Preparative Chromatography, Second Edition

Preface XV
About the Editors XVII
1 Introduction 1
Henner Schmidt-Traub and Reinhard Ditz
1.1 Development of Chromatography 1
1.2 Focus of the Book 3
1.3 Recommendation to Read this Book 4
References 6
2 Fundamentals and General Terminology 7
Andreas Seidel-Morgenstern, Michael Schulte, and Achim Epping
2.1 Principles of Adsorption Chromatography 7
2.1.1 Adsorption Process 9
2.1.2 Chromatographic Process 10
2.2 Basic Effects and Chromatographic Definitions 11
2.2.1 Chromatograms and Parameters 11
2.2.2 Voidage and Porosity 12
2.2.3 Influence of Adsorption Isotherms on Chromatogram Shapes 15
2.3 Fluid Dynamics 18
2.3.1 Extra Column Effects 18
2.3.2 Column Fluid Distribution 19
2.3.3 Packing Nonidealities 19
2.3.4 Sources for Nonideal Fluid Distribution 20
2.3.5 Column Pressure Drop 21
2.4 Mass Transfer Phenomena 22
2.4.1 Principles of Mass Transfer 22
2.4.2 Efficiency of Chromatographic Separations 24
2.4.3 Resolution 27
2.5 Equilibrium Thermodynamics 30
List of Contributors
List of Abbreviations XXI Notations XXV
XIX
jVVIj Contents
2.5.1 Definition of Isotherms 30
2.5.2 Models of Isotherms 32
2.5.2.1 Single-Component Isotherms 32
2.5.2.2 Multicomponent Isotherms Based on the Langmuir Model 34
2.5.2.3 Competitive Isotherms Based on the Ideal Adsorbed Solution
Theory 35
2.5.2.4 Steric Mass Action Isotherms for Ion Exchange Equilibria 38
2.6 Thermodynamic Effects on Mass Separation 40
2.6.1 Mass Load 40
2.6.2 Linear and Nonlinear Isotherms 41
2.6.3 Elution Modes 43
References 45
3 Stationary Phases and Chromatographic Systems 47
Michael 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 47
3.1.1 Survey of Packings and Stationary Phases 47
3.1.2 Generic, Designed, and Customized Adsorbents 48
3.1.2.1 Generic Adsorbents 48
3.1.2.2 Designed Adsorbents 54
3.1.2.3 Customized Adsorbents 62
3.1.3 Reversed Phase Silicas 66
3.1.3.1 Silanisation of the Silica Surface 67
3.1.3.2 Chromatographic Characterization of Reversed Phase Silicas 69
3.1.4 Cross-Linked Organic Polymers 72
3.1.4.1 General Aspects 73
3.1.4.2 Hydrophobic Polymer Stationary Phases 76
3.1.4.3 Hydrophilic Polymer Stationary Phases 76
3.1.4.4 Ion Exchange (IEX) 77
3.1.4.5 Mixed Mode 85
3.1.5 Chiral Stationary Phases 85
3.1.5.1 Antibiotic CSP 91
3.1.5.2 Synthetic Polymers 91
3.1.5.3 Targeted Selector Design 92
3.1.5.4 Further Developments 93
3.1.6 Properties of Packings and their Relevance to Chromatographic
Performance 95
3.1.6.1 Chemical and Physical Bulk Properties 95
3.1.6.2 Mass Loadability 101
3.1.6.3 Comparative Rating of Columns 102
3.1.7 Sorbent Maintenance and Regeneration 103
3.1.7.1 Cleaning in Place (CIP) 103
3.1.7.2 Conditioning of Silica Surfaces 106
Contents jVII
3.1.7.3 Sanitization in Place (SIP) 108
3.1.7.4 Column and Adsorbent Storage 108
3.2 Selection of Chromatographic Systems 109
3.2.1 Definition of the Task 114
3.2.2 Mobile Phases for Liquid Chromatography 118
3.2.2.1 Stability 118
3.2.2.2 Safety Concerns 118
3.2.2.3 Operating Conditions 121
3.2.2.4 Aqueous Buffer Systems 123
3.2.3 Adsorbent and Phase Systems 125
3.2.3.1 Choice of Phase System Dependent on Solubility 127
3.2.3.2 Improving Loadability for Poor Solubilities 128
3.2.3.3 Dependency of Solubility on Sample Purity 130
3.2.3.4 Generic Gradients for Fast Separations 131
3.2.4 Criteria for Choosing NP Systems 132
3.2.4.1 Pilot Technique Thin-layer Chromatography 134
3.2.4.2 Retention in NP Systems 134
3.2.4.3 Solvent Strength in Liquid–Solid Chromatography 136
3.2.4.4 Selectivity in NP Systems 138
3.2.4.5 Mobile-Phase Optimization by TLC Following the PRISMA Model 139
3.2.4.6 Strategy for an Industrial Preparative Chromatography Laboratory 148
3.2.5 Criteria for Choosing RP Systems 153
3.2.5.1 Retention and Selectivity in RP Systems 155
3.2.5.2 Gradient Elution for Small amounts of Product on RP Columns 156
3.2.5.3 Rigorous Optimization for Isocratic Runs 157
3.2.5.4 Rigorous Optimization for Gradient Runs 161
3.2.5.5 Practical Recommendations 164
3.2.6 Criteria for Choosing CSP Systems 167
3.2.6.1 Suitability of Preparative CSP 168
3.2.6.2 Development of Enantioselectivity 169
3.2.6.3 Optimization of Separation Conditions 171
3.2.6.4 Practical Recommendations 172
3.2.7 Downstream Processing of Mabs using Protein A and IEX 174
3.2.8 Size Exclusion (SEC) 179
3.2.9 Overall Chromatographic System Optimization 181
3.2.9.1 Conflicts During Optimization of Chromatographic Systems 181
3.2.9.2 Stationary Phase Gradients 184
References 189
4 Chromatography Equipment: Engineering and Operation 199 Abdelaziz Toumi, Jules Dingenen, Joel Genolet, Olivier Ludemann-Hombourger, Andre Kiesewetter, Martin Krahe,
Michele Morelli, Henner Schmidt-Traub, Andreas Stein, and Eric Valery
4.1 Introduction 199
4.2 Engineering and Operational Challenges 201
VIIIj Contents
4.3 Chromatography Columns Market 207
4.3.1 Generalities – The Suppliers 207
4.3.2 General Design 208
4.3.3 High- and Low-Pressure Columns 210
4.3.3.1 Chemical Compatibility 211
4.3.3.2 Frits Design 211
4.3.3.3 Special Aspects of Bioseparation 215
4.4 Chromatography Systems Market 217
4.4.1 Generalities – The Suppliers 217
4.4.2 General Design Aspects – High Performance and Low-Pressure
Systems 217
4.4.3 Material 219
4.4.4 Batch Low-Pressure Liquid Chromatography (LPLC) Systems 220
4.4.4.1 Inlets 220
4.4.4.2 Valves to Control Flow Direction 220
4.4.4.3 Pumps 221
4.4.4.4 Pump(s) Valves and Gradient Formation 222
4.4.5 Batch High-Pressure Liquid Chromatography (HPLC) Systems 224
4.4.5.1 General Layout 224
4.4.5.2 Inlets and Outlets 224
4.4.5.3 Pumps 226
4.4.5.4 Valves and Pipes 227
4.4.6 Batch SFC Systems 228
4.4.6.1 General Layout 228
4.4.6.2 Inlets 230
4.4.6.3 Pumps, Valves, and Pipes 231
4.4.7 Continuous Systems – Simulated Moving Bed 231
4.4.7.1 General Layout 231
4.4.7.2 A Key Choice: The Recycling Strategy 232
4.4.7.3 Pumps, Inlets, and Outlets 233
4.4.7.4 Valves and Piping 233
4.4.8 Auxiliary Systems 233
4.4.8.1 Slurry Preparation Tank 234
4.4.8.2 Slurry Pumps and Packing Stations 234
4.4.8.3 Cranes and Transport Units 235
4.4.8.4 Filter Integrity Test 235
4.5 Process Control 236
4.5.1 Standard Process Control 236
4.5.2 Advanced Process Control 237
4.5.3 Detectors 240
4.6 Packing Methods 243
4.6.1 Column and Packing Methodology Selection 243
4.6.2 Slurry Preparation 244
4.6.3 Column Preparation 246
4.6.4 Flow Packing 246
4.6.5 Dynamic Axial Compression (DAC) Packing 249
4.6.6 Stall Packing 250
4.6.7 Combined Method (Stall þ DAC) 250
4.6.8 Vacuum Packing 252
4.6.9 Vibration Packing 253
4.6.10 Column Equilibration 254
4.6.11 Column Testing and Storage 254
4.6.11.1 Test Systems 254
4.6.11.2 Hydrodynamic Properties and Column Efficiency 256
4.6.11.3 Column and Adsorbent Storage 257
4.7 Process Troubleshooting 257
4.7.1 Technical Failures 258
4.7.2 Loss of Performance 259
4.7.2.1 Pressure Increase 259
4.7.2.2 Loss of Column Efficiency 262
4.7.2.3 Variation of Elution Profile 263
4.7.2.4 Loss of Purity/Yield 264
4.7.3 Column Stability 265
4.8 Disposable Technology for Bioseparations 265
4.8.1 Market Trend 265
4.8.2 Prepacked Columns 266
4.8.3 Membrane Chromatography 267
4.8.4 Membrane Technology 269
References 270
5 Process Concepts 273
Malte Kaspereit, Michael Schulte, Klaus Wekenborg, and Wolfgang Wewers
5.1 Discontinuous Processes 273
5.1.1 Isocratic Operation 273
5.1.2 Flip-Flop Chromatography 275
5.1.3 Closed-Loop Recycling Chromatography 276
5.1.4 Steady-State Recycling Chromatography 278
5.1.5 Gradient Chromatography 279
5.1.6 Chromatographic Batch Reactors 281
5.2 Continuous Processes 283
5.2.1 Column Switching Chromatography 283
5.2.2 Annular Chromatography 283
5.2.3 Multiport Switching Valve Chromatography (ISEP/CSEP) 284
5.2.4 Isocratic Simulated Moving Bed (SMB) Chromatography 286
5.2.5 SMB Chromatography with Variable Process Conditions 290
5.2.5.1 VariCol 290
5.2.5.2 PowerFeed 291
5.2.5.3 Partial-Feed, Partial-Discard, and Fractionation-Feedback
Concepts 292
5.2.5.4 Improved/Intermittent SMB (iSMB) 293
Contents jIX
Xj Contents
5.2.5.5 ModiCon 294
5.2.5.6 FF-SMB 294
5.2.6 SMB Chromatography with Variable Solvent Conditions 294
5.2.6.1 Gradient SMB Chromatography 295
5.2.6.2 Supercritical Fluid SMB Chromatography 296
5.2.7 Multicomponent Separations 296
5.2.8 Multicolumn Systems for Bioseparations 298
5.2.8.1 Sequential Multicolumn Chromatography (SMCC) 298
5.2.8.2 Multicolumn Countercurrent Solvent Gradient Purification
(MCSGP) 299
5.2.9 Countercurrent Chromatographic Reactors 301
5.2.9.1 SMB Reactor 301
5.2.9.2 Processes with Distributed Functionalities 302
5.3 Choice of Process Concepts 304
5.3.1 Scale 305
5.3.2 Range of k0 306
5.3.3 Number of Fractions 306
5.3.4 Example 1: Lab Scale; Two Fractions 306
5.3.5 Example 2: Lab Scale; Three or More Fractions 308
5.3.6 Example 3: Production Scale – Wide Range of k0
5.3.7 Example 4: Production Scale; Two Main Fractions
5.3.8 Example 5: Production Scale; Three Fractions 311
5.3.9 Example 6: Production Scale; Multi-Stage Process 312
References 315
6 Modeling and Model Parameters 321
Andreas Seidel-Morgenstern, Henner Schmidt-Traub, Mirko Michel, Achim Epping, and Andreas Jupke
6.1 Introduction 321
6.2 Models for Single Chromatographic Columns 322
6.2.1 Classes of Chromatographic Models 322
6.2.2 Derivation of the Mass Balance Equations 324
6.2.2.1 Mass Balance Equations 325
6.2.2.2 Convective Transport 327
6.2.2.3 Axial Dispersion 327
6.2.2.4 Intraparticle Diffusion 327
6.2.2.5 Mass Transfer 328
6.2.2.6 Adsorption Kinetics 329
6.2.2.7 Adsorption Equilibrium 329
6.2.3 Equilibrium (“Ideal”) Model 330
6.2.4 Models with One Band Broadening Effect 334
6.2.4.1 Dispersive Model 334
6.2.4.2 Transport Model 336
6.2.4.3 Reaction Model 337
6.2.5 Lumped Rate Models 338
309 310
6.2.5.1 Transport-Dispersive Model 338
6.2.5.2 Reaction-Dispersive Model 339
6.2.6 General Rate Models 340
6.2.7 Initial and Boundary Conditions of the Column 343
6.2.8 Models of Chromatographic Reactors 344
6.2.9 Stage Models 344
6.2.10 Assessment of Different Model Approaches 346
6.2.11 Dimensionless Model Equations 348
6.3 Modeling HPLC Plants 350
6.3.1 Experimental Setup and Simulation Flow Sheet 350
6.3.2 Modeling Extra Column Equipment 351
6.3.2.1 Injection System 351
6.3.2.2 Piping 352
6.3.2.3 Detector 352
6.4 Calculation Methods 353
6.4.1 Analytical Solutions 353
6.4.2 Numerical Solution Methods 353
353
6.4.2.1 General Solution Procedure
6.4.2.2 Discretization 354
6.5 Parameter Determination 357
6.5.1 Parameter Classes for Chromatographic Separations 357
6.5.1.1 Design Parameters 357
6.5.1.2 Operating Parameters 358
6.5.1.3 Model Parameters 358
6.5.2 Determination of Model Parameters 359
6.5.3 Evaluation of Chromatograms 361
6.5.3.1 Moment Analysis and HETP Plots 362
6.5.3.2 Parameter Estimation 369
6.5.3.3 Peak Fitting Functions 370
6.5.4 Detector Calibration 374
6.5.5 Plant Parameters 375
6.5.6 Determination of Packing Parameters 376
6.5.6.1 Void Fraction and Porosity of the Packing 376
6.5.6.2 Axial Dispersion 377
6.5.6.3 Pressure Drop 378
6.5.7 Isotherms 379
6.5.7.1 Determination of Adsorption Isotherms 379
6.5.7.2 Determination of the Henry Coefficient 382
6.5.7.3 Static Isotherm Determination Methods 382
6.5.7.4 Dynamic Methods 385
6.5.7.5 Frontal Analysis 385
6.5.7.6 Analysis of Disperse Fronts (ECP/FACP) 390
6.5.7.7 Peak Maximum Method 391
6.5.7.8 Minor Disturbance/Perturbation Method 392
6.5.7.9 Curve Fitting of the Chromatogram 394
Contents jXI
XIIj Contents
6.5.7.10 Prediction of Mixture Behavior from Single-Component Data 395
6.5.7.11 Data Analysis and Accuracy 396
6.5.8 Mass Transfer 398
6.5.9 Identification of Isotherms and Mass Transfer Resistance by Neural
Networks 399
6.6 Experimental Validation of Column Models 401
6.6.1 Batch Chromatography 401
6.6.2 SMB Chromatography 404
6.6.2.1 Model Formulation and Parameters 404
6.6.2.2 Experimental Validation of SMB Models 410
References 418
7 Model-Based Design, Optimization, and Control 425
Henner Schmidt-Traub, Malte Kaspereit, Sebastian Engell, Arthur Susanto, Achim Epping, and Andreas Jupke
7.1 Basic Principles and Definitions 425
7.1.1 Performance, Costs, and Optimization 425
7.1.1.1 Performance Criteria 426
7.1.1.2 Economic Criteria 428
7.1.1.3 Objective Functions 429
7.1.2 Degrees of Freedom 430
7.1.2.1 Optimization Parameters 430
7.1.2.2 Dimensionless Operating and Design Parameters 430
7.1.3 Scaling by Dimensionless Parameters 435
7.1.3.1 Influence of Different HETP Coefficients for Every Component 436
7.1.3.2 Influence of Feed Concentration 437
7.1.3.3 Examples for a Single Batch Chromatographic Column 438
7.1.3.4 Examples for SMB Processes 440
7.2 Batch Chromatography 442
7.2.1 Fractionation Mode (Cut Strategy) 442
7.2.2 Design and Optimization of Batch Chromatographic
Columns 444
7.2.2.1 Design and Optimization Strategy 444
7.2.2.2 Process Performance Depending on Number of Stages
and Loading Factor 447
7.2.2.3 Other Strategies 452
7.3 Recycling Chromatography 453
7.3.1 Design of Steady-State Recycling Chromatography 454
7.3.2 Scale-Up of Closed Loop Recycling Chromatography 457
7.4 Conventional Isocratic SMB Chromatography 461 7.4.1 Optimization of Operating Parameters 462
7.4.1.1 Process Design Based on TMB Models (Shortcut Methods) 463
7.4.1.2 Process Design Based on Rigorous SMB Models 471
7.4.2 Optimization of Design Parameters 476
7.5 Isocratic SMB Chromatography under Variable Operating Conditions 481
7.6 Gradient SMB Chromatography 490
7.7 Multicolumn Systems for Bioseparations 495
7.8 Advanced Process Control 497
7.8.1 Online Optimization of Batch Chromatography 498
7.8.2 Advanced Control of SMB Chromatography 501
7.8.2.1 Purity Control for SMB Processes 502
7.8.2.2 Direct Optimizing Control of SMB Processes 503
7.8.3 Advanced Parameter and State Estimation for SMB Processes 509
References 510
Appendix A: Data of Test Systems 519 Index 527