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Impurity Profiling of Challenging Active Pharmaceutical Ingredients Without Chromophore

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Impurity Profiling of Challenging Active Pharmaceutical Ingredients Without Chromophore Impurity Profiling of Challenging Active Pharmaceutical Ingredients without Chromophore DISSERTATION zur Erlangung des naturwissenschaftlichen Doktorgrades der Julius-Maximilians-Universität Würzburg vorgelegt von Oliver Wahl aus Birkenfeld/Nahe Würzburg 2016 Eingereicht bei der Fakultät für Chemie und Pharmazie am: ………………………………. Gutachter der schriftlichen Arbeit: 1. Gutachter ………………………………….. 2. Gutachter ………………………………….. Prüfer des öffentlichen Promotionskolloquiums: 1. Prüfer ………………………………….. 2. Prüfer ………………………………….. 3. Prüfer ………………………………….. Datum des öffentlichen Promotionskolloquiums: ………………………………….. Doktorurkunde ausgehändigt am: ………………………………….. I Adoramos a perfeição, porque não a podemos ter; repugna-la-íamos, se a tivéssemos. O perfeito é o desumano, porque o humano é imperfeito. Fernando Pessoa (1888-1935) Für meine Familie! II Die vorliegende Arbeit wurde auf Anregung und unter Anleitung von Frau Prof. Dr. Ulrike Holzgrabe am Lehrstuhl für Pharmazeutische Chemie des Instituts für Pharmazie und Lebensmittelchemie der Julius-Maximilians Universität Würzburg angefertigt. Ihr gebührt besonderer Dank für die Aufnahme in die Arbeitsgruppe und für das in mich gesetzte Vertrauen. Sie hat mir in zahlreichen Diskussionen wertvolle Anregungen zur Problemlösung gegeben und mir das eigenverantwortliche Anfertigen dieser Arbeit ermöglicht. Außerdem ermöglichte Sie mir mit einem halbjährigen Auslandsaufenthalt tiefe Einblicke in die Arbeit des EDQM in Strasbourg und gab mir damit eine sehr wertvolle Erfahrung mit auf den Weg. Danke! Weiterer Dank gebührt dem Bundesinstitut für Arzneimittel und Medizinprodukte in Bonn für die Finanzierung dieser Arbeit. III Allen anderen, die mich in dieser Zeit auf die eine oder andere Art unterstützt haben und denjenigen, die diese Zeit zu einer unvergesslichen gemacht haben: David, Jogi, Miri, Lu, Christiane, Nina, Melli, Maike, Klaus, Ines, Flo, Regina, Anna, Antonio, Steffi, Daniela, Nils, Alex, Jan, Michael, Raphael, Markus, Katja, Christine,Danke! Lina, Frau Möhler, Frau Ebner, Frau Kosikors Andreas Lodi, Sylvie Jorajuria, Stefan Almeling, Remmelt, Jean-Yves, Gilles, Cédric, Joel, Yusuf, Nicole, Nathalie, Chantal, Jochen, Sebastien, Brigitte, Marianne, Sophie, Stephanie M., Stephanie F., Noud, Christelle, Laurence, Michele, Olivier, Marion, Cees-Jan, Christian,Merci! Pascal, Sophie, Hassina, Christian, Silvia, Sylvie D., Agnès, Fatiha, Valerie, Emilie, Philippe, Matthias, Emilie, Peter, Gwenaelle, Manuela IV V Table of contents Table of contents A. Introduction ....................................................................................................... 1 1. Separation techniques in impurity profiling .......................................................... 2 1.1. High performance liquid chromatography ..................................................... 2 1.2. Capillary electrophoresis .............................................................................. 5 1.3. Amino acid analysis ...................................................................................... 6 2. Detectors used in HPLC and CE ......................................................................... 7 2.1. UV/Vis-Detector ............................................................................................ 7 2.2. Fluorescence detection ................................................................................. 8 2.3. Refractive index detector .............................................................................. 9 2.4. Evaporative light scattering detector ........................................................... 11 2.5. Condensation nucleation light scattering detector ....................................... 12 2.6. Corona charged aerosol detector................................................................ 13 2.7. Electrochemical detector ............................................................................ 16 2.8. Capacitively coupled contactless conductivity detector ............................... 17 2.9. Mass spectrometer ..................................................................................... 18 2.10. Chemiluminescent nitrogen detector ......................................................... 21 3. Challenges in Impurity profiling ......................................................................... 22 3.1. Strategies to overcome the separation issue .............................................. 22 3.2. Coping with the detection issue .................................................................. 27 3.3. Examples for challenging separations ........................................................ 29 4. Chiral separation techniques for amino acids .................................................... 31 4.1. Indirect separation ...................................................................................... 31 4.2. Direct separation using chiral stationary phases ......................................... 32 4.3. Direct separation using chiral CE ................................................................ 33 5. References........................................................................................................ 36 B. Aim of the work ............................................................................................... 49 VI Table of contents C. Results ........................................................................................................... 53 1. Impurity profiling of carbocisteine by HPLC-CAD, qNMR and UV/vis spectroscopy ................................................................................................. 54 2. Evaluation of enantiomeric purity of magnesium-L-aspartate dihydrate ....... 74 3. Impurity profiling of ibandronate sodium by HPLC-CAD .............................. 97 4. Amino acid analysis for pharmacopoeial purposes .................................... 117 5. Impurity profiling of N,N’-ethylenebis-L-cysteine diethyl ester (Bicisate) .... 161 D. Final discussion ............................................................................................ 173 1. The CAD in impurity profiling ..................................................................... 174 2. Enantiomeric purity of magnesium aspartate ............................................. 175 3. Mixed-mode chromatography in impurity profiling ..................................... 175 4. Other applications of the CAD ................................................................... 176 5. Conclusion ................................................................................................ 176 E. Summary ...................................................................................................... 181 F. Zusammenfassung ....................................................................................... 183 G. Appendix ...................................................................................................... 187 1. List of Publications and Documentation of Authorship ............................... 188 2. Conference contributions .......................................................................... 192 3. Abbreviations ............................................................................................ 193 VII A. Introduction A 1 Introduction 1. Separation techniques in impurity profiling The three most important separation techniques used in the European Pharmacopoeia for the assessment of related substances are high performance liquid chromatography, gas chromatography and capillary electrophoresis. The techniques used in this work, HPLC and CE, are introduced in the following part. 1.1. High performance liquid chromatography Chromatography is a process of separation using adsorption and distribution processes between a stationary and a mobile phase moving along the stationary phase. In HPLC, the mobile phase is pumped with moderately high pressure (typically 50 – 350 bar) through a steel column packed with small uniform beads or irregular formed particles of stationary phase. The analytes are detected after the column using a suitable detection device. A chromatogram based on the analog data provided by the detector is yielded by means of an integrator or an appropriate digital interface (see Fig. 1) [1, 2]. Fig. 1. Schematic layout of a HPLC system. In liquid chromatography several separation modes can be distinguished: normal phase, reversed phase, size exclusion, ion exchange, ion-pair, hydrophilic interaction liquid chromatography, and chromatography using chiral modifications [3]. A stationary phase consists of a polymeric support (e.g. silica gel, poly acrylate, etc.) carrying a chemical modifications to introduce the desired characteristics. Popular modifications are listed in Table 1. 2 Separation techniques in impurity profiling Table 1 Types of stationary phases applied in HPLC analytics [1, 2, 4]. Chemistry separation mode main application C-1 reversed phase large biomolecules C-4 reversed phase C-8 reversed phase very lipophilic SM, peptides C-18 reversed phase lipophilic SM, small peptides Phenyl reversed phase alternative to C-18 with modified PFP reversed phase selectivity CN reversed phase or NP hydrophilic SM Diol HILIC very hydrophilic SM Amide HILIC very hydrophilic SM plain silica gel HILIC or NP very hydrophilic SM NH2 HILIC or WAX very hydrophilic SM, carbohydrates sulfonate SCX cationic SM, inorganic cations quaternary amine SAX anionic SM, inorganic anions methacrylate gel size exclusion large biomolecules, polymers HILIC,
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