Right First Time in Fine-Chemical Process Scale-up Avoiding scale-up problems: the key to rapid success Lum(Bert)us A. Hulshof Eindhoven University of Technology Eindhoven, The Netherlands
V Preface About the author Abbreviations i Hi v xi Chapter 1 The scene 1.1 Characteristics of the market 1 1.2 Classification of chemical products 2 1.3 Characteristics of fine-chemical processes 3 1.4 Chemistry features 3 1.4.1 Complicated molecular architectures 3 1.4.2 Process selectivity 3 1.4.3 Waste management 4 1.4.4 Great variety of products and processes 4 1.4.5 Sustainability 8 1.4.6 Practical consequences of waste reduction 9 1.4.7 A labyrinth of options in process selection 15 1.4.8 The role of catalysis in designing fine-chemical processes 21 1.5 Chemical Engineering aspects 28 1.5.1 Destination ofthe fine-chemical processes: the hardware 30 1.5.1.1 Batch-reactors 30 1.5.1.2 Solid-liquid separation equipment 35 1.5.1.3 Dryers 38 1.5.1.4 Miscellaneous 39 1.5.2 Bridging the gap between large and lab-scale: the software 39 1.5.2.1 Classification of chemical reactions 39 1.5.2.2 Heat balance 40 1.5.2.3 Kinetics 43 1.5.2.4 Characteristic time evaluation upon process scale-up 45 1.5.2.5 Runaways avoidance and safety 48 1.5.2.6 Plant procedures 54 1.5.2.7 Mass balances and block-schemes 54 1.5.2.8 Flowsheeting 55 1.5.2.9 Current good manufacturing practice 58 1.5.2.10 Process intensification 59 1.5.2.11 Process architecture 61 1.6 Analytical and quality aspects 62 1.6.1 General 62 1.6.2 Development of suitable analytical methods 63 1.6.3 Process analytical technology 63 1.6.4 Quality-by-design 64 1.7 Conclusions 65 References 66 Chapter 2 Challenges in process development 2.1 Challenges in the collaboration between chemists and chemical engineers 71 2.2 Making the right choices in process development 73 2.2.1 A "flexible" heat balance 73 2.2.2 The relativity oftime (1) 74 2.2.3 The relativity of time (2) 74
v/ 2.3 Multi-variable selection problems 75 2.3.1 Introductory remarks to DoE 77 2.3.2 Basic principles of DoE 78 2.3.3 Modeling of response surfaces 81 2.3.4 Selecting the right reactants and solvents 82 2.3.5 Selecting the right process parameters 84 2.3.6 Reducing the number of experiments and enhancing the number of parameters 84 2.3.7 A brieftour of a multi-variable selection approach 94 2.3.8 Multi-variable screening problems 94 2.3.9 Concluding remarks 96 2.4 High-throughput experimentation 97 2.4.1 Automation in process development 97 2.4.1.1 Route scouting 97 2.4.1.2 Process optimisation 100 2.4.1.3 Process definition and validation 102 2.4.2 Software and data mining 103 2.4.3 Concluding remark 103 2.5 Microprocessing 103 2.6 Continuous processing 109 2.6.1 Learning from dedicated continuous plants 110 2.6.2 A new wave of continuous operation in the fine-chemicals industry 114 2.7 The benefits of microwave heating 116 2.7.1 Dedicated microwave equipment 116 2.7.2 Scope and limitations in microwave applications 117 2.7.2.1 Alleged beneficial microwave effects 117 2.7.2.2 Energy efficiencies of microwave and conventional heating 121 2.7.2.3 Added value of microwave heating 122 2.7.3 Process scalability potential 122 2.7.3.1 Penetration depth and loss tangent 123 2.7.3.2 Larger volume examples 124 2.7.3.3 Various microwave-assisted process scale-up strategies 125 2.7.3.4 Microwave-enhanced microprocessing 126 2.7.4 Concluding remarks on fine-chemical microwave applications 126 2.8 Concluding remarks of this chapter 127 References 128 Chapter 3 Challenges in process scale-up 3.1 Challenges in batch-process design 135 3.2 General challenges in process research, development and scale-up 136 ' 3.3 Challenges of bridging different scales and procedures 136 3.4 Challenges of defining robustness in process scalability 139 3.5 Challenges of defining the scale-up rule 145 3.6 Challenges of mastering mixing as a crucial parameter in process scale-up 146 3.6.1 Single-phase and two-phase systems 149 3.6.1.1 Competitive-consecutive reactions 149 3.6.1.2 Competitive-parallel reactions 152 3.6.1.3 Applications of these mixing-sensitive competitive reactions 154 3.6.2 Liquid-liquid systems 154 3.6.2.1 Breakage of drops 156 3.6.2.2 Drop coalescence 156 3.6.2.3 Drop-size distribution and process scale-up 156 3.6.2.4 Extractive reactions 158 3.6.3 Solid-liquid systems 158 3.6.3.1 Solids in liquids: complete suspension 15 8
vii 3.6.3.2 Solids in liquids: entrainment of floating solids 161 3.6.3.3 Solids in liquids: dissolution of solids 161 3.6.3.4 Crystallisations as solid-liquid systems 164 3.6.3.5 Attrition in crystallisations 169 3.6.3.6 Polymorphism 171 3.6.3.7 Liquids in solids (drying) 173 3.6.4 Gas-liquid systems 176 3.6.4.1 Gas in liquid systems 176 3.6.4.2 Sparged systems (two-phase) 176 3.6.4.3 Sparged systems (three-phase) 179 3.6.4.4 Surface-aerated systems (two-phase) 184 3.6.4.5 Surface-aerated systems (three-phase) 185 3.6.4.6 Foaming 186 3.6.4.7 Gas disengagement 189 3.6.4.8 Batch-evaporations / distillations 189 3.7 Challenges in scaling up non-newtonian reaction mixtures 191 3.8 Challenges in product isolation 193 3.9 Remaining challenges in process scale-up 198 3.9.1 Heat transfer 199 3.9.2 Longer processing times 199 3.9.3 Quality change of raw materials 200 3.9.4 Equipment selection 201 3.9.5 Recycling 201 3.9.6 Cleaning 201 3.10 Concluding remarks 201 References 203 Chapter 4 Historic examples of surprises in fine-chemical process scale-up 4.1 Introduction 209 4.2 Real-life cases 209 4.3 Concluding remarks 382 References 384 Chapter 5 How to deal with the primary causes and solutions? 5.1 Introduction 389 5.2 Evaluation of all 240 cases 389 5.3 Hidden regularities: the ALICE knowledge base 404 5.3.1 Mass transfer and mixing 405 5.3.2 Residence time 405 5.3.3 Heat exchange 407 5.3.4 Quality change in raw materials 408 5.3.5 Isolation 409 5.3.6 Choice of equipment 409 5.3.7 Cleaning of equipment / ancillaries 409 5.3.8 Polymorphism 409 5.3.9 Recycling 410 5.3.10 Changing the large-scale procedure 410 5.3.11 Inertisation 410 5.3.12 Foaming 410 5.3.13 Route selection / process design 410 5.3.14 Downscaling problem 410 5.4 Further analysis of the (non)-flyer examples 410 5.5 Solutions 412
viii 5.5.1 Mass transfer 412 5.5.2 (Meso)-mixing 412 5.5.3 Surprises in residence time 415 5.5.4 Solutions in heat exchange 417 5.5.5 Corrections regarding the quality of raw materials 418 5.5.6 Corrections regarding isolation problems 419 5.5.7 Corrected equipment choices 421 5.5.8 Cleaning corrections 421 5.5.9 Corrections regarding polymorphism issues 422 5.5.10 Corrections regarding recycling issues 422 5.5.11 Corrections regarding risky changes in the large-scale procedure 422 5.5.12 Inertisation corrections 422 5.5.13 Corrections regarding excessive foaming 423 5.5.14 Corrections regarding route selection and process design 423 5.5.15 Corrections in downscaling 423 5.6 Some marginalia 423 5.7 Concluding remarks 425 References 426 Addenda 427 Addendum 5.1: Survey of rel. chemical reactions / physical operations in alphabetical order 427 Addendum 5.2: Survey of related chemical reactions and physical operations 430 Addendum 5.3: Survey of related products 433 Addendum 5.4: Overview ofthe companies and institutes with (non)-flyer experience 437 Addendum 5.5: Survey of the years wherein the cases were collected / published 438 Chapter 6 Could the surprises have been avoided? 6.1 Introduction 439 6.2 Checklist for an interactive approach between chemists and chemical engineers 439 6.3 Consequences for defining the operational window of the chemist in the lab 446 6.3.1 Duration tests 447 6.3.2 Proper downscaling tests in a downscaled lab-reactor 448 6.3.2.1 Downscaling the stirred batch-reactor 448 6.3.2.2 Downscaling the heat-exchange surface area during heat input / removal 449 6.3.2.3 Downscaling dosing 452 6.3.2.4 Downscaling heterogeneous systems 456 6.3.2.5 Downscaling crystallisations 461 6.3.2.6 Downscaling filtrations 463 6.3.2.7 Downscaling drying 464 6.3.2.8 Downscaling batch-evaporations / distillations 465 6.3.2.9 Downscaling batch-extractions 465 6.4 Backcasting (precision in downscaling) recommended 466 6.5 Concluding remarks 468 6.6 ALICE'S dream ofthe future 469 References 471 Index 473