Preparative Chromatography

Edited by H. Schmidt-Traub, M. Schulte and A. Seidel-Morgenstern

Second, Completely Revised and Enlarged Edition

Schmidt-Traub . Schulte

Seidel-Morgenstern (Eds.)

Preparative C

hromatography

 2nd Edition

Henner Schmidt-Traub 

Michael Schulte

Andreas Seidel-Morgenstern

www.wiley-vch.de

Completely revised and substantially extended to reflect the develop-ments in this fast-changing field. It retains the interdisciplinary ap-proach that elegantly combines the chemistry and engineering involved to describe the conception and improvement of chromatographic pro-cesses. It also covers recent advances in preparative chromatographic processes for the separation of „smaller“ molecules using standard laboratory equipment as well as the detailed conception of industrial chemical plants. The increase in biopharmaceutical substances is reflected by new and revised chapters on different modifications of con-tinuous chromatography as well as ion-exchange chromatography and other separation principles widely used in biochromatography.

Following an introductory section on the history of chromatography, the current state of research and the design of chromatographic pro-cesses, the book goes on to define the general terminology. There then follow sections on stationary phases, selection of chromatographic systems and process concepts. A completely new chapter deals with en-gineering and operation of chromatographic equipment. Final chapters on modeling and determination of model parameters as well as model based design, optimization and control of preparative chromatographic processes allow for optimal selection of chromatographic processes.

Essential for chemists and chemical engineers in the chemical, pharmaceutical, and food industries.

From a review of the previous edition:

“I would not hesitate to recommend it to anyone working in this field.”Chromatographia

“... this is a comprehensive reference text, which should find its way into the libraries of all companies who are serious about process scale pre-parative chromatography, whether internally or via outsource contracts.”Organic Process Research and Development

“This special volume is essential for chemists and engineers working in chemical and pharmaceutical industries, as well as for food technolo-gies, due to the interdisciplinary nature of these preparative chromato-graphic processes.”Advances in Food Sciences

57268File AttachmentCover.jpg

Edited by

Henner Schmidt-Traub,

Michael Schulte, and

Andreas Seidel-Morgenstern

PreparativeChromatography

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Edited by Henner Schmidt-Traub, Michael Schulte, andAndreas Seidel-Morgenstern

Preparative Chromatography

Second, Completely Revised and Updated Edition

The Editors

Prof. Dr.-Ing. Henner Schmidt-TraubTU DortmundFakultät für Bio- undChemieingenieurwesenLehrstuhl für Anlagen- undProzesstechnikEmil-Figge-Str. 7044227 DortmundGermany

Dr. Michael SchulteMerck KGaAR&D Performance & Life Science ChemicalsFrankfurter Str. 25064293 DarmstadtGermany

Prof. Dr.-Ing. Andreas Seidel-MorgensternOtto-von-Guericke-UniversitätInstitut für VerfahrenstechnikLehrstuhl für Chemische Verfahrenstechnik

and

Max-Planck-Institut für Dynamik komplexertechnischer SystemeSandtorstraße 1Universitätsplatz 239106 MagdeburgGermany

CoverThe cover figure has been kindly provided byNovasep, France.

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Library of Congress Card No.: applied for

British Library Cataloguing-in-Publication DataA catalogue record for this book is available fromthe British Library.

Bibliographic information published by the DeutscheNationalbibliothekThe Deutsche Nationalbibliothek lists thispublication in the Deutsche Nationalbibliografie;detailed bibliographic data are available on theInternet at http:// dnb.d-nb.d e.

#2012 Wiley-VCH Verlag & Co. KGaA, Boschstr. 12,69469 Weinheim, Germany

All rights reserved (including those of translation intoother languages). No part of this book may bereproduced in any form – by photoprinting,microfilm, or any other means – nor transmitted ortranslated into a machine language without writtenpermission from the publishers. Registered names,trademarks, etc. used in this book, even when notspecifically marked as such, are not to be consideredunprotected by law.

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Contents

Preface XVAbout the Editors XVIIList of Contributors XIXList of Abbreviations XXINotations XXV

1 Introduction 1Henner Schmidt-Traub and Reinhard Ditz

1.1 Development of Chromatography 11.2 Focus of the Book 31.3 Recommendation to Read this Book 4

References 6

2 Fundamentals and General Terminology 7Andreas Seidel-Morgenstern, Michael Schulte, and Achim Epping

2.1 Principles of Adsorption Chromatography 72.1.1 Adsorption Process 92.1.2 Chromatographic Process 102.2 Basic Effects and Chromatographic Definitions 112.2.1 Chromatograms and Parameters 112.2.2 Voidage and Porosity 122.2.3 Influence of Adsorption Isotherms on Chromatogram Shapes 152.3 Fluid Dynamics 182.3.1 Extra Column Effects 182.3.2 Column Fluid Distribution 192.3.3 Packing Nonidealities 192.3.4 Sources for Nonideal Fluid Distribution 202.3.5 Column Pressure Drop 212.4 Mass Transfer Phenomena 222.4.1 Principles of Mass Transfer 222.4.2 Efficiency of Chromatographic Separations 242.4.3 Resolution 272.5 Equilibrium Thermodynamics 30

jV

2.5.1 Definition of Isotherms 302.5.2 Models of Isotherms 322.5.2.1 Single-Component Isotherms 322.5.2.2 Multicomponent Isotherms Based on the Langmuir Model 342.5.2.3 Competitive Isotherms Based on the Ideal Adsorbed Solution

Theory 352.5.2.4 Steric Mass Action Isotherms for Ion Exchange Equilibria 382.6 Thermodynamic Effects on Mass Separation 402.6.1 Mass Load 402.6.2 Linear and Nonlinear Isotherms 412.6.3 Elution Modes 43

References 45

3 Stationary Phases and Chromatographic Systems 47Michael Schulte, Matthias J€ohnck, Romas Skudas, Klaus K. Unger,Cedric du Fresne von Hohenesche, Wolfgang Wewers, Jules Dingenen,and Joachim Kinkel

3.1 Column Packings 473.1.1 Survey of Packings and Stationary Phases 473.1.2 Generic, Designed, and Customized Adsorbents 483.1.2.1 Generic Adsorbents 483.1.2.2 Designed Adsorbents 543.1.2.3 Customized Adsorbents 623.1.3 Reversed Phase Silicas 663.1.3.1 Silanisation of the Silica Surface 673.1.3.2 Chromatographic Characterization of Reversed Phase Silicas 693.1.4 Cross-Linked Organic Polymers 723.1.4.1 General Aspects 733.1.4.2 Hydrophobic Polymer Stationary Phases 763.1.4.3 Hydrophilic Polymer Stationary Phases 763.1.4.4 Ion Exchange (IEX) 773.1.4.5 Mixed Mode 853.1.5 Chiral Stationary Phases 853.1.5.1 Antibiotic CSP 913.1.5.2 Synthetic Polymers 913.1.5.3 Targeted Selector Design 923.1.5.4 Further Developments 933.1.6 Properties of Packings and their Relevance to Chromatographic

Performance 953.1.6.1 Chemical and Physical Bulk Properties 953.1.6.2 Mass Loadability 1013.1.6.3 Comparative Rating of Columns 1023.1.7 Sorbent Maintenance and Regeneration 1033.1.7.1 Cleaning in Place (CIP) 1033.1.7.2 Conditioning of Silica Surfaces 106

VIj Contents

3.1.7.3 Sanitization in Place (SIP) 1083.1.7.4 Column and Adsorbent Storage 1083.2 Selection of Chromatographic Systems 1093.2.1 Definition of the Task 1143.2.2 Mobile Phases for Liquid Chromatography 1183.2.2.1 Stability 1183.2.2.2 Safety Concerns 1183.2.2.3 Operating Conditions 1213.2.2.4 Aqueous Buffer Systems 1233.2.3 Adsorbent and Phase Systems 1253.2.3.1 Choice of Phase System Dependent on Solubility 1273.2.3.2 Improving Loadability for Poor Solubilities 1283.2.3.3 Dependency of Solubility on Sample Purity 1303.2.3.4 Generic Gradients for Fast Separations 1313.2.4 Criteria for Choosing NP Systems 1323.2.4.1 Pilot Technique Thin-layer Chromatography 1343.2.4.2 Retention in NP Systems 1343.2.4.3 Solvent Strength in Liquid–Solid Chromatography 1363.2.4.4 Selectivity in NP Systems 1383.2.4.5 Mobile-Phase Optimization by TLC Following the PRISMAModel 1393.2.4.6 Strategy for an Industrial Preparative Chromatography Laboratory 1483.2.5 Criteria for Choosing RP Systems 1533.2.5.1 Retention and Selectivity in RP Systems 1553.2.5.2 Gradient Elution for Small amounts of Product on RP Columns 1563.2.5.3 Rigorous Optimization for Isocratic Runs 1573.2.5.4 Rigorous Optimization for Gradient Runs 1613.2.5.5 Practical Recommendations 1643.2.6 Criteria for Choosing CSP Systems 1673.2.6.1 Suitability of Preparative CSP 1683.2.6.2 Development of Enantioselectivity 1693.2.6.3 Optimization of Separation Conditions 1713.2.6.4 Practical Recommendations 1723.2.7 Downstream Processing of Mabs using Protein A and IEX 1743.2.8 Size Exclusion (SEC) 1793.2.9 Overall Chromatographic System Optimization 1813.2.9.1 Conflicts During Optimization of Chromatographic Systems 1813.2.9.2 Stationary Phase Gradients 184

References 189

4 Chromatography Equipment: Engineering and Operation 199Abdelaziz Toumi, Jules Dingenen, Joel Genolet, OlivierLudemann-Hombourger, Andre Kiesewetter, Martin Krahe,Michele Morelli, Henner Schmidt-Traub, Andreas Stein, and Eric Valery

4.1 Introduction 1994.2 Engineering and Operational Challenges 201

Contents jVII

4.3 Chromatography Columns Market 2074.3.1 Generalities – The Suppliers 2074.3.2 General Design 2084.3.3 High- and Low-Pressure Columns 2104.3.3.1 Chemical Compatibility 2114.3.3.2 Frits Design 2114.3.3.3 Special Aspects of Bioseparation 2154.4 Chromatography Systems Market 2174.4.1 Generalities – The Suppliers 2174.4.2 General Design Aspects –High Performance and Low-Pressure

Systems 2174.4.3 Material 2194.4.4 Batch Low-Pressure Liquid Chromatography (LPLC) Systems 2204.4.4.1 Inlets 2204.4.4.2 Valves to Control Flow Direction 2204.4.4.3 Pumps 2214.4.4.4 Pump(s) Valves and Gradient Formation 2224.4.5 Batch High-Pressure Liquid Chromatography (HPLC) Systems 2244.4.5.1 General Layout 2244.4.5.2 Inlets and Outlets 2244.4.5.3 Pumps 2264.4.5.4 Valves and Pipes 2274.4.6 Batch SFC Systems 2284.4.6.1 General Layout 2284.4.6.2 Inlets 2304.4.6.3 Pumps, Valves, and Pipes 2314.4.7 Continuous Systems – Simulated Moving Bed 2314.4.7.1 General Layout 2314.4.7.2 A Key Choice: The Recycling Strategy 2324.4.7.3 Pumps, Inlets, and Outlets 2334.4.7.4 Valves and Piping 2334.4.8 Auxiliary Systems 2334.4.8.1 Slurry Preparation Tank 2344.4.8.2 Slurry Pumps and Packing Stations 2344.4.8.3 Cranes and Transport Units 2354.4.8.4 Filter Integrity Test 2354.5 Process Control 2364.5.1 Standard Process Control 2364.5.2 Advanced Process Control 2374.5.3 Detectors 2404.6 Packing Methods 2434.6.1 Column and Packing Methodology Selection 2434.6.2 Slurry Preparation 2444.6.3 Column Preparation 2464.6.4 Flow Packing 246

VIIIj Contents

4.6.5 Dynamic Axial Compression (DAC) Packing 2494.6.6 Stall Packing 2504.6.7 Combined Method (StallþDAC) 2504.6.8 Vacuum Packing 2524.6.9 Vibration Packing 2534.6.10 Column Equilibration 2544.6.11 Column Testing and Storage 2544.6.11.1 Test Systems 2544.6.11.2 Hydrodynamic Properties and Column Efficiency 2564.6.11.3 Column and Adsorbent Storage 2574.7 Process Troubleshooting 2574.7.1 Technical Failures 2584.7.2 Loss of Performance 2594.7.2.1 Pressure Increase 2594.7.2.2 Loss of Column Efficiency 2624.7.2.3 Variation of Elution Profile 2634.7.2.4 Loss of Purity/Yield 2644.7.3 Column Stability 2654.8 Disposable Technology for Bioseparations 2654.8.1 Market Trend 2654.8.2 Prepacked Columns 2664.8.3 Membrane Chromatography 2674.8.4 Membrane Technology 269

References 270

5 Process Concepts 273Malte Kaspereit, Michael Schulte, Klaus Wekenborg, and Wolfgang Wewers

5.1 Discontinuous Processes 2735.1.1 Isocratic Operation 2735.1.2 Flip-Flop Chromatography 2755.1.3 Closed-Loop Recycling Chromatography 2765.1.4 Steady-State Recycling Chromatography 2785.1.5 Gradient Chromatography 2795.1.6 Chromatographic Batch Reactors 2815.2 Continuous Processes 2835.2.1 Column Switching Chromatography 2835.2.2 Annular Chromatography 2835.2.3 Multiport Switching Valve Chromatography (ISEP/CSEP) 2845.2.4 Isocratic Simulated Moving Bed (SMB) Chromatography 2865.2.5 SMB Chromatography with Variable Process Conditions 2905.2.5.1 VariCol 2905.2.5.2 PowerFeed 2915.2.5.3 Partial-Feed, Partial-Discard, and Fractionation-Feedback

Concepts 2925.2.5.4 Improved/Intermittent SMB (iSMB) 293

Contents jIX

5.2.5.5 ModiCon 2945.2.5.6 FF-SMB 2945.2.6 SMB Chromatography with Variable Solvent Conditions 2945.2.6.1 Gradient SMB Chromatography 2955.2.6.2 Supercritical Fluid SMB Chromatography 2965.2.7 Multicomponent Separations 2965.2.8 Multicolumn Systems for Bioseparations 2985.2.8.1 Sequential Multicolumn Chromatography (SMCC) 2985.2.8.2 Multicolumn Countercurrent Solvent Gradient Purification

(MCSGP) 2995.2.9 Countercurrent Chromatographic Reactors 3015.2.9.1 SMB Reactor 3015.2.9.2 Processes with Distributed Functionalities 3025.3 Choice of Process Concepts 3045.3.1 Scale 3055.3.2 Range of k0 3065.3.3 Number of Fractions 3065.3.4 Example 1: Lab Scale; Two Fractions 3065.3.5 Example 2: Lab Scale; Three or More Fractions 3085.3.6 Example 3: Production Scale –Wide Range of k0 3095.3.7 Example 4: Production Scale; Two Main Fractions 3105.3.8 Example 5: Production Scale; Three Fractions 3115.3.9 Example 6: Production Scale; Multi-Stage Process 312

References 315

6 Modeling and Model Parameters 321Andreas Seidel-Morgenstern, Henner Schmidt-Traub, Mirko Michel,Achim Epping, and Andreas Jupke

6.1 Introduction 3216.2 Models for Single Chromatographic Columns 3226.2.1 Classes of Chromatographic Models 3226.2.2 Derivation of the Mass Balance Equations 3246.2.2.1 Mass Balance Equations 3256.2.2.2 Convective Transport 3276.2.2.3 Axial Dispersion 3276.2.2.4 Intraparticle Diffusion 3276.2.2.5 Mass Transfer 3286.2.2.6 Adsorption Kinetics 3296.2.2.7 Adsorption Equilibrium 3296.2.3 Equilibrium (“Ideal”) Model 3306.2.4 Models with One Band Broadening Effect 3346.2.4.1 Dispersive Model 3346.2.4.2 Transport Model 3366.2.4.3 Reaction Model 3376.2.5 Lumped Rate Models 338

Xj Contents

6.2.5.1 Transport-Dispersive Model 3386.2.5.2 Reaction-Dispersive Model 3396.2.6 General Rate Models 3406.2.7 Initial and Boundary Conditions of the Column 3436.2.8 Models of Chromatographic Reactors 3446.2.9 Stage Models 3446.2.10 Assessment of Different Model Approaches 3466.2.11 Dimensionless Model Equations 3486.3 Modeling HPLC Plants 3506.3.1 Experimental Setup and Simulation Flow Sheet 3506.3.2 Modeling Extra Column Equipment 3516.3.2.1 Injection System 3516.3.2.2 Piping 3526.3.2.3 Detector 3526.4 Calculation Methods 3536.4.1 Analytical Solutions 3536.4.2 Numerical Solution Methods 3536.4.2.1 General Solution Procedure 3536.4.2.2 Discretization 3546.5 Parameter Determination 3576.5.1 Parameter Classes for Chromatographic Separations 3576.5.1.1 Design Parameters 3576.5.1.2 Operating Parameters 3586.5.1.3 Model Parameters 3586.5.2 Determination of Model Parameters 3596.5.3 Evaluation of Chromatograms 3616.5.3.1 Moment Analysis and HETP Plots 3626.5.3.2 Parameter Estimation 3696.5.3.3 Peak Fitting Functions 3706.5.4 Detector Calibration 3746.5.5 Plant Parameters 3756.5.6 Determination of Packing Parameters 3766.5.6.1 Void Fraction and Porosity of the Packing 3766.5.6.2 Axial Dispersion 3776.5.6.3 Pressure Drop 3786.5.7 Isotherms 3796.5.7.1 Determination of Adsorption Isotherms 3796.5.7.2 Determination of the Henry Coefficient 3826.5.7.3 Static Isotherm Determination Methods 3826.5.7.4 Dynamic Methods 3856.5.7.5 Frontal Analysis 3856.5.7.6 Analysis of Disperse Fronts (ECP/FACP) 3906.5.7.7 Peak MaximumMethod 3916.5.7.8 Minor Disturbance/Perturbation Method 3926.5.7.9 Curve Fitting of the Chromatogram 394

Contents jXI

6.5.7.10 Prediction of Mixture Behavior from Single-Component Data 3956.5.7.11 Data Analysis and Accuracy 3966.5.8 Mass Transfer 3986.5.9 Identification of Isotherms and Mass Transfer Resistance by Neural

Networks 3996.6 Experimental Validation of Column Models 4016.6.1 Batch Chromatography 4016.6.2 SMB Chromatography 4046.6.2.1 Model Formulation and Parameters 4046.6.2.2 Experimental Validation of SMB Models 410

References 418

7 Model-Based Design, Optimization, and Control 425Henner Schmidt-Traub, Malte Kaspereit, Sebastian Engell, Arthur Susanto,Achim Epping, and Andreas Jupke

7.1 Basic Principles and Definitions 4257.1.1 Performance, Costs, and Optimization 4257.1.1.1 Performance Criteria 4267.1.1.2 Economic Criteria 4287.1.1.3 Objective Functions 4297.1.2 Degrees of Freedom 4307.1.2.1 Optimization Parameters 4307.1.2.2 Dimensionless Operating and Design Parameters 4307.1.3 Scaling by Dimensionless Parameters 4357.1.3.1 Influence of Different HETP Coefficients for Every Component 4367.1.3.2 Influence of Feed Concentration 4377.1.3.3 Examples for a Single Batch Chromatographic Column 4387.1.3.4 Examples for SMB Processes 4407.2 Batch Chromatography 4427.2.1 Fractionation Mode (Cut Strategy) 4427.2.2 Design and Optimization of Batch Chromatographic

Columns 4447.2.2.1 Design and Optimization Strategy 4447.2.2.2 Process Performance Depending on Number of Stages

and Loading Factor 4477.2.2.3 Other Strategies 4527.3 Recycling Chromatography 4537.3.1 Design of Steady-State Recycling Chromatography 4547.3.2 Scale-Up of Closed Loop Recycling Chromatography 4577.4 Conventional Isocratic SMB Chromatography 4617.4.1 Optimization of Operating Parameters 4627.4.1.1 Process Design Based on TMB Models (Shortcut Methods) 4637.4.1.2 Process Design Based on Rigorous SMB Models 4717.4.2 Optimization of Design Parameters 476

XIIj Contents

7.5 Isocratic SMB Chromatography under Variable OperatingConditions 481

7.6 Gradient SMB Chromatography 4907.7 Multicolumn Systems for Bioseparations 4957.8 Advanced Process Control 4977.8.1 Online Optimization of Batch Chromatography 4987.8.2 Advanced Control of SMB Chromatography 5017.8.2.1 Purity Control for SMB Processes 5027.8.2.2 Direct Optimizing Control of SMB Processes 5037.8.3 Advanced Parameter and State Estimation for SMB Processes 509

References 510

Appendix A: Data of Test Systems 519

Index 527

Contents jXIII

Preface

Over 7 years have passed since the 1st edition of this book was published, and prac-tical application as well as theoretical research on preparative chromatography hassince then progressed rapidly. This motivated us to revise the content of the 1stedition.We decided to rearrange the structure in this 2nd edition. Our intention was to

present the aspects of practical equipment design and operation together in a sepa-rate chapter, to merge the discussion on stationary phases and the selection of chro-matographic systems in one chapter, and to reduce the content concerningchromatographic reactors because of their specific features and the still limitedpractical relevance. These changes provided room for important new sections onion exchange, bioseparation, and new process concepts and calculation methods.What else is new in this revised second edition? First of all, the team did change

significantly. Besides the additional editors, there are several new authors fromindustry and academia. The former crew from Dortmund University went to indus-tries and is now active in other fields of chemical engineering. Their names as wellas the names of other authors of the first edition are marked by asterisk in thebyline of the corresponding chapters.We are grateful to Klaus Unger, Jules Dingenen, and Reinhard Ditz that they

agreed to join us as senior authors. The most challenging task to tackle is presentedin Chapter 4 that has been efficiently handled by Abdelaziz Toumi, Joel Genolet,Andre Kiesewetter, Martin Krahe, Michele Morelli, Olivier Ludemann-Hombourger, Andreas Stein, and Eric Valery. It is in the nature of practical designand plant operation that the experience and interests are sometimes different.Additionally, the limited volume further constrains the content. But we hope tomeet most of the practical aspects related to design and operation of chromato-graphic plants.In Chapter 3, Matthias J€ohnck and Romas Skudas with the team of Michael

Schulte combined the formerly separated topics on stationary phases and chro-matographic systems to a unique and completely revised chapter and also extendedit to ion exchange. We are especially indebted to Malte Kaspereit for his valuablecontributions to Chapters 5 and 7. Sebastian Engell provided in Chapter 7 an over-view of the latest research results on advanced process control. We hope that thiswill motivate practitioners to have a closer look at these promising methods.

jXV

Finally, we want to acknowledge the assistance of Fabian Thygs, who producedthe new drawings and was patient enough to handle all our revisions.As in the 1st edition, we have summarized the recently published results. In

addition, we have made efforts to address preparative and process chromatographicissues from both the chemist and the process engineer viewpoints in order toimprove the mutual understanding and to transfer knowledge between bothdisciplines.With this book we want to reach colleagues from industries as well as univer-

sities interested in chromatographic separation with preparative purpose. Studentsand other newcomers looking for detailed information about design and operationof preparative chromatography are hopefully other users. Our message to all ofthem is that chromatography is nowadays rather well understood and not that diffi-cult and expensive as it is often said and perceived. On the other hand, it is ofcourse not the solution for all separation problems.We would like to thank all authors for their contributions. We apologize for

sometimes getting on their nerves pressing them to meet time limits. Last but notleast, we thank our families and friends for their patience and cooperation in bring-ing out this book.

August 2012 Henner Schmidt-TraubMichael SchulteAndreas Seidel-Morgenstern

XVIj Preface

About the Editors

Henner Schmidt-Traub was Professor of Plant and Process Design at the Depart-ment of Biochemical and Chemical Engineering, TU Dortmund University,Germany, until his retirement in 2005. He is still active in the research communityand his main areas of research focus on preparative chromatography, downstreamprocessing, integrated processes, and plant design. Prior to his academic appoint-ment, Prof. Schmidt-Traub gained 15 years of industrial experience in plantengineering.Michael Schulte is Senior Director, Emerging Businesses Energy, at Merck KGaA

Performance Materials, Darmstadt, Germany. In his PhD thesis at the University ofM€unster, Germany, he developed new chiral stationary phases for chromatographicenantioseparations. In 1995 he joined Merck and since then he has been responsi-ble for research and development in the area of preparative chromatography,including the development of new stationary phases, new separation processes,and the implementation of Simulated Moving Bed technology at Merck. In his cur-rent position, one of the areas of his research is the use of ionic liquids for separa-tion processes.Andreas Seidel-Morgenstern is Director at the Max Planck Institute for

Dynamics of Complex Technical Systems, Magdeburg, Germany, and holds theChair in Chemical Process Engineering at the Otto-von-Guericke-University, Mag-deburg, Germany. He received his PhD in 1987 at the Institute of Physical Chemis-try of the Academy of Sciences in Berlin. From there he went on to work aspostdoctoral fellow at the University of Tennessee, Knoxville, TN. In 1994 he fin-ished his habilitation at the Technical University in Berlin. His research is focusedon new reactor concepts, chromatographic reactors, membrane reactors, selectivecrystallization, adsorption and preparative chromatography, and separation ofenantiomers among others.

jXVII

List of Contributors

Jules DingenenHorststraat 512370 ArendonkBelgium

Reinhard DitzMerck KGaATechnology Office Chemicals (TO-I)Frankfurter Str. 25064291 DarmstadtGermany

Sebastian EngellTU DortmundFakult€at Bio- undChemieingenieurwesenLehrstuhl für Systemdynamik undProzessführungEmil-Figge-Str. 7044227 DortmundGermany

Joel GenoletMerck Serono S.A.Corsier sur VeveyZone Industrielle B1809 Fenil sur CorsierSwitzerland

Matthias J€ohnckMerck KGaAR&D Performance & Life ScienceChemicalsFrankfurter Str. 25064291 DarmstadtGermany

Malte KaspereitFriedrich-Alexander-Universit€atErlangen-N€urnbergLehrstuhl f€ur ThermischeVerfahrenstechnikEgerlandstr. 391058 ErlangenGermany

Andre KiesewetterMerck KGaAPC-SRG-BioprocessChromatographyFrankfurter Str. 25064293 DarmstadtGermany

Martin KraheBideco AGBankstr. 138610 UsterSwitzerland

jXIX

Olivier Ludemann-HombourgerPolypeptide laboratories France7 rue de Boulogne67100 StrasbourgFrance

Michele MorelliMerck-Millipore SAS39 Route Industrielle de laHardt – Bldg E67120 MolsheimFrance

Henner Schmidt-TraubTU DortmundFakultät für Bio- undChemieingenieurwesenLehrstuhl f€ur Anlagen- undProzesstechnikEmil-Figge-Str. 7044227 DortmundGermany

Michael SchulteMerck KGaAR&D Performance & Life ScienceChemicalsFrankfurter Str. 25064291 DarmstadtGermany

Andreas Seidel-MorgensternOtto-von-Guericke-Universit€atLehrstuhl f€ur ChemischeVerfahrenstechnikUniversit€atsplatz 2

and

Max-Planck-Institut für Dynamikkomplexer technischer SystemeSandtorstraße 139106 MagdeburgGermany

Romas SkudasMerck KGaAR&D Performance & Life ScienceChemicalsFrankfurter Str. 25064291 DarmstadtGermany

Andreas SteinMerck KGaAChromatography Global AppliedTechnologyFrankfurter Str. 25064291 DarmstadtGermany

Abdelaziz ToumiMerck Serono S.A.Corsier sur VeveyZone Industrielle B1809 Fenil sur CorsierSwitzerland

Klaus K. UngerAm alten Berg 4064342 SeeheimGermany

Eric ValeryNovasep ProcessBoulevard de la MoselleBP 5054340 PompeyFrance

XXj List of Contributors

List of Abbreviations

ACD: At-column dilutionAIEX: Anion exchangerARX: Autoregressive exogenousATEX: Explosion proof (French: ATmospheres EXplosibles)BET: Brunauer–Emmet–TellerBJH: Barrett–Joyner–HalendaBR: Chromatographic batch reactorBV: Bed volumeCACR: Continuous annular chromatographic reactorCD: Circular dichroism (detectors)CEC: Capillary electrochromatographyCFD: Computational fluid dynamicscGMP: Current good manufacturing practiceCIEX: Cation exchangerCIP: Cleaning in placeCLP: Column liquid chromatographyCLRC: Closed-loop recycling chromatographyCOGS: Cost of goods soldCPG: Controlled pore glassCSEP1: Chromatographic separationCSF: Circle suspension flowCSP: Chiral stationary phaseCTA: Cellulose triacetateCTB: Cellulose tribenzoateDAC: Dynamic axial compressionDAD: Diode array detectorDMF: Dimethyl formamideDMSO: Dimethyl sulfoxideDTA: Differential thermal analysisDVB: DivinylbenzeneEC: Elution consumptionECP: Elution by characteristic pointsEDM: Equilibrium dispersive model

jXXI

EMG: Exponential modified Gauss (function)FACP: Frontal analysis by characteristic pointsFDM: Finite difference methodsFFT: Forward flow testFT: Flow throughGC: Gas chromatographyGMP: Good manufacturing practiceGRM: General rate modelHCP: Health care providerHETP: Height of an equivalent theoretical plateHFCS: High fructose corn syrupHIC: Hydrophobic interaction chromatographyH-NMR: Hydrogen nuclear magnetic resonance (spectroscopy)HPLC: High-performance liquid chromatographyHPW: Highly purified waterIAST: Ideal adsorbed solution theoryICH: International Guidelines for HarmonizationIEX: Ion exchangeIMAC: Immobilized metal affinity chromatographyIR: InfraredISEC: Inverse size exclusion chromatographyISEP1: Ion exchange separationISMB: Improved/intermittent simulated moving bedLC: Liquid chromatographyLGE: Linear gradient elutionLHS: Liquid-handling stationLOD: Limit of detectionLOQ: Limit of quantificationLPLC: Low-pressure liquid chromatographyLSB: Large Scale Biotech projectMaB: Monoclonal antibodymAbs: monoclonal antibodiesMD: Molecular dynamicsMPC: Model predictive controlMS: Mass spectroscopyMW: Molecular weightNMPC: Nonlinear model predictive controlNMR: Nuclear magnetic resonance (spectroscopy)NN: Neural networkNP: Normal phaseNPLC: Normal-phase liquid chromatographyNSGA: Non-dominating sorting generic algorithmOC: Orthogonal collocationOCFE: Orthogonal collocation on finite elementsODE: Ordinary differential equation

XXIIj List of Abbreviations

PAT: Process analytical technologyPDE: Partial differential equationPDT: Pressure decay testPEEK: Poly(ether ether ketone)PES: Poly(ethoxy)siloxanePLC: Programmable logic controllerPMP: PolymethylpentenePSD: Particle size distributionQC: Quality controlR&D: Research and DevelopmentRI: Refractive indexRMPC: Repetitive model predictive controlRP: Reversed phaseS/N: Signal-to-noise ratioSEC: Size exclusion chromatographySEM: Scanning electron microscopySFC: Supercritical fluid chromatographySIP: Sanitization in placeSIP: Steaming in placeSMB: Simulated moving bedSMBR: Simulated moving bed reactorSOP: Standard operation procedureSQP: Sequential quadratic programmingSSRC: Steady-state recycling chromatographySt-DVB: Styrene-divinylbenzeneTDM: Transport dispersive modelTEM: Transmission electron microscopyTEOS: TetraethoxysilaneTFA: Trifluoroacetic acidTG/DTA: Thermogravimetric/differential thermal analysisTHF: TetrahydrofuranTLC: Thin-layer chromatographyTMB: True moving bed processTMBR: True moving bed reactorTPXTM: Transparent polymethylpenteneUPLC: Ultrahigh-performance liquid chromatographyUSP: United States pharmacopoeiaUV: UltravioletVSP: Volume-specific productivityWFI: Water for injectionWIT: Water intrusion test

List of Abbreviations jXXIII

Notation

Symbols

Symbol Description Units

ai Coefficient of the Langmuir isotherm cm3 g�1

as Specific surface area cm2 g�1

A Area cm2

Ac Cross section of the column cm2

Ai Coefficient in the Van Deemter equation cmAs Surface area of the adsorbent cm

2

ASP Cross section-specific productivity g cm�2 s�1

bi Coefficient of the Langmuir isotherm cm3 g�1

B Column permeability m2

Bi Coefficient in the Van Deemter equation cm2 s�1

ci Concentration in the mobile phase g cm�3

cp,i Concentration of the solute inside the particlepores

g cm�3

C Annual costs DCi Coefficient in the Van Deemter equation sCDL,i Dimensionless concentration in the liquid phase —Cp,DL,i Dimensionless concentration of the solute inside

the particle pores—

Cspec Specific costs D g�1

dc Diameter of the column cmdp Average diameter of the particle cmdpore Average diameter of the pores cmDan Angular dispersion coefficient cm

2 s�1

Dapp,i Apparent dispersion coefficient cm2 s�1

Dapp,pore Apparent dispersion coefficient inside the pores cm2 s�1

jXXV

Symbol Description Units

Dax Axial dispersion coefficient cm2 s�1

Dm Molecular diffusion coefficient cm2 s�1

Dpore,i Diffusion coefficient inside the pores cm2 s�1

Dsolid,i Diffusion coefficient on the particle surface cm2 s�1

Da Damkoehler number —EC Eluent consumption cm3 g�1

F Prices D l�1, D g�1

fi Fugacity —h Reduced plate height —hRf Retardation factor —Dhvap Heat of vaporization kJ mol

�1

Hi Henry coefficient —Hp Prediction horizon —Hr Control horizon —HETP Height of an equivalent theoretical plate cmkads,i Adsorption rate constant cm

3 g�1 s�1

kdes,i Desorption rate constant cm3 g�1 s�1

keff,i Effective mass transfer coefficient cm2 s�1

Keq Equilibrium constant MiscellaneousKEQ Dimensionless equilibrium coefficient —kfilm,i Boundary or film mass transfer coefficient cm s

�1

k0i Retention factor —~k0i Modified retention factor —k0 Pressure drop coefficient —kreac Rate constant MiscellaneousLF Loading factor —Lc Length of the column cm_mi Mass flow g s

�1

mi Mass gmj Dimensionless mass flow rate in section j —ms Total mass gni Molar cross section of component i —nT Pore connectivity —N Column efficiency, number of plates —Ncol Number of columns —Ncomp Number of components —Np Number of particles per volume element —Dp Pressure drop PaPe P�eclet number —Pri Productivity g cm

3 h�1

Ps Selectivity point —Pui Purity %

XXVIj Notation

Symbol Description Units

qi Solid load g cm�3

qi� Total load g cm�3

�q�i Averaged particle load g cm�3

qsat,i Saturation capacity of the stationary phase g cm�3

QDL,i Dimensionless concentration in the stationaryphase

—

r Radial coordinate cmri Reaction rate Miscellaneousrp Particle radius cmRf Retardation factor —Ri Regulation term —Rs Resolution —Re Reynolds number —SBET Specific surface area m

2 g�1

Sc Schmidt number —Sh Sherwood number —St Stanton number —t Time st0 Dead time of the column (for total liquid holdup) st0,int Dead time of the column (for interstitial liquid

holdup)s

tcycle Cycle time stg Gradient time stinj Injection time stlife Lifetime of adsorbent htplant Dead time of the plant without column stR,i Retention time stR,i,net Net retention time stshift Switching time of the SMB plant sttotal Total dead time sT Temperature KT Degree of peak asymmetry —u0 Velocity in the empty column cm s

�1

uint Interstitial velocity in the packed column cm s�1

um Effective velocity (total mobile phase) cm s�1

vsp Specific pore volume cm3 g�1

V Volume cm3

_V Volume flow cm3 s�1

Vads Volume of the stationary phase within a column cm3

Vc Total volume of a packed column cm3

Vi Molar volume cm3 mol�1

Vint Interstitial volume cm3

Vm Overall fluid volume cm3

Symbols jXXVII

Symbol Description Units

Vpore Volume of the pore system cm3

Vsolid Volume of the solid material cm3

VSP Volume-specific productivity g cm3 s�1

wi Velocity of propagation cm s�1

x Coordinate cmxi State of the plant —Xi Mole fraction —X Conversion %Xcat Fraction of catalyst of the fixed bed —Yi Yield %Z Dimensionless distance —

Greek Symbols

Symbol Description Units

a Selectivity —aexp Ligand density mmol m

�2

b Modified dimensionless mass flow rate —c Obstruction factor for diffusion or external tortuosity —C Objective function —e Void fraction —e0 Solvent strength parameter —ep Porosity of the solid phase —et Total column porosity —g Dynamic viscosity mPa sH Angle of rotation �

L Total ion exchange capacity mMl Irregularity in the packing —mi Chemical potential J mol

�1

mt First absolute moment —n Kinematic viscosity cm2 sni Stoichiometric coefficient —p Spreading pressure Par Density g cm�3

st Standard deviation —si Steric shielding parameter —t Dimensionless time —

XXVIIIj Notation