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