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Green Techniques for Organic Synthesis and Medicinal Chemistry

Wei Zhang (Editor), Berkeley Cue (Editor)
ISBN: 978-0-470-71151-4
768 pages
July 2012
Green Techniques for Organic Synthesis and Medicinal Chemistry (0470711515) cover image
Green chemistry is a new way of looking at organic synthesis and the design of drug molecules, offering important environmental and economic advantages over traditional synthetic processes. Pharmaceutical companies are increasingly turning to the principles of green chemistry in an effort to reduce waste, reduce costs and develop environmentally benign processes.

Green Techniques for Organic Synthesis and Medicinal Chemistry presents an overview of the established and emerging techniques in green organic chemistry, highlighting their applications in medicinal chemistry. The book is divided into four parts:

Introduction: Introduces the reader to the toxicology of organic chemicals,their environmental impact, and the concept of green chemistry.

Green Catalysis: Covers a variety of green catalytic techniques including organocatalysis, supported catalysis, biocatalysis, fluorous catalysis, and catalytic direct C-H bond activation reactions.

Green Synthetic Techniques: Presents a series of new techniques, assessing the green chemistry aspects and limitations (i.e. cost, equipment, expertise). Techniques include reactions in alternative solvents, atom economic multicomponent reactions, microwave and ultrasonic reactions, solid-supported synthesis, fluorous and ionic liquid-based recycling techniques, and flow reactors.

Green Techniques in Pharmaceutical Industry: Covers applications of green chemistry concepts and special techniques for medicinal chemistry, including synthesis, analysis, separation, formulation, , and drug delivery. Process and business case studies are included to illustrate the applications in the pharmaceutical industry.

Green Techniques for Organic Synthesis and Medicinal Chemistry is an essential resource on green chemistry technologies for academic researchers, R&D professionals and students working in organic chemistry and medicinal chemistry.

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List of Contributors xix

I INTRODUCTION 1

1 Green Toxicology 3

Nicholas D. Anastas

1.1 Introduction 3

1.2 History and Scope of Toxicology 4

1.2.1 The need for green toxicology 5

1.3 Principles of Toxicology 5

1.3.1 Characteristics of exposure 6

1.3.2 Spectrum of toxic effects 6

1.3.3 The dose–response relationship 7

1.4 Disposition of Toxicants in Organisms 8

1.4.1 Absorption 9

1.4.2 Distribution 11

1.4.3 Metabolism 11

1.4.4 Excretion 12

1.5 Nonorgan System Toxicity 12

1.5.1 Carcinogenesis 13

1.5.2 Reproductive and developmental toxicity 13

1.5.3 Immunotoxicology 14

1.6 Mechanistic Toxicology 15

1.7 Quantitative Structure–Activity Relationships 16

1.8 Environmental Toxicology 18

1.8.1 Persistence and bioaccumulation 18

1.9 Risk Assessment 19

1.9.1 NonCancer risk assessment 20

1.9.2 Cancer risk assessment 21

1.10 Conclusions 21

References 22

2 Green Chemistry and the Pharmaceutical Industry 25

Amy S. Cannon, Joseph L. Pont and John C. Warner

2.1 Introduction 25

2.2 Green Chemistry versus Sustainable Chemistry 26

2.3 Trend: The Ongoing Use of Hazardous Chemistry 27

2.4 Myth: To Do Green Chemistry One Must Sacrifice Performance and Cost 28

2.5 Green Chemistry and the Future of the Pharmaceutical Industry 29

2.6 Green Chemistry in Pharmaceutical Process Development and Manufacturing 30

2.7 Conclusions 30

References 31

II GREEN CATALYSIS 33

3 Environmental Science and Green Chemistry; Guiding Environmentally Preferred

Manufacturing, Materials, and Products 35

Richard T. Williams and Travis R. Williams

3.1 Introduction 35

3.2 Market Forces 36

3.2.1 Chemicals in the natural and human environment 37

3.2.2 Precautionary decision making 37

3.2.3 Chemical control laws 37

3.2.4 Green chemistry initiatives 38

3.2.5 Drug registration Environmental Risk Assessment (ERA) 39

3.2.6 Extended Producer Responsibility (EPR) 39

3.2.7 Ecosystem valuation 39

3.2.8 Company expectations 39

3.2.9 Public expectations 39

3.2.10 Environmental labeling, standards, and classification 39

3.3 Indicators (Attributes) of Environmental Performance 40

3.4 Environmental Impact 40

3.5 Strategic Approach to Greener Manufacturing Processes and Products 42

3.6 Manufacturing Process Improvements 43

3.6.1 Business and Professional Advantages from Manufacturing

Process Improvements 44

3.7 Product Improvements 45

3.8 Environmental Decision Making 46

3.8.1 E-factor 47

3.8.2 Process Mass Intensity (PMI) 47

3.8.3 Life Cycle Assessment (LCA) 47

3.8.4 Individual company initiatives 48

3.8.5 Environmental (Ecological) Risk Assessment (ERA) 49

3.8.6 Alternatives Assessment (AA)/Chemical Alternatives Assessment (CAA) 49

3.8.7 Green Screen 50

3.8.8 iSUSTAINTM Green chemistry index 50

3.8.9 Computational Science and Quantitative Structure–Activity

Relationships (QSARs) 51

3.8.10 Tiered testing 52

3.8.11 Databases and lists of chemicals 52

3.9 Case Study – Pharmaceuticals/Biologics 53

3.9.1 Pharmaceutical manufacturing 53

3.9.2 Pharmaceutical products 54

3.10 Case Study – Nanotechnology 58

3.11 Green Credentials and Environmental Standards 59

3.12 Inspiring Innovation – Academic and Industry Programs 60

3.12.1 Academic programs 60

3.12.2 Industry programs 60

3.13 Conclusions and Recommendations 61

References 64

4 Direct CH Bond Activation Reactions 69

Anna Tomin, Seema Bag and Bela T€or€ok

4.1 Introduction 69

4.2 Homogeneous CH Activation by Metal Complex Catalysis 70

4.2.1 Pd-catalyzed carbon–carbon bond formations 70

4.2.2 Pd-catalyzed carbon–heteroatom bond formation 73

4.2.3 CH activation by other metals 74

4.3 Heterogeneous Catalytic Methods for CH Activation 75

4.3.1 Supported metal complexes 75

4.3.2 Supported metals 78

4.4 CH Activation by Organocatalysts 80

4.5 Enzymatic CH Activations 83

References 87

5 Supported Asymmetric Organocatalysis 99

Long Zhang, Lingyun Cui, Sanzhong Luo and Jin-Pei Cheng

5.1 Introduction 99

5.2 Polymer-Supported Organocatalysts 99

5.2.1 Polymer-supported chiral amines for enamine and iminiun catalysis 99

5.2.2 Polymer-supported phase transfer catalysts 106

5.2.3 Polymer-supported phosphoric acid catalyst 107

5.2.4 Miscellaneous 108

5.3 Solid Acid-Supported Organocatalysis 108

5.3.1 Polyoxometalate-supported chiral amine catalysts 109

5.3.2 Solid sulfonic acid supported chiral amine catalysts 110

5.4 Ionic Liquid-Supported Organocatalysts 111

5.5 Magnetic Nanoparticle-Supported Organocatalysts 119

5.6 Silica-Supported Asymmetric Organocatalysts 119

5.6.1 Silica-supported proline and its derivatives 120

5.6.2 Silica-supported MacMillan catalysts 121

5.6.3 Other silica-supported organocatalysts 122

5.7 Clay Entrapped Organocatalysts 123

5.8 Miscellaneous 124

5.9 Conclusion 126

Acknowledgments 126

References 127

6 Fluorous Catalysis 137

Laszlo T. Mika and Istvan T. Horvath

6.1 Introduction and the Principles of Fluorous Catalysis 137

6.2 Ligands for Fluorous Transition Metal Catalysts 142

6.3 Synthetic Application of Fluorous Catalysis 142

6.3.1 Hydroformylation 142

6.3.2 Hydrogenation 147

6.3.3 Hydrosylilation 150

6.3.4 Cross-coupling reactions 154

6.3.5 Hydroboration 161

6.3.6 Oxidation 163

6.3.7 Esterification, transesterification and acetylation 167

6.3.8 Other metal catalyzed carbon–carbon bond forming reactions 168

6.4 Fluorous Organocatalysis 174

References 177

7 Solid-Supported Catalysis 185

Michelle L. Richards and Peter J.H. Scott

7.1 Introduction 185

7.1.1 General Introduction 185

7.1.2 The impact of solid-phase organic synthesis on green chemistry 187

7.2 Immobilized Palladium Catalysts for Green Chemistry 188

7.2.1 Introduction 188

7.2.2 Suzuki reactions 189

7.2.3 Heck–Mizoroki reactions in water 193

7.2.4 Sonogashira reactions in water 194

7.2.5 Tsuji–Trost reactions in water 196

7.3 Immobilized Rhodium Catalysts for Green Chemistry 197

7.3.1 Introduction 197

7.3.2 Rhodium(II) carbenoid chemistry 197

7.3.3 Rhodium (I)-catalyzed conjugate addition reactions 198

7.3.4 Rhodium-catalyzed hydrogenation reactions 198

7.3.5 Rhodium-catalyzed carbonylation reactions 199

7.4 Immobilized Ruthenium Catalysts for Green Chemistry 199

7.4.1 Introduction 199

7.4.2 Ruthenium-catalyzed metathesis reactions 199

7.4.3 Ruthenium-catalyzed transfer hydrogenation 204

7.4.4 Ruthenium-catalyzed opening of epoxides 206

7.4.5 Ruthenium-catalyzed cyclopropanation reactions 206

7.4.6 Ruthenium-catalyzed halogenation reactions 207

7.5 Other Immobilized Catalysts for Green Chemistry 208

7.5.1 Immobilized cobalt catalysts 208

7.5.2 Immobilized copper catalysts 208

7.5.3 Immobilized iridium catalysts 209

7.6 Conclusions 210

References 210

8 Biocatalysis 217

Qi Wu and Junhua Tao

8.1 Introduction 217

8.2 Brief History of Biocatalysis 217

8.3 Biocatalysis Toolboxes 218

8.4 Enzymatic Synthesis of Pharmaceuticals 218

8.4.1 Synthesis of atorvastatin and rosuvastatin 219

8.4.2 Synthesis of b-lactam antibiotics 222

8.4.3 Synthesis of glycopeptides 225

8.4.4 Synthesis of tyrocidine antibiotics 227

8.4.5 Synthesis of polyketides 230

8.4.6 Synthesis of taxoids and epothilones 231

8.4.7 Synthesis of pregabalin 234

8.5 Summary 237

Acknowledgment 237

References 237

III GREEN SYNTHETIC TECHNIQUES 241

9 Green Solvents 243

Simon W. Breeden, James H. Clark, Duncan J. Macquarrie and James Sherwood

9.1 Introduction 243

9.2 Origins of the Neoteric Solvents 244

9.2.1 Ionic liquids 244

9.2.2 Supercritical carbon dioxide 245

9.2.3 Water 245

9.2.4 Perfluorinated solvents 246

9.2.5 Biosolvents 246

9.2.6 Petroleum solvents 247

9.3 Application of Green Solvents 248

9.3.1 Synthetic organic chemistry overview 248

9.3.2 Diels–Alder cycloaddition 248

9.3.3 Cross-coupling 250

9.3.4 Ring-closing metathesis 253

9.4 Recapitulation and Possible Future Developments 256

References 257

10 Organic Synthesis in Water 263

Marc-Olivier Simon and Chao-Jun Li

10.1 Introduction 263

10.2 Pericyclic Reactions 264

10.3 Passerini and Ugi Reactions 268

10.4 Nucleophilic Ring-Opening Reactions 269

10.5 Transition Metal Catalyzed Reactions 271

10.5.1 Pericyclic reactions 271

10.5.2 Addition reactions 273

10.5.3 Coupling reactions 274

10.5.4 Transition metal catalyzed reactions of carbenes 279

10.5.5 Oxidations and reductions 280

10.6 Organocatalytic Reactions 283

10.6.1 Aldol reaction 283

10.6.2 Michael addition 284

10.6.3 Mannich reaction 285

10.6.4 Cycloaddition reactions 286

10.7 Miscellaneous 288

10.8 Conclusion 290

References 291

11 Solvent-Free Synthesis 297

James Mack and Sivaramakrishnan Muthukrishnan

11.1 Introduction 297

11.2 Alternative Methods to Solution Based Synthesis 300

11.2.1 Mortar and pestle 300

11.2.2 Ball milling 301

11.2.3 Microwave assisted solvent-free synthesis 309

References 318

12 Microwave Synthesis 325

Michael P. Pollastri and William G. Devine

12.1 Introduction 325

12.2 The Mechanism of Microwave Heating 326

12.3 The Green Properties of Microwave Heating 326

12.3.1 Green solvents 326

12.3.2 Energy reduction 328

12.3.3 Improved reaction outcomes resulting in less purification 328

12.4 Microwaves versus Green Chemistry Principles 329

12.5 Green Solvents in Microwave Chemistry 329

12.5.1 Water 329

12.5.2 Solventless reactions 330

12.5.3 Ionic liquids 331

12.5.4 Glycerol 332

12.6 Catalysis 333

12.6.1 Microwave assisted CH bond activation 333

12.6.2 Microwave assisted carbonylation reactions 334

12.7 Microwave Chemistry Scale-Up 334

12.7.1 Flow microwave reactors 335

12.7.2 Energy efficiency of large-scale microwave reactions 336

12.7.3 Large-scale batch microwave reactors 339

12.7.4 Future work in microwave scale-up 340

12.8 Summary 340

References 341

13 Ultrasonic Reactions 343

Rodrigo Cella and Helio A. Stefani

13.1 Introduction 343

13.2 How Does Cavitation Work? 344

13.3 Condensation Reactions 345

13.4 Michael Additions 348

13.5 Mannich Reactions 349

13.6 Heterocycles Synthesis 350

13.7 Coupling Reactions 353

13.8 Miscellaneous 358

13.9 Conclusions 359

References 359

14 Photochemical Synthesis 363

Stefano Protti, Maurizio Fagnoni and Angelo Albini

14.1 Introduction 363

14.2 Synthesis and Rearrangement of Open-Chain Compounds 365

14.3 Synthesis of Three- and Four-Membered Rings 370

14.3.1 Synthesis of three-membered rings 370

14.3.2 Synthesis of four-membered rings 372

14.4 Synthesis of Five-, Six (and Larger)-Membered Rings 378

14.4.1 Synthesis of five-membered rings 379

14.4.2 Synthesis of six-membered rings 381

14.4.3 Synthesis of larger rings 383

14.5 Oxygenation and Oxidation 385

14.6 Conclusions 387

Acknowledgment 388

References 388

15 Solid-Supported Organic Synthesis 393

Gorakh S. Yellol and Chung-Ming Sun

15.1 Introduction 393

15.2 Techniques of Solid-Supported Synthesis 394

15.2.1 General method of solid-supported synthesis 394

15.2.2 Supports for supported synthesis 395

15.2.3 Linkers for solid-supported synthesis 398

15.2.4 Reaction monitoring 401

15.2.5 Separation techniques 402

15.2.6 Automation technique 404

15.2.7 Split and combine (split and mix) technique 405

15.3 Solid-Supported Heterocyclic Chemistry 406

15.3.1 Multicomponent reaction 406

15.3.2 Combinatorial library synthesis 408

15.3.3 Diversity-oriented synthesis 412

15.3.4 Multistep parallel synthesis 412

15.4 Solid-Supported Natural Product Synthesis 417

15.4.1 Total synthesis of natural product 418

15.4.2 Synthesis of natural product-like libraries 420

15.4.3 Synthesis of natural product inspired compounds 421

15.5 Solid-Supported Synthesis of Peptides and Carbohydrates 422

15.5.1 Solid-supported synthesis of peptides 422

15.5.2 Solid-supported synthesis of carbohydrates 424

15.6 Soluble-Supported Synthesis 426

15.6.1 Poly(ethylene glycol) 426

15.6.2 Linear polystyrene (LPS) 427

15.6.3 Ionic liquids 428

15.7 Multidisciplinary Synthetic Approaches 429

15.7.1 Solid-supported synthesis and microwave synthesis 429

15.7.2 Solid-supported synthesis under sonication 431

15.7.3 Solid-supported synthesis in green media 433

15.7.4 Solid-supported synthesis and photochemical reactions 433

References 434

16 Fluorous Synthesis 443

Wei Zhang

16.1 Introduction 443

16.2 “Heavy” versus “Light” Fluorous Chemistry 443

16.3 Green Aspects of Fluorous Techniques 444

16.3.1 Fluorous solid-phase extraction to reduce the amount of

waste solvent 444

16.3.2 Recycling techniques in fluorous synthesis 444

16.3.3 Monitoring fluorous reactions 446

16.3.4 Two-in-one strategy for using fluorous linkers 448

16.3.5 Efficient microwave-assisted fluorous synthesis 448

16.3.6 Atom economic fluorous multicomponent reactions 451

16.3.7 Fluorous reactions and separations in aqueous media 451

16.4 Fluorous Techniques for Discovery Chemistry 451

16.4.1 Fluorous ligands for metal catalysis 451

16.4.2 Fluorous organocatalysts for asymmetric synthesis 451

16.4.3 Fluorous reagents 453

16.4.4 Fluorous scavengers 454

16.4.5 Fluorous linkers 454

16.5 Conclusions 465

References 465

17 Reactions in Ionic Liquids 469

Hui Wang, Xiaosi Zhou, Gabriela Gurau and Robin D. Rogers

17.1 Introduction 469

17.2 Finding the Right Role for ILs in the Pharmaceutical Industry 470

17.2.1 Use of ILs as solvents in the synthesis of drugs or drug intermediates 470

17.2.2 Use of ILs for pharmaceutical crystallization 472

17.2.3 Use of ILs in pharmaceutical separations 472

17.2.4 Use of ILs for the extraction of drugs from natural products 476

17.2.5 Use of ILs for drug delivery 477

17.2.6 Use of ILs for drug detection 478

17.2.7 ILs as pharmaceutical ingredients 479

17.3 Conclusions and Prospects 489

References 490

18 Multicomponent Reactions 497

Yijun Huang, Ahmed Yazbak and Alexander D€omling

18.1 Introduction 497

18.2 Multicomponent Reactions in Aqueous Medium 498

18.2.1 Multicomponent reactions are accelerated in water 498

18.2.2 Multicomponent reactions “on water” 500

18.3 Solventless Multicomponent Reactions 503

18.4 Case Studies of Multicomponent Reactions in Drug Synthesis 507

18.4.1 Schistosomiasis drug praziquantel 507

18.4.2 Schizophrenia drug olanzapine 509

18.4.3 Oxytocin antagonist GSK221149A 510

18.4.4 Miscellaneous 511

18.5 Perspectives of Multicomponent Reactions in Green Chemistry 512

18.5.1 The union of multicomponent reactions 512

18.5.2 Sustainable synthesis technology by multicomponent reactions 515

18.5.3 Alternative solvents for green chemistry 516

18.6 Outlook 518

References 518

19 Flow Chemistry 523

Frederic G. Buono, Michael A. Gonzalez and Jale M€uslehiddinoglu

19.1 Introduction 523

19.2 Types of Flow Reactors 525

19.2.1 Microreactors 526

19.2.2 Miniaturized tubular reactors 527

19.2.3 Spinning Disk Reactor (SDR) 528

19.2.4 Spinning tube-in-tube reactor 530

19.2.5 Heat exchanger reactors 531

19.3 Application of Flow Reactors 532

19.3.1 Prevention of waste and yield improvement 532

19.3.2 Increase energy efficiency and minimize potential

for accidents 535

19.3.3 Use of heterogeneous catalysts and atom efficiency 540

19.3.4 Use of supported reagents 543

19.3.5 Photochemistry 543

19.4 Conclusion 544

Acknowledgment 544

References 545

20 Green Chemistry Strategies for Medicinal Chemists 551

Berkeley W. Cue Jr.

20.1 Introduction 551

20.2 Historical Background: The Evolution of Green Chemistry

in the Pharmaceutical Industry 552

20.3 Green Chemistry in Process Chemistry, Manufacturing and

Medicinal Chemistry and Barriers to Rapid Uptake 553

20.4 Green Chemistry Activity Among PhRMA

Member Companies 554

20.5 Modeling Waste Generation in Pharmaceutical R&D 555

20.6 Strategies to Reduce the Use of Solvents 556

20.7 Green Reactions for Medicinal Chemistry 558

20.8 Modeling Waste Co-Produced During R&D Synthesis 560

20.9 Green Chemistry and Drug Design: Benign by Design 562

20.10 Green Biology 565

20.11 Conclusions and Recommendations 565

References 567

IV GREEN TECHNIQUES FOR MEDICINAL CHEMISTRY 571

21 The Business of Green Chemistry in the Pharmaceutical Industry 573

Andrea Larson and Mark Meier

21.1 Introduction 573

21.2 Green Chemistry as a Business Opportunity 574

21.3 The Need for Green Chemistry 574

21.4 The Business Case for Green Chemistry Principles 576

21.5 An Idea whose Time Has Arrived 579

21.6 What Green Chemistry Is and What It Is Not 582

21.7 Overcoming Obstacles to Green Chemistry 583

21.8 Conclusion 586

References 586

22 Preparative Chromatography 589

Kathleen Mihlbachler and Olivier Dapremont

22.1 Introduction 589

22.2 Preparative Chromatography for Intermediates and APIs 590

22.2.1 Early discovery 590

22.2.2 Clinical and commercial scale quantities 590

22.2.3 Chiral separations 591

22.3 Chromatography and the 12 Principles of Green Chemistry 592

22.3.1 The 12 principles 592

22.3.2 The metrics 593

22.3.3 The impact of chromatography on the environment 594

22.4 Overview of Chromatography Systems 595

22.4.1 Chromatographic separation mechanisms 595

22.4.2 Elution modes: isocratic versus gradient 596

22.4.3 Batch chromatography 596

22.4.4 Continuous chromatography 598

22.4.5 Supercritical fluid chromatography 600

22.4.6 Solvent Recycling 601

22.5 Examples of Process Chromatography 602

22.5.1 Early process development 602

22.5.2 Implementation of SMB technology for chiral resolution 603

22.5.3 Global process optimization: combining synthesis and

impurity removal 605

22.5.4 Chromatography versus crystallization to remove a genotoxic impurity 607

22.5.5 SMB mining – recover product from waste stream 608

22.6 Conclusions 609

References 610

23 Green Drug-Delivery Formulations 613

Scott B. McCray and David K. Lyon

23.1 Introduction and Summary 613

23.2 Application of Green Chemistry in the Pharmaceutical Industry 614

23.3 Need for Green Chemistry Technologies to Deliver Low-Solubility Drugs 615

23.3.1 The need 615

23.3.2 Characteristics of low-solubility drugs 616

23.3.3 Low bioavailability 616

23.4 SDD Drug-Delivery Platform 617

23.4.1 Technology overview 617

23.4.2 Polymer choice 619

23.4.3 Process description 620

23.4.4 Formulation description 622

23.4.5 Dissolved drug 622

23.4.6 Drug in colloids and micelles 623

23.4.7 SDD efficacy 623

23.4.8 In Vitro testing 624

23.4.9 In Vivo testing 624

23.5 Green Chemistry Advantages of SDD Drug-Delivery Platform 625

23.5.1 Modeling 625

23.5.2 Reduction in waste due to efficient screening 626

23.5.3 Reduction of waste during manufacturing 626

23.5.4 Reduction in waste due to nonprogression of candidates 627

23.5.5 Reduction in waste due to lower dose requirements 627

23.5.6 Reduction in amount of drug that enters the environment 627

23.5.7 Calculated impact on waste reduction 627

23.6 Conclusions 628

23.7 Acknowledgments 628

References 628

24 Green Process Chemistry in the Pharmaceutical Industry: Recent Case Studies 631

Ji Zhang and Berkeley W. Cue Jr

24.1 Introduction 631

24.2 Sitagliptin: From Green to Greener; from a Catalytic Reaction to a

Metal-Free Enzymatic Process 632

24.3 Saxagliptin: Elimination of Toxic Chemicals and the Use of a Biocatalytic Approach 637

24.4 Armodafinil: From Classical Resolution to Catalytic Asymmetric

Oxidation to Maximize the Output 639

24.5 Emend: Elimination of the Use of Tebbe Reagent for Pollution Prevention

and Utilization of Catalytic Asymmetric Transfer Hydrogenation 642

24.6 Greening a Process via One-pot or Telescoped Processing 646

24.7 Greening a Process via Salt Formation 651

24.8 Metal-free Organocatalysis: Applications of Chiral

Phase-transfer Catalysis 652

24.9 Conclusions 653

References 657

25 Green Analytical Chemistry 659

Paul Ferguson, Mark Harding and Jennifer Young

25.1 Introduction 659

25.2 Method Assessment 660

25.3 Solvents and Additives for pH Adjustment 661

25.4 Sample Preparation 665

25.5 Techniques and Methods 666

25.5.1 Screening methods 666

25.5.2 Liquid chromatography 667

25.5.3 Gas chromatography 676

25.5.4 Supercritical fluid chromatography 678

25.5.5 Chiral analysis 679

25.5.6 Process analytical technology 680

25.6 Conclusions 681

Acknowledgments 682

References 682

26 Green Chemistry for Tropical Disease 685

Joseph M.D. Fortunak, David H. Brown Ripin and David S. Teager

26.1 Introduction 685

26.2 Interventions in Drug Dosing 686

26.2.1 Dose reduction through innovative drug formulation 686

26.2.2 Dose optimization: green dose setting 687

26.3 Active Pharmaceutical Ingredient Cost Reduction with Green Chemistry 688

26.3.1 Revision of the original manufacturing process 688

26.3.2 Case studies: manufacture of drugs for AntiRetroviral therapy 689

26.3.3 Case studies: Artemisinin combination therapies for malaria treatment 695

26.4 Conclusions 698

References 698

27 Green Engineering in the Pharmaceutical Industry 701

Concepcion Jimenez- Gonzalez, Celia S. Ponder, Robert E. Hannah and James R. Hagan

27.1 Introduction 701

27.2 Green Engineering Principles 702

27.2.1 Optimizing the use of resources 702

27.2.2 Life cycle thinking 706

27.2.3 Minimizing environment, health and safety hazards by design 709

27.3 More Challenge Areas for Sustainability in the Pharmaceutical Industry 709

27.4 Future Outlook and Challenges 712

References 712

Index

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“In summary, the book covers new advances in green chemistry, which are applied in the pharmaceutical industry.  It also shows ways of introducing innovation in a more holistic manner, through the development of smart equipment, techniques, or innovative chemicals.”  (Green Processing and Synthesis, 1 August 2012)

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