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1.Introduction1

1.1 Mass Conservation as an Accounting Method1

1.2 Interpreting Differentials and Integrals:World Population Statistics3

1.3 Accounting for Diffusion,Convection,and Reaction for Mass Conservation:The Microscopic Scale5

1.4 Summary7

1.5 References7

Part Ⅰ.Commercial Bioseparations and Product Measurement9

2.Industrial Bioseparation Processes11

2.1 Bioseparation Process Selection11

2.1.1 Scale,Concentration,and Price13

2.1.2 Product Properties14

2.2 Monoclonal Antibodies16

2.3 Human Insulin17

24 Rabies Vaccine17

2.5 Penicillin19

2.6 Protease20

2.7 L-lysine21

2.8 Citric Acid22

2.9 Summary23

2.10 Problems24

2.11 References28

3.Concentration Determination and Bioactivity Assays29

3.1 Amino Acids29

3.1.1 High-Performance Liquid Chromatography31

3.1.2 Reverse-Phase High-Performance Liquid Chromatography32

3.1.3 Capillary Electrophoresis32

3.1.4 Micellar Electrokinetic Chromatography33

3.1.5 Electrodialysis34

3.1.6 Gas Chromatography35

3.2 Peptides and Proteins35

3.2.1 Analytical Chromatography35

3.2.2 Analytical Electrophoresis37

3.2.3 Immunoassays40

3.3 Nucleic and Polynucleic Acids41

3.3.1　Ion-Exchange Chromatography41

3.3.2　Reverse-Phase High-Performance Liquid Chromatography42

3.3.3　Ion-Pair Chromatography43

3.3.4　Slalom Chromatography43

3.3.5　Gel Electrophoresis44

3.3.6　Pulsed-Field Gel Electrophoresis45

3.3.7　Capillary Isotachophoresis45

3.3.8　Capillary Zone Electrophoresis45

3.4 Carbohydrates46

3.4.1　Monosaccharides46

3.4.2　Oligosaccharides49

3.4.3　Glycoproteins51

3.5　Lipids51

3.5.1　Fatty Acids51

3.5.2　Fats and Oils56

3.6 Steroids and Antibiotics56

3.7　Vitamins57

3.8 Summary58

3.9　Problems59

3.10　References61

Part Ⅱ.Application of Chemical,Physical,and Biological Properties to Bioseparations65

4.Thermodynamic and Transport Properties67

4.1 Chemical Equilibria67

4.2 Solubility69

4.2.1　Protein and Amino Acid Solubility70

4.3　Diffusivity73

4.3.1　Uncharged Low-Molecular-Weight Biochemicals73

4.3.2　Proteins73

4.4 Isoelectric Points and Charge Dependence on pH74

4.4.1　Carboxylic Acids74

4.4.2　Amino Acids76

4.4.3　Proteins82

4.5　Hydrophobicity-Hydrophilicity Scales84

4.6 Acid-Base Scales84

4.6.1　Gutmann Donor-Acceptor Theory84

4.6.2　Drago E&C Equation86

4.6.3 Solvatochromatic Comparison Method86

4.6.4 Hard and Soft Acid and Base Theory86

4.6.5 Comparison and Correlation of Different Scales88

4.7 Metal Ion Binding Constants88

4.7.1 Nucleic Acids89

4.7.2 Amino Acids89

4.8 Summary90

4.9 Problems91

4.10 References93

5.Biocolloidal Interactions and Forees95

5.1 Short-Range Interactions95

5.2 Long-Range Interactions96

5.2.1 Van der Waals Forces96

5.2.2 Electrostatic Interactions and DLVO Theory100

5.2.3 Hydrophobic Effects102

5.2.4 Magnetic Interactions103

5.3 Summary104

5.4 Problems105

5.5 References106

6.Bioaffinity108

6.1 Molecular Recognition Processes108

6.2 Receptor-Ligand Interactions110

6.2.1 Ionic Bonds110

6.2.2 Hydrogen Bonds110

6.2.3 Hydrophobic Interactions111

6.2.4 Van der Waals Forces111

6.3 Theoretical Aspects of Receptor-Ligand Affinity111

6.3.1 Thermodynamic Approach112

6.3.2 Equilibrium Approach112

6.4 Specific Interactions115

6.4.1 Antibody-Antigen Interactions116

6.4.2 DNA-Protein Interactions117

6.4.3 Cell Receptor-Ligand Interactions119

6.4.4 Enzyme-Substrate Interactions120

6.4.5 Biotin-Avidin/Streptavidin Interactions121

6.4.6 Lectin-Carbohydrate Interactions122

6.5 Summary122

6.6 Problems123

6.7 References124

Part Ⅲ.Bioseparation Methods125

7.Crystallization and Precipitation127

7.1 Saturation and Supersaturation127

7.2 Nucleation Phenomena128

7.3 Growth of Crystals130

7.4 Batch Crystallization131

7.4.1 Solution Balance132

7.4.2 Solid-Phase Balance132

7.4.3 Crystal Size Distribution134

7.4.4 Organic Solvent and Salt Precipitation136

7.4.5 Growth Rate Dispersion137

7.5 Continuous Crystallization140

7.6 Yield141

7.6.1 Removal of Solvent and Diluent141

7.7 Summary142

7.8 Problems142

7.9 References145

8.Membrane Filtration146

8.1 Membrane Materials146

8.2 Driving Forces in Membrane Separations147

8.3 General Theory of Microfiltration147

8.3.1 Incompressible Cakes148

8.3.2 Compressible Cakes149

8.4 Microfiltration149

8.4.1 Staging in Microfiltration151

8.5 Ultrafiltration152

8.5.1 Ultrafiltration Process Application154

8.5.2 Ultrafiltration Membrane Application and Modification156

8.6 Reverse Osmosis156

8.7 Flux Equations158

8.8 Electrodialysis158

8.9 Emulsion Liquid Membranes159

8.10 Summary160

8.11 Problems160

8.12 References163

9.Centrifugation164

9.1 Governing Principles164

9.2 Advantages and Disadvantages of Centrifugation166

9.3 Selection of Centrifuges166

9.4 Types of Centrifuges168

9.4.1 Tubular Bowl Centrifuges169

9.4.2 Disc-Type Centrifuges170

9.4.3 Batch-Basket Centrifuges172

9.5 Industrial-Scale Centrifugation173

9.6 Summary176

9.7 Problems176

9.8 References177

10.Chromatography178

10.1 Detection Methods178

10.2 Summary of the Types of Chromatography181

10.3 Stationary Phases183

10.4 Six Ways to Analyze Chromatographic Processes187

10.4.1 Gaussian Solution187

10.4.2 Staged Models190

10.4.3 Newtonian Continuum Mechanics and Linear Equilibria196

10.4.4 Constant Pattern and Saturation Equilibria200

10.4.5 Van Deemter Equation205

10.4.6 Gel Partitioning Model205

10.5 Gel-Permeation Chromatography206

10.6 Ion-Exchange Chromatography208

10.7 Affinity Chromatography213

10.8 Hydrophobic Interaction and Reverse-Phase Chromatography216

10.9 Perfusion Chromatography216

10.10 Other Chromatographic Methods217

10.10.1 Gradient Methods217

10.10.2 Displacement Chromatography218

10.10.3 Radial-Flow Chromatography218

10.10.4 Membrane Chromatography218

10.11 Scale-Up Strategies and Considerations219

10.11.1 Scale-Up Method 1:No Change in Stationary-Phase Particle Size220

10.11.2 Scale-Up Method 2:Increasing Stationary-Phase Particle Size221

10.11.3 Scale-Up Method 3:Gel Permeation and On-Off Cycling Approach222

10.12 Summary223

10.13 Problems224

10.14 References228

11.Extraction230

11.1 Chemical Thermodynamics of Partitioning230

11.2 Organic-Aqueous Extraction231

11.2.1 Extractant/Diluent Systems233

11.2.2 Removing Biochemicals from the Organic Phase237

11.3 Two-Phase Aqueous Extraction238

11.3.1 Partitioning Due to Size239

11.3.2 The Effect of Protein Charge on Partitioning240

11.3.3 Other Effects241

11.4 Reverse Micelles243

11.5 Supercritical Fluids244

11.6 Large-Scale Vessels for Extraction246

11.6.1 Mixer-Settlers246

11.6.2 Extraction Columns247

11.6.3 Centrifugal Contactors250

11.6.4 Comparison251

11.7 Configurations for Stage-Wise Contacting252

11.7.1 Cocurrent Contacting252

11.7.2 Crosscurrent Contacting253

11.7.3 Countercurrent Contacting254

11.7.4 A Comparison of Contacting Modes255

11.7.5 Graphical Solution263

11.7.6 Fractional Extraction265

11.7.7 Continuous Countercurrent Extraction269

11.8 Summary270

11.9 Problems271

11.10 References276

12.Electrophoresis277

12.1 A Brief Introduction to Some Popular Electrophoretic Methods277

12.1.1 Gel Electrophoresis278

12.1.2 Capillary Electrophoresis281

12.1.3 Isoelectric Focusing282

12.1.4 Isotachophoresis283

12.1.5 Moving Boundary283

12.2 Basic Concepts of Electrophoresis283

12.2.1 Electro-osmosis and the Relaxation Effect as Retardation Forces286

12.2.2 Situations That Can Hamper Electrophoretic Separation286

12.3 Zone Electrophoresis287

12.3.1 Band Dispersion288

12.4 Isoelectric Focusing290

12.5 Isotachophoresis291

12.6 Two-Dimensional Electrophoresis292

12.7 Summary294

12.8 Problems294

12.9 References298

13.Magnetic Bioseparations299

13.1 Magnetic Properties of Materials299

13.2 Magnetic Particle Classification305

13.3 Theoretical Considerations306

13.4 Magnetic Particle Separations308

13.4.1 High-Gradient Magnetic Separations309

13.4.2 Affinity Chromatography310

13.4.3 Aqueous Two-Phase Separations311

13.5 Applications312

13.5.1 Cell Separation312

13.5.2 Immunoassays313

13.6 Summary313

13.7 Problems313

13.8 References314

14.Solvent Removal and Drying315

14.1 Methods of Solvent Removal315

14.2 Theory316

14.2.1 Vapor-Liquid Systems317

14.2.2 Liquid-Liquid Systems321

14.2.3 Liquid-Solid Systems323

14.3 Rayleigh Distillation325

14.4 Equipment327

14.4.1 Evaporation327

14.4.2 Drying331

14.5 Summary334

14.6 Problems334

14.7 References336

15.Cell Disruption337

15.1 Cells and Cell Membranes337

15.2 Cell Disruption Techniques339

15.2.1 Mechanical Cell Disruption340

15.2.2 Chemical Cell Disruption348

15.3 Summary350

15.4 Problems351

15.5 References352

Part Ⅳ.Bioprocess Synthesis355

16.Integration of Individual Separation Steps357

16.1 Bioseparation Process Heuristics357

16.1.1 Reduce Volume Early in the Process Sequence358

16.1.2 Save the Most Expensive Step for Last358

16.1.3 Follow the KISS Principle360

16.1.4 Resolve Components Well as Early as Possible361

16.1.5 Minimize Inhibition Mechanisms in the Bioreactor362

16.2 Issues in Concurrent Bioseparation and Bioreactor Process Development362

16.2.1 Take the Lab-Scale Process and Scale It Directly with No Changes362

16.2.2 Design a Bioseparation Process Based on the Closest Existing Commercial Product363

16.2.3 Pilot-Scale Experimentation with"Spiked" Bioreactor Fluid363

16.3 Expert Systems in Process Synthesis364

16.4 Integration of Bioreaction and Bioseparation Steps364

16.5 Making the Bioreactor Step Bioseparation-Friendly366

16.6 Considerations in Final Product Formulation and Environmental Impact367

16.7 Summary368

16.8 Problems369

16.9 References371

17.Production Formulation372

17.1 Formulation Characteristics372

17.2 Excipients373

17.2.1 Thickeners and Binders373

17.2.2 Surface-Active Agents374

17.2.3 Colors and Flavors374

17.2.4 Preservatives374

17.3 Dosage Forms375

17.4 Encapsulation375

17.5 Freeze Drying377

17.5.1 Theory378

17.5.2 Technique381

17.6 Summary383

17.7 Problems383

17.8 References383

18.Bioprocess Economics385

18.1 Resources Available for Cost Estimation385

18.1.1 Capital Cost Estimation386

18.1.2 Operating Cost Estimation388

18.2 Economic Decision-Making Models389

18.2.1 Internal Rate of Return391

18.2.2 Payback Period,Including Interest391

18.2.3 Net Present Value391

18.2.4 Return on Investment392

18.2.5 Choosing Among Projects and Alternative Investments394

18.3 Sensitivity Analyses394

18.4 Summary398

18.5 Problems398

18.6 References399

Appendix A.The Laplace Transform400

Appendix B.Numerical Inversion,van der Laan's Theorem,and Huchel and Helmholtz-Smoluchowski Equations405

Index409