Professor Schmidt-Traub was Professor for Plant and Process Design at the Department of Biochemical and Chemical Engineering, University of Dortmund, Germany until his retirement in 2006. He is still active in the research community and his main areas of research focus on preparative chromatography, down stream processing, integrated processes, plant design and innovative energy transfer. Prior to his academic appointment, Prof. Schmidt-Traub gained 15 years of industrial experience in plant engineering.

Prof. Seidel-Morgenstern is the Director of the Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany and holds the Chair in Chemical Process Engineering at the Otto-von-Guericke-Universität, Magdeburg, Germany. He received his Ph.D. in 1987 at the Institute of Physical Chemistry of the Academy of Sciences in Berlin. From there he went on to work as postdoctoral fellow at the University of Tennessee, Knoxville, USA. In 1994 he finished his habilitation at the Technical University in Berlin. His research is focused on new reactor concepts, chromatographic reactors, membrane reactors, adsorption and preparative chromatography and separation of enantiomers amongst others.

Dr. Michael Schulte is Senior Director Emerging Businesses Energy at Merck KGaA Performance Materials, Darmstadt, Germany. In his Ph.D. thesis at the University of Münster, Germany, he developed new chiral stationary phases for chromatographic enantioseparations. In 1995 he joined Merck and has since then been responsible 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 current position one of his areas of research is the use of Ionic Liquids for separation processes.

Preface xv About the Editors xvii List of Abbreviations xix Notation xxiii 1 Introduction 1Henner Schmidt-Traub and Reinhard Ditz 1.1 Chromatography, Development, and Future Trends 1 1.2 Focus of the Book 4 1.3 Suggestions on How to Read this Book 4 References 6 2 Fundamentals and General Terminology 9Andreas Seidel-Morgenstern 2.1 Principles and Features of Chromatography 9 2.2 Analysis and Description of Chromatograms 13 2.2.1 Voidage and Porosity 13 2.2.2 Retention Times and Capacity Factors 16 2.2.3 Efficiency of Chromatographic Separations 17 2.2.4 Resolution 20 2.2.5 Pressure Drop 23 2.3 Mass Transfer and Fluid Dynamics 25 2.3.1 Principles of Mass Transfer 25 2.3.2 Fluid Distribution in the Column 27 2.3.3 Packing Nonidealities 28 2.3.4 Extra-Column Effects 29 2.4 Equilibrium Thermodynamics 29 2.4.1 Definition of Isotherms 29 2.4.2 Models of Isotherms 31 2.4.2.1 Single-Component Isotherms 31 2.4.2.2 Multicomponent Isotherms Based on the Langmuir Model 33 2.4.2.3 Competitive Isotherms Based on the Ideal Adsorbed Solution Theory 34 2.4.2.4 Steric Mass Action Isotherms 37 2.4.3 Relation Between Isotherms and Band Shapes 38 2.5 Column Overloading and Operating Modes 44 2.5.1 Overloading Strategies 44 2.5.2 Beyond Isocratic Batch Elution 45 References 46 3 Stationary Phases 49Michael Schulte 3.1 Survey of Packings and Stationary Phases 49 3.2 Inorganic Sorbents 50 3.2.1 Activated Carbons 50 3.2.2 Synthetic Zeolites 54 3.2.3 Porous Oxides: Silica, Activated Alumina, Titania, Zirconia, and Magnesia 54 3.2.4 Silica 55 3.2.4.1 Surface Chemistry 57 3.2.4.2 Mass Loadability 59 3.2.5 Diatomaceous Earth 59 3.2.6 Reversed Phase Silicas 60 3.2.6.1 Silanization of the Silica Surface 60 3.2.6.2 Silanization 60 3.2.6.3 Starting Silanes 61 3.2.6.4 Parent Porous Silica 61 3.2.6.5 Reaction and Reaction Conditions 62 3.2.6.6 Endcapping 62 3.2.6.7 Chromatographic Characterization of Reversed Phase Silicas 63 3.2.6.8 Chromatographic Performance 63 3.2.6.9 Hydrophobic Properties Retention Factor (Amount of Organic Solvent for Elution), Selectivity 65 3.2.6.10 Shape Selectivity 65 3.2.6.11 Silanol Activity 67 3.2.6.12 Purity 68 3.2.6.13 Improved pH Stability Silica 68 3.2.7 Aluminum Oxide 69 3.2.8 Titanium Dioxide 70 3.2.9 Other Oxides 71 3.2.9.1 Magnesium Oxide 71 3.2.9.2 Zirconium Dioxide 71 3.2.10 Porous Glasses 72 3.3 Cross-Linked Organic Polymers 73 3.3.1 General Aspects 74 3.3.2 Hydrophobic Polymer Stationary Phases 77 3.3.3 Hydrophilic Polymer Stationary Phases 78 3.3.4 Ion Exchange (IEX) 79 3.3.4.1 Optimization of Ion-Exchange Resins 81 3.3.5 Mixed Mode 88 3.3.6 Hydroxyapatite 88 3.3.7 Designed Adsorbents 91 3.3.7.1 Protein A Affinity Sorbents 91 3.3.7.2 Other IgG Receptor Proteins: Protein G and Protein L 96 3.3.7.3 Sorbents for Derivatized/Tagged Compounds: Immobilized Metal Affinity Chromatography (IMAC) 96 3.3.7.4 Other Tag-Based Affinity Sorbents 101 3.3.8 Customized Adsorbents 102 3.3.8.1 Low Molecular Weight Ligands 105 3.3.8.2 Natural Polymers (Proteins, Polynucleotides) 108 3.3.8.3 Artificial Polymers 111 3.4 Advective Chromatographic Materials 111 3.4.1 Adsorptive Membranes and Grafted-Polymer Membranes 114 3.4.2 Adsorptive Nonwovens 115 3.4.3 Fiber/Particle Composites 117 3.4.4 Area-Enhanced Fibers 117 3.4.5 Monolith 118 3.4.6 Chromatographic Materials for Larger Molecules 121 3.5 Chiral Stationary Phases 121 3.5.1 Cellulose- and Amylose-Based CSP 122 3.5.2 Antibiotic CSP 128 3.5.3 Cyclofructan-Based CSP 128 3.5.4 Synthetic Polymers 128 3.5.5 Targeted Selector Design 130 3.5.6 Further Developments 132 3.6 Properties of Packings and Their Relevance to Chromatographic Performance 132 3.6.1 Chemical and Physical Bulk Properties 132 3.6.2 Morphology 133 3.6.3 Particulate Adsorbents: Particle Size and Size Distribution 133 3.6.4 Pore Texture 134 3.6.5 Pore Structural Parameters 137 3.6.6 Comparative Rating of Columns 137 3.7 Sorbent Maintenance and Regeneration 138 3.7.1 Cleaning in Place (CIP) 138 3.7.2 CIP for IEX 140 3.7.3 CIP of Protein A Sorbents 140 3.7.4 Conditioning of Silica Surfaces 143 3.7.5 Sanitization in Place (SIP) 145 3.7.6 Column and Adsorbent Storage 145 References 146 4 Selection of Chromatographic Systems 159Michael Schulte 4.1 Definition of the Task 164 4.2 Mobile Phases for Liquid Chromatography 167 4.2.1 Stability 168 4.2.2 Safety Concerns 172 4.2.3 Operating Conditions 172 4.2.4 Aqueous Buffer Systems 176 4.3 Adsorbent and Phase Systems 178 4.3.1 Choice of Phase System Dependent on Solubility 178 4.3.2 Improving Loadability for Poor Solubilities 180 4.3.3 Dependency of Solubility on Sample Purity 183 4.3.4 Generic Gradients for Fast Separations 184 4.4 Criteria for Choosing Normal Phase Systems 184 4.4.1 Retention in NP Systems 186 4.4.2 Solvent Strength in Liquid-Solid Chromatography 188 4.4.3 Pilot Technique Thin-Layer Chromatography Using the PRISMA Model 190 4.4.3.1 Step (1): Solvent Strength Adjustment 199 4.4.3.2 Step (2): Optimization of Selectivity 199 4.4.3.3 Step (3): Final Optimization of the Solvent Strength 200 4.4.3.4 Step (4): Determination of the Optimum Mobile Phase Composition 200 4.4.4 Strategy for an Industrial Preparative Chromatography Laboratory 202 4.4.4.1 Standard Gradient Elution Method on Silica 203 4.4.4.2 Simplified Procedure 204 4.5 Criteria for Choosing Reversed Phase Systems 206 4.5.1 Retention and Selectivity in RP Systems 208 4.5.2 Gradient Elution for Small Amounts of Product on RP Columns 212 4.5.3 Rigorous Optimization for Isocratic Runs 213 4.5.4 Rigorous Optimization for Gradient Runs 217 4.5.5 Practical Recommendations 222 4.6 Criteria for Choosing CSP Systems 223 4.6.1 Suitability of Preparative CSP 223 4.6.2 Development of Enantioselectivity 224 4.6.3 Optimization of Separation Conditions 226 4.6.3.1 Determination of Racemate Solubility 226 4.6.3.2 Selection of Elution Order 226 4.6.3.3 Optimization of Mobile/Stationary Phase Composition, Including Temperature 226 4.6.3.4 Determination of Optimum Separation Step 227 4.6.4 Practical Recommendations 227 4.7 Downstream Processing of mAbs Using Protein A and IEX 231 4.8 Size-Exclusion Chromatography (SEC) 236 4.9 Overall Chromatographic System Optimization 237 4.9.1 Conflicts During Optimization of Chromatographic Systems 237 4.9.2 Stationary Phase Gradients 241 References 246 5 Process Concepts 251Malte Kaspereit and Henner Schmidt-Traub 5.1 Discontinuous Processes 252 5.1.1 Isocratic Operation 252 5.1.2 Gradient Chromatography 253 5.1.3 Closed-Loop Recycling Chromatography 256 5.1.4 Steady-State Recycling Chromatography (SSRC) 258 5.1.5 Flip-Flop Chromatography 259 5.1.6 Chromatographic Batch Reactors 260 5.2 Continuous Processes 261 5.2.1 Column Switching Chromatography 262 5.2.2 Annular Chromatography 262 5.2.3 Multiport Switching Valve Chromatography (ISEP/CSEP) 263 5.2.4 Isocratic Simulated Moving Bed (SMB) Chromatography 264 5.2.5 SMB Chromatography with Variable Process Conditions 268 5.2.5.1 Varicol 269 5.2.5.2 PowerFeed 270 5.2.5.3 Partial-Feed, Partial-Discard, and Fractionation-Feedback Concepts 271 5.2.5.4 Improved/Intermittent SMB (iSMB) 271 5.2.5.5 Modicon 273 5.2.5.6 FF-SMB 273 5.2.6 Gradient SMB Chromatography 274 5.2.7 Supercritical Fluid Chromatography (SFC) 275 5.2.7.1 Supercritical Batch Chromatography 276 5.2.7.2 Supercritical SMB processes 277 5.2.8 Multicomponent Separations 277 5.2.9 Multicolumn Systems for Bioseparations 278 5.2.9.1 Multicolumn Capture Chromatography (MCC) 279 5.2.9.2 Multicolumn Countercurrent Solvent Gradient Purification (MCSGP) 286 5.2.10 Countercurrent Chromatographic Reactors 288 5.2.10.1 SMB Reactor 288 5.2.10.2 SMB Reactors with Distributed Functionalities 290 5.3 Choice of Process Concepts 292 5.3.1 Scale 292 5.3.2 Range of k' 292 5.3.3 Number of Fractions 293 5.3.4 Example 1: Lab Scale; Two Fractions 293 5.3.5 Example 2: Lab Scale; Three or More Fractions 294 5.3.6 Example 3: Production Scale; Wide Range of k' 296 5.3.7 Example 4: Production Scale; Two Main Fractions 297 5.3.8 Example 5: Production Scale; Three Fractions 298 5.3.9 Example 6: Production Scale; Multistage Process 300 References 302 6 Modeling of Chromatographic Processes 311Andreas Seidel-Morgenstern 6.1 Introduction 311 6.2 Models for Single Chromatographic Columns 311 6.2.1 Equilibrium Stage Models 312 6.2.1.1 Discontinuous Model According to Craig 313 6.2.1.2 Continuous Model According to Martin and Synge 315 6.2.2 Derivation of Continuous Mass Balance Equations 316 6.2.2.1 Mass Balance Equations 318 6.2.2.2 Convective Transport 320 6.2.2.3 Axial Dispersion 320 6.2.2.4 Intraparticle Diffusion 321 6.2.2.5 Mass Transfer Between Phases 321 6.2.2.6 Finite Rates of Adsorption and Desorption 322 6.2.2.7 Adsorption Equilibria 323 6.2.3 Equilibrium Model of Chromatography 323 6.2.4 Models with One Band Broadening Effect 329 6.2.4.1 Equilibrium Dispersion Model 329 6.2.4.2 Finite Adsorption Rate Model 331 6.2.5 Continuous Lumped Rate Models 331 6.2.5.1 Transport Dispersion Models 332 6.2.5.2 Lumped Finite Adsorption Rate Model 333 6.2.6 General Rate Models 333 6.2.7 Initial and Boundary Conditions of the Column 335 6.2.8 Dimensionless Model Equations 336 6.2.9 Comparison of Different Model Approaches 338 6.3 Including Effects Outside the Columns 343 6.3.1 Experimental Setup and Simulation Flow Sheet 343 6.3.2 Modeling Extra-Column Equipment 345 6.3.2.1 Injection System 345 6.3.2.2 Piping 345 6.3.2.3 Detector 345 6.4 Calculation Methods and Software 346 6.4.1 Analytical Solutions 346 6.4.2 Numerical Solution Methods 346 6.4.2.1 Discretization 346 6.4.2.2 General Solution Procedure and Software 349 References 350 7 Determination of Model Parameters 355Andreas Seidel-Morgenstern, Andreas Jupke, and Henner Schmidt-Traub 7.1 Parameter Classes for Chromatographic Separations 355 7.1.1 Design Parameters 355 7.1.2 Operating Parameters 356 7.1.3 Model Parameters 356 7.2 Concept to Determine Model Parameters 357 7.3 Detectors and Parameter Estimation 359 7.3.1 Calibration of Detectors 359 7.3.2...