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Practical Process Research and Development

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ISBN-10: 0120594757

ISBN-13: 9780120594757

Edition: 2000

Authors: Neal G. Anderson

List price: $170.00
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Description:

This text provides a comprehensive, step-by-step approach to organic process research and development in the pharmaceutical, fine chemical, and agricultural chemical industries.
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Book details

List price: $170.00
Copyright year: 2000
Publisher: Elsevier Science & Technology Books
Publication date: 6/5/2000
Binding: Hardcover
Pages: 354
Size: 6.25" wide x 9.25" long x 0.75" tall
Weight: 1.386
Language: English

Roy Davies is a Professor of Machine Vision at Royal Holloway, University of London, and has extensive experience of machine vision, image analysis, automated visual inspection, and noise suppression techniques. His book Electronics, Noise, and Signal Recovery was published in 1993 by Academic Press, and is a useful companion to the present volume.Neal G. Anderson, Ph.D., has worked for over 20 years in chemical process R&D in the pharmaceutical industry. He earned a B.S. degree from the University of Illinois and a Ph.D. in medicinal chemistry from the University of Michigan and completed post-doctoral studies at McNeil Laboratories. With almost 18 years in process R&D at Bristol-Myers Squibb Co. in New Brunswick, New Jersey, Dr. Anderson has extensive hands-on experience in the laboratory, pilot plant, and manufacturing facilities. He has made key contributions to processes for the manufacture of four major drug substances, including captopril, and has participated in 12 manufacturing start-ups and successfully introduced many processes to pilot plants. He received the Bristol-Myers Squibb President's Award and spot awards, and his final position was Principal Scientist.In 1997, Dr. Anderson established Process Solutions L.L.C., a consulting firm offering practical guidance on developing and implementing processes for bulk pharmaceuticals and fine chemicals. As part of these consulting services, he presents courses on selected aspects of practical process R&D.

Foreword
Foreword
Preface
About the Author
Approaches to Process Development
Introduction
The Importance of Simple Scale-up Operations
The Importance of Teamwork
Determining Operations That Can and Cannot Readily Be Used On Scale
Rotary Evaporation
Concentrating to Dryness
Triturating
Flammable Solvents
Decanting and Siphoning
Column Chromatography for Purification
Drying over Solid Desiccants
Drying Solutions by Azeotropic Distillation
Addition of Dangerous Reagents
Extended Additions
Maintaining Cryogenic Temperature
Fine Control of Heating and Cooling
Maintaining Constant pH
Efficient Mixing of Heterogeneous Systems
Tubular Flow Reactors
Rapid Quench and Transfers
Distillation
Solvent Displacement by Distillation (Solvent Chasing)
Reslurry
Charcoal Treatment
Filtration of Solid Particles
Drying Solids
Lyophilization
Safety Considerations
Taking Advantage of Serendipity and Good Observations
Define the Time Available for Process Optimization
References
Route Selection
Introduction
Characteristics of Expedient Routes
Familiarity
Technical Feasibility
Availability of Suitable Equipment
Characteristics of Cost-Effective Routes
Technical Feasibility
Availability of Suitable Equipment
Long-Term Availability of Inexpensive Reagents and Starting Materials
Convergent Synthesis
Using Telescopic Work-ups
Minimizing Impact from Protecting Groups
Minimizing Number of Steps
Avoiding Adjusting Oxidation States
Enantiospecific and Stereospecific Reactions
Incorporating Unexpected Processing
Incorporating Rearrangements
Focusing on a Common Penultimate or Key Intermediate
Facile Rework for Final Product and Intermediates
Patent Protection for Manufacturing Route
Minimized Environmental Impact
Using Cost Estimates to Assess the Ultimate Route
Summary
References
Reagent Selection
Introduction
The Ideal Reagent for Scale-up
Importance of Writing a Balanced Equation
Safety and Toxicity Considerations
Cost of Reagents
Atom Efficiency
Families of Reagents Useful for Scale-up
Reagents for Deprotonation
Alkoxide Bases
Amine Bases
Oxidations
Reductants
Hydroboration
Catalytic Reagents
Polymeric Reagents
Biocatalysts as Preparative Reagents
References
Solvent Selection
Introduction
Solvation and Primary Solvent Characteristics
Primary Solvent Characteristics
Selecting Solvents Based on Physical Characteristics
Solvents Inappropriate for Scale-up
Solvents Useful for Scale-up
Selected Solvent Impurities
Applications of Solvents
Choosing Solvents for Homogeneous Reactions
Choosing Solvents to Increase the Desired Reaction Rate
Choosing Solvents to Provide Heterogeneous Reaction Conditions
Choosing Solvents to Increase the "Stir-ability" of Reactions
Choosing Solvents to Remove Impurities by Azeotropic Distillation
Choosing Solvents to Remove Impurities by Adding an Immisicible Solvent and Extraction
Choosing Solvents to Remove By-products by Crystallization or Precipitation
Choosing Solvents to Purify the Product by Crystallization or Recrystalization
Choosing Solvents to Increase the Safety of Operations
Choosing Solvents to Decrease Atmospheric Emissions and Losses to Process Streams
Choosing Readily Available Solvents
Choosing Solvents to Decrease Immediate Contributions to Overall Product Cost
Alternatives to Classical Solvents
Water
Neat Reactions
Possible Future Directions
References
Running the Reaction
Introduction
Determining Reaction Safety
Assessing Safe Operating Conditions for the Laboratory
Selecting the Reaction Scale
Choose Equivalents of Reagents, Starting Materials, and Solvents
Employ Inert Conditions if Needed
Charge Starting Materials and Solvents
Select Reaction Temperature
Select the Duration and Temperature of an Addition
Select the Sequence of Additions
Select Reaction Pressure
Adjust Stirring
Monitor the Reaction Conditions
References
Effects of Water
Introduction
Detecting and Quantitating Water
Removing Water from Routine Organic Processing
Entry of Water through Processing Air
Entry of Water through Solvents
Entry of Water through Reagents
Formation of Water as a By-product and Its Removal
Removing Water from Processing Equipment
References
In-Process Controls
Introduction
The Importance of IPC for Processes Filed with the FDA
Choosing the Appropriate IPC
Generating Reproducible IPCs
Obtaining a Representative Sample of the Process Stream
Reproducible Sample Preparation
In-Line Assays
Generating Reproducible Assay Data
References
Optimizing the Reaction by Minimizing Impurities
Introduction
Steps to Optimizing Reactions
Optimizing Reaction Temperature
Optimizing Number of Reagent Equivalents
Optimizing Addition of Reagents
Optimizing Use of Solvents and Cosolvents
Optimizing Reaction Concentration
Changing Reagents and Intermediates
Optimizing Catalysts and Ligands
Optimizing Stirring
Importance of Extending Reaction Times
Examine Other Operating Conditions
Minimizing Impurity Formation by Identifying Impurities First
Statistical Design of Experiments
Robotics and Automated Process Optimization
References
Optimizing Catalytic Reactions
Introduction
Catalyst Selection/Ligand Selection
Optimizing Catalyst Concentration
Generating Active Catalysts
Importance of Extended Additions
Influence of Co-catalysts and Impurities
Catalyst Decomposition
Nonlinear Catalyst Effects
The Difficulty of Optimizing a Catalytic Reaction
References
Work-up
Introduction
Aspects of Work-up
Quench
Extraction
Activating Carbon Treatment
Filtration
Concentrating Solutions and Solvent Displacement
Deionization and Removing Metals
Destruction of Process Streams
Derivatization
Solid-Supported Reagents
References
Tools for Purifying the Product: Column Chromatography, Crystallization, and Reslurrying
Introduction
Purification by Column Chromatography
Crystallization
Crystallization Theory and Crystallization Pressures
Classification of Solids: Morphic States
Salt Selection
Predicting the Ability to Scale Up a Crystallization Process by Lab Examination
Washing and Drying Solid Products
Purification by Reslurrying
References
Final Product Form and Impurity Considerations
Introduction
The Importance of Solid State Characteristics
Stability Testing
The Importance of Controlling Particle Size of a Drug Substance
Preparing and Selecting the Polymorph
Varying Crystallization Conditions in Order to Prepare Polymorphs
Purity and Impurity Considerations: Freezing the Final Process
Considerations for Preparing the Toxicology Batch and Subsequent Batches
Minimizing Impurities in the Drug Substance
References
Vessels and Mixing
Introduction
Batch vs. Continuous Processing
Batch Processing
Continuous Operations
Semicontinuous Operations
Drawbacks of Continuous Processes
Use of Continuous Flow Reactors to Scale Up Processes
Static Mixers
Immobilized Catalysts
Photochemical Reactors
Microwave Reactors
Sonochemical Reactors
Plug Flow Reactors
Electrochemical Reactors
References
Preparing for and Implementing the Scale-up Run
Introduction
Anticipating Scale-up Problems
Scale-up Considerations
Identify the Goals of Scale-up
Safety Considerations
Identify Critical Processing Steps
Define Equipment Limitations
Use a Rugged IPC for the Scale-up Operation
Develop Contingency Plans for Incomplete and Runaway Reactions
Know Effects of Extended and Interrupted Processing
Develop Methods to Qualify Components
Examine Process Tolerances for Scale-up
Ensure That Thorough Product Analyses Are in Place
Identify Cleaning Procedures and Waste Disposal Procedures
Guidelines for Documentation: Efficient Process Transfer
Implementing the Scale-up Run
Checklists to Prepare for the Scale-up Run
Guidelines for Executing the Run in a Pilot Plant or Manufacturing Operation
Guidelines for Executing the Run in a Kilo Lab Operation
References
Troubleshooting
Introduction
Physical and Chemical Causes of Processing Problems
Steps for Troubleshooting a Process
Debottlenecking a Problem
References
Chiral Syntheses
Introduction
Some Examples of Molecules Prepared by Asymmetric Synthesis
Products from Fermentation and the Chiral Pool
The Crystalline Nature of Enantiomeric Compounds and Approaches for Resolution
Compounds Prepared by Asymmetric Synthesis
Perspective on Asymmetric Synthesis
References
General Index
Reaction Type Index
Reagent Index