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The Use of Aerosol-Based Detection Systems in the Quality Control of Drug Substances

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The Use of Aerosol-Based Detection Systems in the Quality Control of Drug Substances 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 Quantity Analyte Detector (NQAD) ............................................... 43 4. RESULTS AND DISCUSSION .......................................................................... 45 4.1 Suitability of ELSD for the impurities control - analysis of the performance characteristics and appearance of spike peaks 45 4.1.1 Influence of the ELSD parameters and of the mobile phase composition and flow-rate on the detector response ............................................................... 47 4.1.2 Influence of the ELSD parameters and of the mobile phase composition and flow-rate on the appearance of spike peaks ................................................ 51 4.1.2.1 Influence of the mobile phase composition ............................................ 51 4.1.2.2 Influence of the mobile phase
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