The Handbook of Continuous Crystallization

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