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The influence of atomization conditions on protein secondary and tertiary structure during microparticle formation by spray-freeze-drying [Elektronische Ressource] / vorgelegt von Sebastian Vonhoff

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195 pages
THE INFLUENCE OF ATOMIZATION CONDITIONS ON PROTEIN SECONDARY AND TERTIARY STRUCTURE DURING MICROPARTICLE FORMATION BY SPRAY-FREEZE-DRYING Der Naturwissenschaftlichen Fakultät der Friedrich-Alexander Universität Erlangen-Nürnberg zur Erlangung des Doktorgrades Dr. rer. nat. vorgelegt von Sebastian Vonhoff aus Kemnath Als Dissertation genehmigt von der Naturwissenschaftlichen Fakultät der Friedrich-Alexander-Universität Erlangen-Nürnberg Tag der mündlichen Prüfung: 12.April.2010 Vorsitzender der Promotionskommission: Prof. Dr. Eberhard Bänsch Erstberichterstatter: Prof. Dr. Geoffrey Lee Zweitberichterstatter: Prof. Dr. Wolfgang Frieß Für meinen Vater, der genau in diesem Moment (immer noch) in der Apotheke steht. Tu ne quaesieris, scire nefas, quem mihi, quem tibi finem di dederint, Leuconoe, nec Babylonios temptaris numeros. ut melius, quidquid erit, pati. seu pluris hiemes seu tribuit Iuppiter ultimam, quae nunc oppositis debilitat pumicibus mare Tyrrhenum: sapias, vina liques, et spatio brevi spem longam reseces. dum loquimur, fugerit invida aetas: carpe diem quam minimum credula postero. Horaz, Carmen 1,11 ACKNOWLEDGEMENTS The research work presented in this thesis has been performed between June 2006 and November 2009 at the Department of Pharmaceutical Technology, University of Erlangen-Nuremberg, Erlangen, Germany. First of all, Prof. Dr.
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THE INFLUENCE OF ATOMIZATION
CONDITIONS ON PROTEIN SECONDARY AND
TERTIARY STRUCTURE DURING
MICROPARTICLE FORMATION BY
SPRAY-FREEZE-DRYING



Der Naturwissenschaftlichen Fakultät
der Friedrich-Alexander Universität Erlangen-Nürnberg
zur
Erlangung des Doktorgrades Dr. rer. nat.



vorgelegt von
Sebastian Vonhoff
aus Kemnath


Als Dissertation genehmigt von der
Naturwissenschaftlichen Fakultät der Friedrich-Alexander-Universität
Erlangen-Nürnberg














Tag der mündlichen Prüfung: 12.April.2010
Vorsitzender der Promotionskommission: Prof. Dr. Eberhard Bänsch
Erstberichterstatter: Prof. Dr. Geoffrey Lee
Zweitberichterstatter: Prof. Dr. Wolfgang Frieß





Für meinen Vater,
der genau in diesem Moment
(immer noch) in der Apotheke steht.







Tu ne quaesieris, scire nefas, quem mihi, quem tibi
finem di dederint, Leuconoe, nec Babylonios
temptaris numeros. ut melius, quidquid erit, pati.
seu pluris hiemes seu tribuit Iuppiter ultimam,
quae nunc oppositis debilitat pumicibus mare
Tyrrhenum: sapias, vina liques, et spatio brevi
spem longam reseces. dum loquimur, fugerit invida
aetas: carpe diem quam minimum credula postero.

Horaz, Carmen 1,11
ACKNOWLEDGEMENTS

The research work presented in this thesis has been performed between June 2006 and
November 2009 at the Department of Pharmaceutical Technology, University of Erlangen-
Nuremberg, Erlangen, Germany.
First of all, Prof. Dr. Geoffrey Lee is gratefully acknowledged for offering me the opportunity
to work in the Division of Pharmaceutics, for serving as my doctoral advisor, and for
refereeing this thesis.
Many thanks go to Dr. Heiko Schiffter, for his continuous and extensive support throughout
my work. You always found time for discussing arising problems with me and made the
distance between Erlangen and Oxford completely insignificant. In addition, you supervised
me in a cooperative and friendly way that I did not take for granted. Thank you for that and I
hope we stay in contact in the years to come.
Prof. Dr. Wolfgang Frieß, Department of Pharmaceutics, University of Munich, is thanked for
kindly being co-referee for this thesis.
Dr. Stefan Schneid, aka “Snütje”, is kindly acknowledged for thoroughly proof-reading this
work, for introducing me to “How I met your mother” - the by far greatest sitcom on the
planet, and the fruitful scientific and personal discussions we had in our lab. This thesis would
not have been possible without you in this form.
I would also like to thank all my present and former colleagues in the Department of
Pharmaceutics. First of all Georg Straller, with whom I had the pleasure of battling for the
title “sWdW”. We experienced the same ups and downs during our work which made things a
lot easier. Then of course Simone Reismann, whose sunny disposition was always a welcome
diversion, Jakob Beirowski for lots of open-minded discussions in a wide variety of subjects,
and Susanne Rutzinger for our many funny conversations. I’d also like to thank Elke
Lorentzen, Peter Lassner, Eva Wulsten, Harald Pudritz, Anke Sass and Eva Meister for the
friendly atmosphere and the good times at the department as well as Dr. Henning Gieseler for
the good discussions we had and his clear point-of-view. Within the department, I would first like to thank Josef Hubert for building or fixing almost
anything that I came up with. You made McGyver look like an innocent school boy. Also, I
will never forget our mutual trip to the Netherlands and back - all in one day without even
having a working car radio. Then, Petra Neubarth for taking care of administrative things and
the very nice conversations we had, Dr. Stefan Seyferth for our good talks and for handling
any issues I had concerning IT and the Playstation 3, Luise Schedl for taking all of the SEM
pictures presented in this work and Christiane Blaha for the fast and reliable ordering of
supplies.
I’d also like to acknowledge my former students Steffi Purkl and Joachim Schäfer for the hard
work they provided while working under my supervision. You have been a great help.
Finally, I want to express my gratitude to my father Hans-Jürgen, my brother Christian and
my aunt Susanne for their continuous support during the last years - you made all of this
possible. And last but not least, I would like to thank my girlfriend Joanna for her never-
ending patience over the last months, for starting a complete new life with me, and for being a
wonderful mother to our little daughter Lea. You’re far from ordinary :*
PARTS OF THIS THESIS HAVE ALREADY BEEN PRESENTED OR PUBLISHED

I. Sebastian Vonhoff, Heiko Schiffter, Jamie Condliffe, Geoffrey Lee (2007).
“Investigation of protein process stability during spray-freeze-drying (SFD) using
FTIR and fluorescence spectroscopy.” AAPS Annual Meeting. San Diego (USA).
II. Sebastian Vonhoff, Heiko Schiffter (2008). “Implementation of an FTIR calibration
curve for fast and objective determination of changes in protein secondary structure.”
AAPS Annual Meeting. Atlanta (USA).
III. Sebastian Vonhoff, Heiko Schiffter (2008). “Influence of nozzle-type and atomization
conditions on protein secondary and tertiary structure during spray-freeze-drying.”
AAPS
IV. Sebastian Vonhoff, Jamie Condliffe, Heiko Schiffter (2009). “Implementation of an
FTIR calibration curve for fast and objective determination of changes in protein
secondary structure during formulation development.” Journal of Pharmaceutical and
Biopharmaceutical Analysis 51(1): 39-45
List of abbreviations

ΔT Temperature difference
ε Absorptivityconstantλ
λ Wavelength
A Absorbance at given wavelength λ
a-CT α-chymotrypsin
API Active pharmaceutical ingredient
AU Arbitrary unit
b Pathlength
c Concentration
CD Circular dichroism
CLS Classic least squares
CMC Critical micelle concentration
d Mean volume diameter v
d Median of volume diameters v,50
EMEA European medicines agency
FD Freeze-drying
FDA Food and drug administration
Fe Ammonium iron(II) sulfate hexahydrate
FTIR Fourier transform infrared spectroscopy
HSA Human serum albumin
IEP Isoelectric point ILS Inverse least squares
IR Infrared
K Proportionality factor at given wavelength λ
KI Potassiumiodide
LN Liquid nitrogen 2
MRDP Major R drug portfolio x
PLS Partial least squares
PRESS Predicted residual error sum of squares
r Correlation coefficient
2R Coefficient of determination
Re Reynolds number
rh Relative humidity
RMSE Root mean square error
R Available on prescription x
sdv standard deviation
SEM Scanning electron microscopy
SFD or SFV/L Spray-freeze-drying into vapor over liquid
SSA Specific surface area
SVD Singular value decomposition
T Transpose
T Glass transition temperature g
’T perature of the maximum concentrated g
solute
T Melting temperature mTA Terephthalic acid
We Weber number

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