Separation of Enantiomers by a Process Combination of Chromatography and Crystallisation Dissertation zur Erlangung des akademischen Grades Doktoringenieur (Dr.-Ing.) von: Dipl.-Ing. Malte Kaspereit geboren am: 31. Juli 1973 in: Merseburg genehmigt durch die Fakult¨at f¨ur Verfahrens- und Systemtechnik der Otto-von-Guericke Universit¨at Magdeburg. Gutachter: Prof. Dr.-Ing. habil. Andreas Seidel-Morgenstern Prof. Dr.-Ing. habil. Henner Schmidt-Traub eingereicht am: 28. Oktober 2005 Promotionskolloquium am 10. M¨arz 2006. Forschungsberichte aus dem Max-Planck-Institut für Dynamik komplexer technischer Systeme Band 14 Malte Kaspereit Separation of Enantiomers by a Process Combination of Chromatrography and Crystallisation Shaker Verlag Aachen 2006 Bibliographic information published by Die Deutsche Bibliothek Die Deutsche Bibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data is available in the internet at http://dnb.ddb.de. Zugl.: Magdeburg, Univ., Diss., 2006 Copyright Shaker Verlag 2006 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission of the publishers. Printed in Germany. ISBN-10: 3-8322-5130-8 ISBN-13: 978-3-8322-5130-7 ISSN 1439-4804 Shaker Verlag GmbH • P.O. BOX 101818 • D-52018 Aachen Phone: 0049/2407/9596-0 • Telefax: 0049/2407/9596-9 Internet: www.shaker.de • eMail: [email protected] Acknowledgements This thesis evolved from research I performed at the Max Planck Institute for Dynamics of Com- plex Technical Systems in Magdeburg, Germany. First and foremost I am deeply grateful to Prof. Andreas Seidel-Morgenstern, who enabled me to work at the MPI and allowed me great latitude in performing my research. Without his patient but encouraging guidance, his many ideas and deliberate advices the preparation of this work would have been impossible. I am very thankful to Prof. Henner Schmidt-Traub who acted as a referee for this thesis. For his complaisant support I am indebted to Prof. Achim Kienle, who gave me financial funding while I was largely busy with writing up. Scientific work certainly requires a stimulating and productive atmosphere, which is what I found at the MPI. Decent technical facilities and, much more important, numerous discussions with and collaborative support by my colleagues were utmost valuable. In this respect I am particularly grateful to the group for Physical and Chemical Fundamentals of Process Engineering. Here spe- cial thanks go to Knut Gedicke and, furthermore, to Dorota Antos, Jacqueline Kaufmann, Alan Mahoney, Dragomir Sapoundjiev, Patrick Sheehan, Volker Zahn, and Grzegorz Ziomek. Life was made much easier by many friends I found at the MPI, in particular by the ”veterans” from the institute’s early years. I’ll never forget the daily routine of a dozen or more colleagues squeezing into a ridiculously small tea kitchen, while performing an incredible and unachieved mixture of in-depth discussions and hilarious jokes. The accumulation of so many perceptive and nice people within one institute is certainly one of the most enjoyable aspects of science. There are too many people I’d have to mention here – so just many thanks to all of you. Finally, I want to thank my family and, especially, my girlfriend Anke, who provided a calm asy- lum and endured all the little crises I brought home with me – while managing her own successful research and dissertation in an admirable fashion. Magdeburg, April 2006 Malte Kaspereit Contents Introduction 1 1 Concept of a Process Combination for Enantioseparations 3 1.1 Background . .............................. 3 1.1.1 Fundamentals of Stereochemistry . .................... 3 1.1.2 Biological and Economical Relevance .................... 5 1.1.3 Production Methods for Pure Enantiomers . .......... 7 1.2ConceptoftheProcessCombination......................... 13 1.2.1 SomeRemarksonProcessIntensification.................. 13 1.2.2 BasicConcept................................ 15 1.2.3 PossibleSynergisms............................. 16 1.2.4 StateofResearch............................... 18 2 Theoretical Foundations of Individual Unit Operations 21 2.1 Continuous Chromatography . .................... 21 2.1.1 Principle................................... 21 2.1.2 Adsorption Equilibria . .................... 24 2.1.3 Fundamental Relations . .................... 26 2.1.4 Modelling of Batch Chromatography .................... 28 2.1.5 Modelling of TMB Chromatography . .................... 30 2.1.6 Modelling of SMB Chromatography . .................... 31 2.1.7 DesignAspects................................ 32 2.2 Enantioselective Crystallisation . .................... 32 2.2.1 Principle................................... 32 2.2.2 Solid-Liquid Equilibria in Enantiomeric Systems . .......... 33 2.2.3 Enantioselective Cooling Crystallisation from Solution . .......... 36 2.2.4 Modelling . .............................. 37 2.2.5 DesignAspects................................ 38 3 Model Systems 39 3.1SystemI–MandelicAcid.............................. 39 3.1.1 ChromatographicSeparation......................... 40 3.1.2 Ternary Solubility Equilibria . .................... 42 3.2SystemII–Threonine................................ 44 3.2.1 ChromatographicSeparation......................... 44 3.2.2 Solubility Equilibrium . .................... 46 3.3 System III – Pharmaceutical Intermediate PDE . .......... 47 3.3.1 ChromatographicSeparation......................... 47 3.3.2 Solubility Equilibrium . .................... 48 3.4ChemicalsandEquipmentUsed........................... 48 4 Impact of Adsorption Isotherms on SMB Processes 51 4.1 Background . .............................. 51 4.2 Theoretical Fundamentals . .............................. 52 4.2.1 PerformanceParameters........................... 52 4.2.2 IsothermModel................................ 52 4.2.3 Equilibrium Design of SMB processes .................... 52 4.2.4 Determination of Productivities from Equilibrium Design . 55 4.3 Analysis for Pure Products Based on Equilibrium Design . .......... 56 4.3.1 ParameterSpecifications........................... 56 4.3.2 Definition of Reference Isotherms . .................... 56 4.3.3 ResultsfortheModelSystems........................ 57 4.3.4 ParametricStudyBasedonaReferenceIsotherm.............. 58 4.4AnalysisforVariablePurityBasedonNumericalSimulations............ 60 4.4.1 ParameterSpecifications........................... 60 4.4.2 SeparationRegionsforVaryingOutletPurity................ 60 4.4.3 Productivity as Function of Feed Concentration and Purity . 62 4.5Conclusions...................................... 64 5 Design of SMB Processes for Predefined Purity 65 5.1 Background . .............................. 65 5.2ModelandParameters................................ 66 5.2.1 GenericExampleSystem........................... 67 5.3InfluenceoftheRegenerationZones......................... 68 5.3.1 InternalConcentrationProfiles........................ 68 5.3.2 SeparationRegions.............................. 69 5.4OptimisationofRestrictiveandNon-restrictiveDesigns............... 70 5.4.1 ProcessPerformance............................. 70 5.4.2 InternalConcentrationProfiles........................ 72 5.4.3 ProcessRobustness.............................. 72 5.5Conclusions...................................... 74 6 Impact of Solubility Equilibria on Enantioselective Crystallisation 77 6.1 Modelling of Ternary Solid-Liquid Equilibria .................... 77 6.1.1 Thermodynamic Models . .................... 77 6.1.2 SLE Model based on Solubility Approximation . .......... 79 6.2 Equilibrium Design of Enantioselective Crystallisation . .......... 82 6.2.1 MassBalancesandGeneralRelations.................... 83 6.2.2 DeterminationofCompositions....................... 84 6.2.3 DeterminationofTemperatures....................... 85 6.3 Performance of Crystallisation for the Model Systems . .......... 86 6.3.1 TheoreticalYield............................... 86 6.3.2 OperatingTemperatures........................... 86 6.3.3 Yield Limitation and Stepwise Crystallisation . .......... 87 6.3.4 ConsiderationsonSolutionDensityandConcentrations.......... 89 6.3.5 SpecificSolventRemovalinaProcessCombination............ 90 6.3.6 Supersaturation................................ 91 6.3.7 SummaryofPerformancefortheModelSystems.............. 92 6.4Conclusions...................................... 93 7 Evaluation and Design of the Process Combination 95 7.1DetailedConceptoftheProcessCombination.................... 95 7.2MassBalancingApproachforSeparatorNetworks................. 97 7.2.1 NonsharpBinarySeparators......................... 97 7.2.2 NetworksofNonsharpSeparatorswithRecycles.............. 99 7.3ShortcutApproachforEvaluationoftheProcessCombination...........101 7.3.1 BasicConcept................................102 7.3.2 Derivation of Process Parameters for the Process Combination . 102 7.3.3 DeterminationofCharacteristicsforSMBProcesses............105 7.3.4 IllustrativeExample.............................106 7.4EvaluationandDesignoftheProcessCombination.................107 7.4.1 DetailedProcedure..............................107 7.4.2 EvaluationforDifferentProcessConfigurations...............108 7.4.3 EvaluationforDifferentModelSystems...................113 7.4.4 RemarksandLimitationsoftheApproach..................115 7.5FurtherAspectsofProcessEngineering.......................116