Right. First Time in Fine-Chemical Process Scale-up. Lum(Bert)us A. Hulshof. Avoiding scale-up problems: the key to rapid success

Transcription

1 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

2 V Preface About the author Abbreviations i Hi v xi Chapter 1 The scene 1.1 Characteristics of the market Classification of chemical products Characteristics of fine-chemical processes Chemistry features Complicated molecular architectures Process selectivity Waste management Great variety of products and processes Sustainability Practical consequences of waste reduction A labyrinth of options in process selection The role of catalysis in designing fine-chemical processes Chemical Engineering aspects Destination ofthe fine-chemical processes: the hardware Batch-reactors Solid-liquid separation equipment Dryers Miscellaneous Bridging the gap between large and lab-scale: the software Classification of chemical reactions Heat balance Kinetics Characteristic time evaluation upon process scale-up Runaways avoidance and safety Plant procedures Mass balances and block-schemes Flowsheeting Current good manufacturing practice Process intensification Process architecture Analytical and quality aspects General Development of suitable analytical methods Process analytical technology Quality-by-design Conclusions 65 References 66 Chapter 2 Challenges in process development 2.1 Challenges in the collaboration between chemists and chemical engineers Making the right choices in process development A "flexible" heat balance The relativity oftime (1) The relativity of time (2) 74

3 v/ 2.3 Multi-variable selection problems Introductory remarks to DoE Basic principles of DoE Modeling of response surfaces Selecting the right reactants and solvents Selecting the right process parameters Reducing the number of experiments and enhancing the number of parameters A brieftour of a multi-variable selection approach Multi-variable screening problems Concluding remarks High-throughput experimentation Automation in process development Route scouting Process optimisation Process definition and validation Software and data mining Concluding remark Microprocessing Continuous processing Learning from dedicated continuous plants A new wave of continuous operation in the fine-chemicals industry The benefits of microwave heating Dedicated microwave equipment Scope and limitations in microwave applications Alleged beneficial microwave effects Energy efficiencies of microwave and conventional heating Added value of microwave heating Process scalability potential Penetration depth and loss tangent Larger volume examples Various microwave-assisted process scale-up strategies Microwave-enhanced microprocessing Concluding remarks on fine-chemical microwave applications Concluding remarks of this chapter 127 References 128 Chapter 3 Challenges in process scale-up 3.1 Challenges in batch-process design General challenges in process research, development and scale-up 136 ' 3.3 Challenges of bridging different scales and procedures Challenges of defining robustness in process scalability Challenges of defining the scale-up rule Challenges of mastering mixing as a crucial parameter in process scale-up Single-phase and two-phase systems Competitive-consecutive reactions Competitive-parallel reactions Applications of these mixing-sensitive competitive reactions Liquid-liquid systems Breakage of drops Drop coalescence Drop-size distribution and process scale-up Extractive reactions Solid-liquid systems Solids in liquids: complete suspension 15 8

4 vii Solids in liquids: entrainment of floating solids Solids in liquids: dissolution of solids Crystallisations as solid-liquid systems Attrition in crystallisations Polymorphism Liquids in solids (drying) Gas-liquid systems Gas in liquid systems Sparged systems (two-phase) Sparged systems (three-phase) Surface-aerated systems (two-phase) Surface-aerated systems (three-phase) Foaming Gas disengagement Batch-evaporations / distillations Challenges in scaling up non-newtonian reaction mixtures Challenges in product isolation Remaining challenges in process scale-up Heat transfer Longer processing times Quality change of raw materials Equipment selection Recycling Cleaning Concluding remarks 201 References 203 Chapter 4 Historic examples of surprises in fine-chemical process scale-up 4.1 Introduction Real-life cases Concluding remarks 382 References 384 Chapter 5 How to deal with the primary causes and solutions? 5.1 Introduction Evaluation of all 240 cases Hidden regularities: the ALICE knowledge base Mass transfer and mixing Residence time Heat exchange Quality change in raw materials Isolation Choice of equipment Cleaning of equipment / ancillaries Polymorphism Recycling Changing the large-scale procedure Inertisation Foaming Route selection / process design Downscaling problem Further analysis of the (non)-flyer examples Solutions 412

5 viii Mass transfer (Meso)-mixing Surprises in residence time Solutions in heat exchange Corrections regarding the quality of raw materials Corrections regarding isolation problems Corrected equipment choices Cleaning corrections Corrections regarding polymorphism issues Corrections regarding recycling issues Corrections regarding risky changes in the large-scale procedure Inertisation corrections Corrections regarding excessive foaming Corrections regarding route selection and process design Corrections in downscaling Some marginalia 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 Checklist for an interactive approach between chemists and chemical engineers Consequences for defining the operational window of the chemist in the lab Duration tests Proper downscaling tests in a downscaled lab-reactor Downscaling the stirred batch-reactor Downscaling the heat-exchange surface area during heat input / removal Downscaling dosing Downscaling heterogeneous systems Downscaling crystallisations Downscaling filtrations Downscaling drying Downscaling batch-evaporations / distillations Downscaling batch-extractions Backcasting (precision in downscaling) recommended Concluding remarks ALICE'S dream ofthe future 469 References 471 Index 473