生物分离过程科学PDF电子书下载

1.Introduction 1

1.1 Mass Conservation as an Accounting Method 1

1.2 Interpreting Differentials and Integrals:World Population Statistics 3

1.3 Accounting for Diffusion,Convection,and Reaction for Mass Conservation:The Microscopic Scale 5

1.4 Summary 7

1.5 References 7

Part Ⅰ.Commercial Bioseparations and Product Measurement 9

2.Industrial Bioseparation Processes 11

2.1 Bioseparation Process Selection 11

2.1.1 Scale,Concentration,and Price 13

2.1.2 Product Properties 14

2.2 Monoclonal Antibodies 16

2.3 Human Insulin 17

24 Rabies Vaccine 17

2.5 Penicillin 19

2.6 Protease 20

2.7 L-lysine 21

2.8 Citric Acid 22

2.9 Summary 23

2.10 Problems 24

2.11 References 28

3.Concentration Determination and Bioactivity Assays 29

3.1 Amino Acids 29

3.1.1 High-Performance Liquid Chromatography 31

3.1.2 Reverse-Phase High-Performance Liquid Chromatography 32

3.1.3 Capillary Electrophoresis 32

3.1.4 Micellar Electrokinetic Chromatography 33

3.1.5 Electrodialysis 34

3.1.6 Gas Chromatography 35

3.2 Peptides and Proteins 35

3.2.1 Analytical Chromatography 35

3.2.2 Analytical Electrophoresis 37

3.2.3 Immunoassays 40

3.3 Nucleic and Polynucleic Acids 41

3.3.1　Ion-Exchange Chromatography 41

3.3.2　Reverse-Phase High-Performance Liquid Chromatography 42

3.3.3　Ion-Pair Chromatography 43

3.3.4　Slalom Chromatography 43

3.3.5　Gel Electrophoresis 44

3.3.6　Pulsed-Field Gel Electrophoresis 45

3.3.7　Capillary Isotachophoresis 45

3.3.8　Capillary Zone Electrophoresis 45

3.4 Carbohydrates 46

3.4.1　Monosaccharides 46

3.4.2　Oligosaccharides 49

3.4.3　Glycoproteins 51

3.5　Lipids 51

3.5.1　Fatty Acids 51

3.5.2　Fats and Oils 56

3.6 Steroids and Antibiotics 56

3.7　Vitamins 57

3.8 Summary 58

3.9　Problems 59

3.10　References 61

Part Ⅱ.Application of Chemical,Physical,and Biological Properties to Bioseparations 65

4.Thermodynamic and Transport Properties 67

4.1 Chemical Equilibria 67

4.2 Solubility 69

4.2.1　Protein and Amino Acid Solubility 70

4.3　Diffusivity 73

4.3.1　Uncharged Low-Molecular-Weight Biochemicals 73

4.3.2　Proteins 73

4.4 Isoelectric Points and Charge Dependence on pH 74

4.4.1　Carboxylic Acids 74

4.4.2　Amino Acids 76

4.4.3　Proteins 82

4.5　Hydrophobicity-Hydrophilicity Scales 84

4.6 Acid-Base Scales 84

4.6.1　Gutmann Donor-Acceptor Theory 84

4.6.2　Drago E&C Equation 86

4.6.3 Solvatochromatic Comparison Method 86

4.6.4 Hard and Soft Acid and Base Theory 86

4.6.5 Comparison and Correlation of Different Scales 88

4.7 Metal Ion Binding Constants 88

4.7.1 Nucleic Acids 89

4.7.2 Amino Acids 89

4.8 Summary 90

4.9 Problems 91

4.10 References 93

5.Biocolloidal Interactions and Forees 95

5.1 Short-Range Interactions 95

5.2 Long-Range Interactions 96

5.2.1 Van der Waals Forces 96

5.2.2 Electrostatic Interactions and DLVO Theory 100

5.2.3 Hydrophobic Effects 102

5.2.4 Magnetic Interactions 103

5.3 Summary 104

5.4 Problems 105

5.5 References 106

6.Bioaffinity 108

6.1 Molecular Recognition Processes 108

6.2 Receptor-Ligand Interactions 110

6.2.1 Ionic Bonds 110

6.2.2 Hydrogen Bonds 110

6.2.3 Hydrophobic Interactions 111

6.2.4 Van der Waals Forces 111

6.3 Theoretical Aspects of Receptor-Ligand Affinity 111

6.3.1 Thermodynamic Approach 112

6.3.2 Equilibrium Approach 112

6.4 Specific Interactions 115

6.4.1 Antibody-Antigen Interactions 116

6.4.2 DNA-Protein Interactions 117

6.4.3 Cell Receptor-Ligand Interactions 119

6.4.4 Enzyme-Substrate Interactions 120

6.4.5 Biotin-Avidin/Streptavidin Interactions 121

6.4.6 Lectin-Carbohydrate Interactions 122

6.5 Summary 122

6.6 Problems 123

6.7 References 124

Part Ⅲ.Bioseparation Methods 125

7.Crystallization and Precipitation 127

7.1 Saturation and Supersaturation 127

7.2 Nucleation Phenomena 128

7.3 Growth of Crystals 130

7.4 Batch Crystallization 131

7.4.1 Solution Balance 132

7.4.2 Solid-Phase Balance 132

7.4.3 Crystal Size Distribution 134

7.4.4 Organic Solvent and Salt Precipitation 136

7.4.5 Growth Rate Dispersion 137

7.5 Continuous Crystallization 140

7.6 Yield 141

7.6.1 Removal of Solvent and Diluent 141

7.7 Summary 142

7.8 Problems 142

7.9 References 145

8.Membrane Filtration 146

8.1 Membrane Materials 146

8.2 Driving Forces in Membrane Separations 147

8.3 General Theory of Microfiltration 147

8.3.1 Incompressible Cakes 148

8.3.2 Compressible Cakes 149

8.4 Microfiltration 149

8.4.1 Staging in Microfiltration 151

8.5 Ultrafiltration 152

8.5.1 Ultrafiltration Process Application 154

8.5.2 Ultrafiltration Membrane Application and Modification 156

8.6 Reverse Osmosis 156

8.7 Flux Equations 158

8.8 Electrodialysis 158

8.9 Emulsion Liquid Membranes 159

8.10 Summary 160

8.11 Problems 160

8.12 References 163

9.Centrifugation 164

9.1 Governing Principles 164

9.2 Advantages and Disadvantages of Centrifugation 166

9.3 Selection of Centrifuges 166

9.4 Types of Centrifuges 168

9.4.1 Tubular Bowl Centrifuges 169

9.4.2 Disc-Type Centrifuges 170

9.4.3 Batch-Basket Centrifuges 172

9.5 Industrial-Scale Centrifugation 173

9.6 Summary 176

9.7 Problems 176

9.8 References 177

10.Chromatography 178

10.1 Detection Methods 178

10.2 Summary of the Types of Chromatography 181

10.3 Stationary Phases 183

10.4 Six Ways to Analyze Chromatographic Processes 187

10.4.1 Gaussian Solution 187

10.4.2 Staged Models 190

10.4.3 Newtonian Continuum Mechanics and Linear Equilibria 196

10.4.4 Constant Pattern and Saturation Equilibria 200

10.4.5 Van Deemter Equation 205

10.4.6 Gel Partitioning Model 205

10.5 Gel-Permeation Chromatography 206

10.6 Ion-Exchange Chromatography 208

10.7 Affinity Chromatography 213

10.8 Hydrophobic Interaction and Reverse-Phase Chromatography 216

10.9 Perfusion Chromatography 216

10.10 Other Chromatographic Methods 217

10.10.1 Gradient Methods 217

10.10.2 Displacement Chromatography 218

10.10.3 Radial-Flow Chromatography 218

10.10.4 Membrane Chromatography 218

10.11 Scale-Up Strategies and Considerations 219

10.11.1 Scale-Up Method 1:No Change in Stationary-Phase Particle Size 220

10.11.2 Scale-Up Method 2:Increasing Stationary-Phase Particle Size 221

10.11.3 Scale-Up Method 3:Gel Permeation and On-Off Cycling Approach 222

10.12 Summary 223

10.13 Problems 224

10.14 References 228

11.Extraction 230

11.1 Chemical Thermodynamics of Partitioning 230

11.2 Organic-Aqueous Extraction 231

11.2.1 Extractant/Diluent Systems 233

11.2.2 Removing Biochemicals from the Organic Phase 237

11.3 Two-Phase Aqueous Extraction 238

11.3.1 Partitioning Due to Size 239

11.3.2 The Effect of Protein Charge on Partitioning 240

11.3.3 Other Effects 241

11.4 Reverse Micelles 243

11.5 Supercritical Fluids 244

11.6 Large-Scale Vessels for Extraction 246

11.6.1 Mixer-Settlers 246

11.6.2 Extraction Columns 247

11.6.3 Centrifugal Contactors 250

11.6.4 Comparison 251

11.7 Configurations for Stage-Wise Contacting 252

11.7.1 Cocurrent Contacting 252

11.7.2 Crosscurrent Contacting 253

11.7.3 Countercurrent Contacting 254

11.7.4 A Comparison of Contacting Modes 255

11.7.5 Graphical Solution 263

11.7.6 Fractional Extraction 265

11.7.7 Continuous Countercurrent Extraction 269

11.8 Summary 270

11.9 Problems 271

11.10 References 276

12.Electrophoresis 277

12.1 A Brief Introduction to Some Popular Electrophoretic Methods 277

12.1.1 Gel Electrophoresis 278

12.1.2 Capillary Electrophoresis 281

12.1.3 Isoelectric Focusing 282

12.1.4 Isotachophoresis 283

12.1.5 Moving Boundary 283

12.2 Basic Concepts of Electrophoresis 283

12.2.1 Electro-osmosis and the Relaxation Effect as Retardation Forces 286

12.2.2 Situations That Can Hamper Electrophoretic Separation 286

12.3 Zone Electrophoresis 287

12.3.1 Band Dispersion 288

12.4 Isoelectric Focusing 290

12.5 Isotachophoresis 291

12.6 Two-Dimensional Electrophoresis 292

12.7 Summary 294

12.8 Problems 294

12.9 References 298

13.Magnetic Bioseparations 299

13.1 Magnetic Properties of Materials 299

13.2 Magnetic Particle Classification 305

13.3 Theoretical Considerations 306

13.4 Magnetic Particle Separations 308

13.4.1 High-Gradient Magnetic Separations 309

13.4.2 Affinity Chromatography 310

13.4.3 Aqueous Two-Phase Separations 311

13.5 Applications 312

13.5.1 Cell Separation 312

13.5.2 Immunoassays 313

13.6 Summary 313

13.7 Problems 313

13.8 References 314

14.Solvent Removal and Drying 315

14.1 Methods of Solvent Removal 315

14.2 Theory 316

14.2.1 Vapor-Liquid Systems 317

14.2.2 Liquid-Liquid Systems 321

14.2.3 Liquid-Solid Systems 323

14.3 Rayleigh Distillation 325

14.4 Equipment 327

14.4.1 Evaporation 327

14.4.2 Drying 331

14.5 Summary 334

14.6 Problems 334

14.7 References 336

15.Cell Disruption 337

15.1 Cells and Cell Membranes 337

15.2 Cell Disruption Techniques 339

15.2.1 Mechanical Cell Disruption 340

15.2.2 Chemical Cell Disruption 348

15.3 Summary 350

15.4 Problems 351

15.5 References 352

Part Ⅳ.Bioprocess Synthesis 355

16.Integration of Individual Separation Steps 357

16.1 Bioseparation Process Heuristics 357

16.1.1 Reduce Volume Early in the Process Sequence 358

16.1.2 Save the Most Expensive Step for Last 358

16.1.3 Follow the KISS Principle 360

16.1.4 Resolve Components Well as Early as Possible 361

16.1.5 Minimize Inhibition Mechanisms in the Bioreactor 362

16.2 Issues in Concurrent Bioseparation and Bioreactor Process Development 362

16.2.1 Take the Lab-Scale Process and Scale It Directly with No Changes 362

16.2.2 Design a Bioseparation Process Based on the Closest Existing Commercial Product 363

16.2.3 Pilot-Scale Experimentation with"Spiked" Bioreactor Fluid 363

16.3 Expert Systems in Process Synthesis 364

16.4 Integration of Bioreaction and Bioseparation Steps 364

16.5 Making the Bioreactor Step Bioseparation-Friendly 366

16.6 Considerations in Final Product Formulation and Environmental Impact 367

16.7 Summary 368

16.8 Problems 369

16.9 References 371

17.Production Formulation 372

17.1 Formulation Characteristics 372

17.2 Excipients 373

17.2.1 Thickeners and Binders 373

17.2.2 Surface-Active Agents 374

17.2.3 Colors and Flavors 374

17.2.4 Preservatives 374

17.3 Dosage Forms 375

17.4 Encapsulation 375

17.5 Freeze Drying 377

17.5.1 Theory 378

17.5.2 Technique 381

17.6 Summary 383

17.7 Problems 383

17.8 References 383

18.Bioprocess Economics 385

18.1 Resources Available for Cost Estimation 385

18.1.1 Capital Cost Estimation 386

18.1.2 Operating Cost Estimation 388

18.2 Economic Decision-Making Models 389

18.2.1 Internal Rate of Return 391

18.2.2 Payback Period,Including Interest 391

18.2.3 Net Present Value 391

18.2.4 Return on Investment 392

18.2.5 Choosing Among Projects and Alternative Investments 394

18.3 Sensitivity Analyses 394

18.4 Summary 398

18.5 Problems 398

18.6 References 399

Appendix A.The Laplace Transform 400

Appendix B.Numerical Inversion,van der Laan's Theorem,and Huchel and Helmholtz-Smoluchowski Equations 405

Index 409