Alice, Andrea, Angelika,
Gerd, Jan, Julia, Kathrin, Klaus, Martin, Michael, Sandra and Virginie and the entire crew.
Thank you for the many inspiring discussions, for all the help and support and for the
numerous activities also off the job. Especially, I would like to thank Stefan and Rainer for the
great time we had - and for the music.

Wolfgang Wünschheim is acknowledged for his help with the powder diffractometer and Tina
Reuther for performing the BET measurements.

Alice Pahnke is acknowledged for the good job she has done during her bachelor thesis.

Thanks are extended to Prof. Dr. A. Vollmar, Prof. Dr. F. Bracher, Prof. Dr. F. Paintner and
PD Dr. S. Zahler for kindly serving as a member of my thesis advisory committee.

I am very thankful to Patrick Garidel, Sandra Schulze, Julia Myschik and Tim Serno for proof-
reading this thesis.

To my parents, my sisters Stephanie and Caroline and my grand-parents: Thank you for all
your encouragement and support, thank you for always being there for me.

Finally, I would like to thank Tim, for all your help and support. And for your love.





For my parents
TABLE OF CONTENTS

TABLE OF CONTENTS

CHAPTER 1: GENERAL INTRODUCTION
1 INTRODUCTION...................................................................................................................1
2 FREEZE-DRYING OF PROTEINS ............................................................................................3
2.1 THE FREEZE-DRYING PROCESS IN BRIEF......................................................................3
2.2 FREEZE-DRYING OF PROTEIN PHARMACEUTICALS ........................................................6
3 THE COLLAPSE PHENOMENON9
3.1 DEFINITION.................................................................................................................9
3.2 MECHANISM .............................................................................................................10
3.3 THE COLLAPSE TEMPERATURE..................................................................................12
3.4 DETERMINANTS OF COLLAPSE...................................................................................14
3.4.1 Viscosity..........................................................................................................14
3.4.2 Time scale ......................................................................................................15
3.4.3 Pore radius .....................................................................................................17
3.5 THE OCCURRENCE OF COLLAPSE ..............................................................................17
3.5.1 Collapse during freeze-drying.........................................................................17
3.5.2 ring storage..................................................................................18
3.6 EFFECTS OF COLLAPSE: CURRENT OPINION ...............................................................18
3.7 PRO & CONTRA OF DRYING CLOSE TO THE COLLAPSE TEMPERATURE:
WHY IT IS WORTH INVESTIGATING THE COLLAPSE PHENOMENON IN DETAIL .................21
4 STABILITY OF PROTEIN PHARMACEUTICALS IN THE SOLID STATE ........................................24
4.1 FACTORS AFFECTING STABILITY OF PROTEINS IN THE SOLID STATE .............................24
4.1.1 Water replacement hypothesis .......................................................................24
4.1.2 Vitrification hypothesis ....................................................................................25
4.1.3 Temperature ...................................................................................................25
4.1.4 Moisture ..........................................................................................................26
4.1.5 Hydrogen ion activity ......................................................................................26
4.2 IMPLICATIONS OF COLLAPSE FOR THE CONCEPTS OF SOLID STATE PRESERVATION......26
4.2.1 Effect of collapse on thermodynamic stabilization concepts...........................26
4.2.2 effect of collapse on kinetic stabilization concepts .........................................26
4.3 CHARACTERISTICS OF GLASSY SYSTEMS ...................................................................27
4.3.1 Temperature dependence of molecular mobility.............................................28
4.4 STABILITY OF GLASSY SYSTEMS ................................................................................31
4.5 CORRELATION OF MOLECULAR MOBILITY AND PROTEIN STABILITY...............................33
I TABLE OF CONTENTS

4.5.1 Global mobility ................................................................................................34
4.5.2 Local mobility ..................................................................................................34
5 REFERENCES...................................................................................................................36
CHAPTER 2: OBJECTIVES OF THE THESIS
OBJECTIVES OF THE THESIS .....................................................................................................47
CHAPTER 3: MATERIALS AND METHODS
1 MATERIALS..