The use of aerosol-based detection systems in the quality control of drug substances [Elektronische Ressource] / Stefan Almeling. Betreuer: Ulrike Holzgrabe

Informations

• Publié par: julius-maximilians-universitat_wurzburg
• Publié le: 01 janvier 2011
• Nombre de lectures: 11
• Langue: English
• Poids de l'ouvrage: 3 Mo

Extrait

THE USE OF AEROSOL-BASED DETECTION SYSTEMS
IN THE
QUALITY CONTROL OF DRUG SUBSTANCES








Dissertation zur Erlangung des naturwissenschaftlichen Doktorgrades
der
Julius-Maximilians-Universität Würzburg


vorgelegt von
Stefan Almeling


aus Hann. Münden



Würzburg 2011
Eingereicht bei der Fakultät für Chemie und Pharmazie am

_________________




Gutachter der schriftlichen Arbeit

1. Gutachter: Prof. Dr. Ulrike Holzgrabe

2. Gutachter: ______________________




Prüfer des öffentlichen Promotionskolloquiums

1. Prüfer: __________________________

2. Prüfer: ___________________________

3. Prüfer: ___





Datum des öffentlichen Promotionskolloquiums

___________________________




Doktorurkunde ausgehändigt am

____________________________















Gelingt es dir nicht
in die Quelle der Dinge einzudringen
wird dein Geist
vergeblich nach Ruhe suchen.
Kanchi Sõsan (? – 606 B.C.)
Acknowledgement

This doctoral thesis was elaborated at the European Directorate for the Quality of
Medicines & HealthCare (EDQM) in Strasbourg (France) and was guided and
supervised by

Prof. Dr. Ulrike Holzgrabe

to whom I would like to express my warmest thanks for the opportunity to work on
these interesting subjects, for her very efficient guidance, support and many fruitful
discussions as well as for the time devoted to this thesis.
Moreover, I thank the Director of the European Directorate for the Quality of
Medicines and Healthcare (EDQM), Dr. Susanne Keitel, and the Head of the EDQM
Laboratory Department, Dr. Andrea Lodi, for offering the possibility of using the
facilities and technical resources of the EDQM without which the practical conduct of
the work would not have been possible.
My special thanks and high regards also to Mr. Cees-Jan Nap who assisted in the
technical conduct of the work and who also acted as a tireless, critical and creative
partner in many discussions we had around the subject.
Concerning the comparative study of possible detection method for alanine I would
like to express my thanks to Tanja Beyer for her collaboration and contribution in the
field of NMR.
I am also very thankful to Prof. Dr. emeritus Jos Hoogmartens and Prof. Dr. Erwin
Adams (both University of Leuven, Belgium) for the provision of the streptomycin
sulfate samples and to Nathalie Kunz for her contributions to the corresponding lab
work.
Last but not least I would like to express my special gratitude to my wife Anke, who
always backed me up and provided unreserved support, especially in difficult
moments (and there were many!).
This thesis is dedicated to my children Celine and Nicolai, who had to relinquish their
father during countless evenings and weekends and who would have liked to play
with him instead of seeing him sitting in front of a computer screen during holidays. Parts of this thesis have already been published in:

Articles
1. Almeling, S., Holzgrabe, U.
“Use of evaporative light scattering detection for the quality control of drug
substances: influence of different liquid chromatographic and evaporative light
scattering detector parameters on the appearance of spike peaks”
Journal of Chromatography A 2010, 1217, 2163-2170.
2. Holzgrabe, U., Nap, C.-J., Almeling, S.
“Control of impurities in L-aspartic acid and L-alanine by high-performance liquid
chromatography coupled with a corona charged-aerosol detector”
Journal of Chromatography A 2010, 1217, 294-301.
3. Holzgrabe, U., Nap, C.-J., Beyer, T., Almeling, S.
“Alternatives to amino-acid-analysis for the purity control of pharmaceutical grade L-
Alanine”
Journal of Separation Science 2010 33, 2402-2410.
4. Holzgrabe, U., Nap, C.-J., Almeling, S.
“Use of collision induced dissociation mass spectrometry as a rapid technique for the
identification of pharmacologically active peptides in pharmacopoeial testing.”
Journal of Pharmaceutical and Biomedical Analysis 2011, 55, 957-963.
5. Holzgrabe, U., Nap, C.-J., Kunz, N., Almeling, S.
“Identification and control of impurities in streptomycin sulfate by high-performance
liquid chromatography coupled with mass detection and corona charged-aerosol
detection”
Journal of Pharmaceutical and Biomedical Analysis 2011,
doi:10.1016/ j.jpba.2011.05.027

Book contributions
Holzgrabe, U., Brinz, D., Weber, C., Almeling, S.
Use of evaporative light scattering detection (ELSD) for the quality control of drug
substances in: T.J. Quintin (Hrsg.), Chromatography: Types, Techniques and
Methods, Nova Publishers, Inc. New York, 2010, 483-496. TABLE OF CONTENTS I
TABLE OF CONTENTS

LIST OF ABBREVIATIONS VI
1. INTRODUCTION ................................................................................................. 1
1.1.1 History ............................................................................................................ 3
1.1.2 Legal Background .......................................................................................... 4
1.1.3 Organisation ................................................................................................... 5
1.1.3.1 The Technical Secretariat ........................................................................ 5
1.1.3.2 The European Pharmacopoeia Commission ............................................ 6
1.1.3.3 Groups of Experts .................................................................................... 6
1.1.4 Structure of the European Pharmacopoeia .................................................... 7
1.1.4.1 Volume 1 .................................................................................................. 7
1.1.4.2 Volume 2 8
1.1.5 Elaboration of Monographs ............................................................................ 9
1.2 Impurities Control 12
1.2.1 Appearance of solution ................................................................................. 12
1.2.2 pH or Acidity/Alkalinity .................................................................................. 12
1.2.3 Enantiomeric purity ....................................................................................... 13
1.2.4 Absorption spectrophotometry ...................................................................... 13
1.2.5 Heavy metals ................................................................................................ 13
1.2.6 Loss on drying / Thermogravimetry / Water determination ........................... 13
1.2.7 Sulfated ash ................................................................................................. 14
1.2.8 Residual solvents ......................................................................................... 14
1.2.9 Related substances ...................................................................................... 14
2. SUBJECT OF THIS DOCTORAL THESIS ........................................................ 17
3. ANALYTICAL INSTRUMENTATION AND TECHNIQUES ............................... 19
3.1 Liquid Chromatography (LC) 19
3.1.1 General ........................................................................................................ 19
3.1.2 Reversed Phase Liquid Chromatography (RP-LC) ....................................... 23
3.1.2.1 Stationary phases used in RP-LC .......................................................... 23
3.1.2.2 Ion-pair chromatography ........................................................................ 25
3.1.2.3 Volatile mobile phases ........................................................................... 27
3.1.3 Hydrophilic Interaction Chromatography (HILIC) .......................................... 28
II TABLE OF CONTENTS
3.2 Detectors 29
3.2.1 UV/Vis spectrophotometry ............................................................................ 29
3.2.2 Pulsed amperometry .................................................................................... 30
3.2.3 Mass spectrometry ....................................................................................... 31
3.2.3.1 Ionization methods ................................................................................. 31
3.2.3.2 Mass analyzers ...................................................................................... 33
3.2.3.3 Data acquisition and analysis ................................................................. 36
3.2.4 Evaporation based detection systems .......................................................... 38
3.2.4.1 General .................................................................................................. 38
3.2.4.2 Evaporative Light Scattering Detector (ELSD) ....................................... 38
3.2.4.3 Corona Charged Aerosol Detector (CAD) .............................................. 42
3.2.4.4 Nano Q