The Handbook of Continuous Crystallization

Description

Continuous crystallization is an area of intense research, with particular respect to the pharmaceutical industry and fine chemicals. Improvements in continuous crystallization technologies offer chemical industries significant financial gains, through reduced expenditure and operational costs, and consistent product quality. Written by well-known leaders in the field, The Handbook of Continuous Crystallization presents fundamental and applied knowledge, with attention paid to application and scaling up, and the burgeoning area of process intensification. Beginning with concepts around crystallization techniques and control strategies, the reader will learn about experimental methods and computational tools. Case studies spanning fine and bulk chemicals, the pharmaceutical industry, and employing new mathematical tools, put theory into context. Cover The Handbook of Continuous Crystallization Preface Contents Chapter 1 - Nucleation and Crystal Growth in Continuous Crystallization† 1.2 Crystal Nucleation 1.2.1 Primary Nucleation 1.2.1.1 Mixing- induced Supersaturation 1.2.1.2 Shear 1.2.1.3 External Fields (Ultrasound, Laser, Electromagnetic) 1.2.1.3.1 Ultrasound- induced Nucleation.Sonocrystallization is the application of ultrasound to influence crystallization processes. The ... 1.2.1.3.2 Laser- induced Nucleation.Application of continuous wave42,43 or pulsed lasers44,45 can dramatically shorten induction times in ... 1.2.1.3.3 Effects of Electric or Magnetic Fields on Nucleation.A theoretical description of the effect of an electric field on the homogen... 1.2.2 Secondary Nucleation 1.2.2.1 Seeded Crystallization 1.2.2.2 Attrition, Fragmentation, Breakage 1.3 Continuous Crystallization 1.3.1 Crystalline Product Quality Attributes 1.3.2 Continuous Heterogeneous Crystallization on Excipient Surfaces 1.3.3 Agitated Vessel Type Crystallization Process 1.3.4 Plug Flow Type Crystallization Process 1.4 Continuous Seeding and Nucleators 1.4.1 Continuous Seeding 1.4.2 Decoupling Nucleation and Growth in Continuous Crystallization 1.4.3 Continuous Nucleators 1.4.4 Supersaturation Control by Rapid or Non- rapid Mixing 1.4.5 Ultrasound Induced Nucleation 1.4.6 Fully Continuous Crystallization in an MSMPR Cascade 1.4.7 Continuous MSMPR Cascade with Batch Crystallization Start Up 1.4.8 High Shear Wet Mill in MSMPR Configuration 1.4.9 Secondary Nucleators Abbreviations Roman Symbols Greek Symbols References Chapter 2 - Fundamentals of Population Balance Based Crystallization Process Modeling 2.1 Introduction 2.2 Modeling of Fundamental Crystallization Mechanisms 2.2.1 The Supersaturation 2.2.2 Nucleation 2.2.3 Growth and Dissolution 2.2.4 Modeling Crystal Agglomeration 2.2.5 Modeling Crystal Breakage 2.3 Modeling the MSMPR Crystallizer 2.3.1 MSMPR Crystallizer Configurations 2.4 Modeling the Tubular Crystallizer 2.4.1 Case Study: PFC With Multiple Feeding Points 2.5 Numerical Solution Methods for the Population Balance Equations 2.5.1 Moment Based Methods 2.5.2 Method of Characteristics 2.5.3 Finite Volume Methods 2.6 Advanced Crystallization Modeling – Case Studies 2.6.1 Modeling Solvent Mediated Polymorphic Transformation 2.6.1.1 Model Equations for a MSMPR Crystallizer 2.6.1.2 Solution Mediated Polymorphic Transformation in a PFC 2.6.2 Modeling Preferential Crystallization of Enantiomers 2.7 The Growth Rate Dispersion (GRD) Appendix A1 Derivation of the Population Balance Equation for Plug Flow Crystallizer A2 Derivation of the Mass Balance Equation for Plug Flow Crystallizer A3 Derivation of the Energy Balance Equation for Plug Flow Crystallizer Abbreviations Roman Symbols Greek Symbols References Chapter 3 - Continuous Crystallisation With Oscillatory Baffled Crystalliser Technology 3.1 Introduction 3.2 Plug Flow 3.2.1 The Definition 3.2.2 How to Measure Plug Flow 3.2.3 How Could Near Plug Flow Be Achieved in the Real World 3.3 Continuous Oscillatory Baffled Crystalliser 3.3.1 Principles 3.3.2 Mixing Evaluation in Single Phase 3.3.3 Mixing Evaluation in Two Phases 3.3.3.1 Liquid–Liquid 3.3.3.2 Solid–Liquid 3.3.3.3 Gas–Liquid 3.3.4 Moving Fluid vs. Moving Baffles 3.3.5 Scaling Up and Down 3.3.5.1 Scale Up 3.3.5.2 Scale Down 3.3.6 Power Dissipation 3.4 Design and Operation of Continuous Oscillatory Baffled Crystalliser 3.4.1 Linking the Design and Operation With Science 3.4.1.1 Start- up Process 3.4.1.2 Operation 3.4.1.3 Shut Down Process 3.4.1.4 The Presence of Bubbles 3.4.1.5 Generic Comments 3.5 What Has Been Done 3.5.1 Cooling Crystallisation 3.5.1.1 Unseeded Cases 3.5.1.2 Seeded Cases 3.5.2 Antisolvent Crystallisation and Seed Generator 3.5.2.1 Antisolvent Crystallisation 3.5.2.2 Seed Generator 3.5.3 Nucleation by Scraping 3.5.3.1 Experimental Setup and Procedure 3.5.3.2 Seeded Experiments 3.5.3.3 Unseeded Experiments 3.5.4 Encrustation 3.5.4.1 Case 1 – Due to Local Temperature 3.5.4.2 Case 2 – Due to Incorrect Seeding 3.5.4.3 Case 3 – Due to Insufficient Nuclei 3.5.4.4 Case 4 – Due to Suboptimal Hardware 3.5.4.5 Case 5 – Due to Recycle 3.5.4.6 Case 6 – Due to Oil out 3.5.5 PAT Implementation 3.6 What Are the Opportunities and Challenges 3.6.1 Reactive Crystallisation 3.6.2 Co- crystallisation 3.6.3 Crystallisation of Energetic Materials 3.6.4 Pressurized Crystallisation 3.6.5 Solvent Swap 3.7 Operational Boundary Roman Symbols Greek Symbols Acknowledgements References Chapter 4 - Process Control 4.1 Introduction 4.2 Controlled Variables 4.3 Measured Variables 4.4 Model-free Control Strategies 4.4.1 MSMPR Crystallizer 4.4.2 Plug-flow Crystallizer 4.4.3 Quality-by-design 4.5 Model-based Control Strategies 4.6 Fault Detection and Isolation 4.7 Actuators 4.8 Conclusions and Perspective References Chapter 5 - Slug-flow Continuous Crystallization: Fundamentals and Process Intensification 5.1 Introduction to Slug Flow Crystallization 5.1.1 State-of-the-art 5.1.2 Chapter Outline 5.2 Control Slug Stability 5.2.1 Stable Slug Flow for Crystallization Purposes 5.2.2 Hydrodynamically Stable Regime Analysis for Slug Flow 5.2.3 Flow Transition of Slug Flow 5.2.3.1 Transition from Bubbly to Slug- flow Regime 5.2.3.2 Transition from Short- bubble Slug Flow to Elongated- bubble Slug Flow 5.2.3.3 Transition from Slug Flow to Aerated Slug Flow 5.2.3.4 Effect of Inner Surface Property of Tubing 5.2.3.5 Effect of Tubing Diameter 5.3 Control Slug Geometry for Recirculation 5.3.1 Control Slug Size and Shape for Crystallization Purpose 5.3.2 Flow Analysis for Recirculation within Slugs 5.3.2.1 Dimensionless Recirculation Time 5.3.2.2 Absolute Recirculation Times 5.3.2.3 Mixing Efficiency 5.4 Controlled Crystal Growth in Slugs with Temperature Zones 5.4.1 Heat Baths for T Zones 5.4.2 Heat Exchangers for T Zones 5.5 Controlled Nucleation before Slug Formation 5.5.1 Micromixers 5.5.2 Sonication 5.6 Conclusions and Future Perspectives Roman Symbols References Chapter 6 - Continuous Crystallization of Bulk and Fine Chemicals 6.1 Introduction 6.2 Recommended General Literature 6.3 Challenges 6.4 Fundamentals 6.4.1 Solubility, Supersaturation and Particle Size 6.4.2 Growth Rate, Particle Size, Residence Time and Crystallizer Volume 6.4.3 Reaction Crystallization, Precipitation and Drowning- out Crystallization 6.4.4 Importance of Mixing and Classification 6.5 The Idealized Continuous Crystallizer– MSMPR 6.6 Variants of Crystallizers for Satisfying Special Product Requirements 6.6.1 Classified Product Removal 6.6.2 Fines Dissolution 6.6.3 Minimisation of the Nucleation Rate 6.6.4 Mother Liquor Advance 6.7 Energy Consumption 6.8 Process Integration 6.9 Summary References Chapter 7 - Process Intensification in Continuous Crystallization 7.1 Introduction 7.2 Time Domain 7.2.1 Crystallizer Designs 7.2.2 Periodic Operation 7.3 Space Domain 7.3.1 Structure 7.3.2 Miniaturization 7.3.2.1 Microfluidic Devices 7.4 Function Domain 7.4.1 Hybrid Processes 7.4.1.1 Chromatography- crystallization Process 7.4.1.2 Membrane- crystallization Process 7.4.1.3 Distillation- crystallization Process 7.4.2 Process Integration 7.4.2.1 Spherical Crystallization 7.4.2.2 Integrated Wet Mill Crystallization 7.4.2.3 Multifunctional Equipment 7.5 Energy Domain 7.5.1 Ultrasound 7.5.2 Electric Fields 7.5.3 Microwave Fields 7.6 New Challenges for Process Intensification in Continuous Crystallization References Chapter 8 - Continuous Membrane Crystallization 8.1 Introduction 8.2 Principles of Membrane Crystallization Technology 8.3 Membrane Materials and Transport Phenomena 8.4 Heterogeneous Nucleation on Membranes 8.5 Membrane Crystallization of Proteins 8.6 Crystal Morphology and Polymorphism 8.6.1 Influence of the Transmembrane Flux 8.6.2 Influence of the Chemistry of the Surface 8.7 Continuous Membrane Crystallization Processes 8.8 Operational Stability Abbreviations References Chapter 9 - Process Analytical Technology in Continuous Crystallization† 9.2 Process Analytical Technology Instruments 9.2.1 Focused Beam Reflectance Measurement 9.2.2 Ultraviolet- visible and Attenuated Total Reflectance Fourier- transform Infrared Spectroscopy 9.2.3 Raman Spectroscopy 9.2.4 Imaging and Particle Vision Measurement (PVM) 9.3 Data Analysis and Management 9.4 Systematic Steady- state Detection Using Econometrics 9.5 Model- free PAT- based Control Strategies 9.6 MSMPR Crystallizer Monitoring 9.7 Monitoring of Tubular Crystallizers References Chapter 10 - Continuous Protein Crystallization 10.1 Downstream Processing of Proteins 10.2 Protein Crystals 10.3 Development of Continuous Protein Crystallisation 10.3.1 Screening and Phase Diagram 10.3.2 Scale- up and Mixing 10.3.3 Transition from Batch to Continuous Crystallisation 10.3.4 Case Study: Development of Oscillatory Flow Protein Crystallisation 10.4 Outlooks and Perspectives Abbreviations Acknowledgements References Chapter 11 - Continuous Melt Crystallization 11.1 Introduction 11.1.1 Definitions for Melt Crystallization 11.1.2 Features of Melt Crystallization 11.1.3 Material Selection 11.2 Theoretical Basis 11.2.1 Phase Diagram 11.2.2 Crystallization Kinetics 11.2.2.1 Crystal Nucleation15,16 11.2.2.2 Crystal Growth15–17 11.2.3 Model Description of Melt Crystallization 11.2.3.1 Mass Transfer 11.2.3.2 Heat Transfer 11.3 Post- crystallization Processes 11.3.1 Sweating 11.3.2 Washing 11.4 Continuous Melt Crystallization 11.4.1 Continuous Suspension Crystallization 11.4.1.1 MSMPR Crystallizer 11.4.1.2 Inclined Column Crystallizer 11.4.1.3 Cooling Disk Crystallizer 11.4.1.4 Schildknecht Column 11.4.1.5 Philips Crystallizer 11.4.1.6 Brodie Crystallizer 11.4.1.7 TNO Purifier 11.4.1.8 Kureha Crystal Purifier (KCP) 11.4.1.9 Brennan–Koppers Purifier 11.4.1.10 Counter Current Cooling Crystallization (CCCC Crystallizer) 11.4.1.11 Sulzer Suspension Crystallization Technology 11.4.1.12 Sulzer Multiblok Suspension Melt Crystallizer 11.4.1.13 Other Suspension Melt Crystallizers 11.4.2 Solid Layer Crystallization 11.4.2.1 Crystallization on a Cooled Belt 11.4.2.2 Crystallization on a Rotary Drum 11.4.2.3 Zone Melting Crystallization 11.4.3 Other Crystallization Methods 11.4.3.1 Pastille Crystallization Method 11.4.3.2 Eutectic Freeze Crystallization (EFC) 11.5 Applications of Continuous Melt Crystallization 11.5.1 Separation of Organic Mixtures 11.5.2 Production of Ultra- pure Inorganic Products 11.5.3 Concentration 11.6 Outlook Roman Symbols Greek Symbols References Chapter 12 - Continuous Enantioselective Crystallization of Chiral Compounds 12.1 Introduction 12.2 Phase Equilibria of Chiral Systems 12.3 Preferential Crystallization: Kinetics, Driving Forces and Metastable Zones 12.4 Process Variants of PC 12.4.1 Batch Processes of PC 12.4.1.1 Conventional and Cyclic Preferential Batch Crystallization (PC) 12.4.1.2 Coupled Batch Preferential Crystallization (CPC) 12.4.1.3 Coupled Preferential Crystallization and Selective Dissolution (CPC- D) 12.4.2 Continuous Processes of PC 12.4.2.1 MSPMR Concept 12.4.2.2 Continuous Enantioseparation in Fluidized Bed Crystallizers 12.5 Case Studies 12.5.1 Resolution of dl- Threonine 12.5.1.1 Solubility Data for the dl- Threonine System 12.5.1.2 Metastable Zone Width and Crystallization Kinetics 12.5.1.3 Cyclic Batch Operation of PC 12.5.1.4 Batch PC Coupled with Selective Dissolution (CPC- D) 12.5.1.5 PC in Continuously Operated Coupled MSPMR 12.5.1.6 Comparison of Different Process Options 12.5.2 Resolution of Racemic Asparagine Monohydrate 12.5.2.1 Solubility Data for Asparagine Monohydrate 12.5.2.2 Metastable Zone Width and Crystallization Kinetics 12.5.2.3 Implementation of Coupled Continuously Operated Fluidized Bed Crystallizers 12.5.2.4 Application of Coupled Continuously Operated Fluidized Bed Crystallizers 12.5.2.5 Comparison with Batchwise Operated PC 12.6 Conclusions and Outlook Abbreviations Roman Symbols Greek Symbols Superscripts Subscripts Acknowledgements References Chapter 13 - Continuous Isolation of Active Pharmaceutical Ingredients 13.1 Introduction 13.2 Underlying Science and Engineering 13.3 Filtration 13.3.1 Filter Medium and Medium Resistance 13.3.2 Specific Cake Resistance 13.3.3 Mother Liquor Viscosity 13.4 Washing 13.4.1 Displacement Washing 13.4.2 Deliquored Cake Washing 13.4.3 Resuspension Washing 13.4.4 Wash Solvent Selection – Washing to Purify 13.4.5 Washing to Avoid Granule Formation During Drying 13.4.6 Deliquoring the Washed Cake Prior to Drying 13.5 Drying 13.5.1 Determining the Thermal Energy Required for Drying 13.5.2 Agitation 13.5.3 Drying Kinetics 13.6 Application of These Principles to Continuous Isolation 13.6.1 Drum Filtration 13.6.2 Belt Filtration 13.6.3 Semi Continuous (Sequential Batch Filtration) 13.7 Commercially Available Filtration and Drying Technologies 13.7.1 Rotary Drum Vacuum Filters (RDVF) 13.7.2 Rotary Pressure Filter/Dryer (RPF) 13.7.3 Indexing Belt Filter (BF) 13.7.4 Carousel Vacuum and Pressure Filter/Dryer 13.7.5 Agitated Nutsche Filter Dryers (ANFDs) 13.8 General Guidance and Troubleshooting 13.8.1 Cake Formation 13.8.2 Cake Cracking 13.8.3 Isolating Large Crystals/Agglomerates 13.8.4 Reasonable Washing Expectations 13.8.5 Drying 13.8.6 Further Troubleshooting Strategies 13.9 Solutions to Issues Observed in Isolation Systems References Chapter 14 - Continuous Eutectic Freeze Crystallization 14.1 Introduction 14.1.1 What is Eutectic Freeze Crystallization (EFC) 14.1.2 EFC Compared With Other Separation Technologies 14.1.3 Theoretical Basis – Binary Phase Diagrams 14.1.4 Theoretical Basis – Ternary and Quaternary Phase Diagrams 14.2 Thermodynamic Modelling of EFC for Saline Streams 14.2.1 ASPEN Plus V10 14.2.2 FactSage V7.2 14.2.3 HSC Chemistry V5.1 14.2.4 MINTEQ V3.1 14.2.5 PHREEQC V3 14.2.6 OLI Stream Analyzer 9.5 14.2.7 Summary of Thermodynamic Software Packages 14.3 Understanding EFC from a Melt Crystallization Point of View 14.4 Defining Supersaturation in Eutectic Freeze Crystallization 14.5 Mechanisms 14.5.1 Metastable Zone Width 14.5.2 Nucleation 14.5.2.1 Primary Nucleation 14.5.2.2 Secondary Nucleation 14.5.3 Growth 14.5.4 Ice Growth 14.5.5 Salt Crystal Growth 14.6 Coupled Heat and Mass Transfer Problem 14.7 Heat Transfer 14.8 Why Continuous EFC 14.8.1 Continuous EFC Process Flow 14.9 Stages in Continuous Eutectic Freeze Crystallization 14.10 Scaling 14.10.1 Thermal Boundary Layer 14.11 Adhesion 14.12 Establishing the Feasibility of EFC for Treatment of Saline Streams 14.12.1 What Is a Saline Stream 14.12.2 Options for Treatment of Highly Saline Streams 14.13 Example of Thermodynamic Modelling of a Brine Stream Being Subjected to EFC 14.13.1 Modelling Using the OLI Stream Analyzer 9.5 14.14 Scaling Up EFC 14.15 Conclusions and Future Perspectives Roman Symbols Greek Symbols Abbreviations Acknowledgements References Chapter 15 - Economic Analysis of Continuous Crystallisation† 15.1 Introduction 15.2 Economic Analysis of Pharmaceutical Processes 15.2.1 Capital Expenditure (CapEx) 15.2.2 Operating Expenditure (OpEx) 15.2.3 Prices and Costing Factor Databases 15.2.4 Costing of Continuous Processes 15.3 Continuous Crystalliser Designs 15.3.1 Mixed Suspension- mixed Product Removal Crystalliser (MSMPR) 15.3.2 Plug Flow Crystalliser (PFC) 15.3.3 Continuous Oscillatory Baffled Crystallisers (COBC) 15.4 Nonlinear Optimisation 15.5 Economic Analysis and Optimisation Case Studies of Various Active Pharmaceutical Ingredients 15.5.1 Comparative Economic Evaluation of MSMPR Configurations: Cyclosporine 15.5.1.1 Steady- state MSMPR Crystallisation: With and Without Solids Recycle 15.5.1.2 Operational Performances of Different Process Configurations 15.5.1.3 Technoeconomic Comparative Evaluations 15.5.2 Cost Optimisation of MSMPR Cascades: Cyclosporine, Paracetamol, Aliskiren 15.5.2.1 Nonlinear Optimisation of MSMPR Configurations 15.5.2.2 Cost Optimal MSMPR Design and Operating Parameters 15.5.2.3 Minimum Total Cost Components 15.5.3 Design and Optimisation of COBCs: Paracetamol 15.5.3.1 COBC Design Space Investigation for Paracetamol Crystallisation 15.5.3.2 Nonlinear Optimisation Problem Formulation 15.6 Conclusions Roman Symbols Greek Symbols Abbreviations Acknowledgements References Chapter 16 - Digital Design and Operation of Continuous Crystallization Processes via Mechanistic Modelling Tools 16.1 Introduction 16.2 Process Development Workflows for Continuous Crystallization 16.3 Fundamentals of Mechanistic Process Modelling in Continuous Crystallization Processes 16.3.1 Purposes of Process Modelling in Pharmaceutical Applications 16.3.2 Considerations for Continuous Crystallization Processes 16.3.3 Process Systems Engineering Tools 16.3.4 Model Verification and Validation 16.3.5 Uncertainty Analysis 16.3.6 Risk Management through Sensitivity Analysis 16.4 Digital Design Case Study – Batch to Continuous Workflow 16.5 Digital Operation Case Study: Utilizing Mechanistic Modelling for Development of a Model Predictive Controller (MPC) 16.5.1 Introduction to Model Predictive Control 16.5.2 Data Driven Approach to Advanced Control for Crystallization 16.5.3 Digital Design Approach to Advanced Control for Crystallization 16.6 Conclusion 16.7 Summary References Subject Index