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Book Description

A guide to the development and manufacturing of pharmaceutical products written for professionals in the industry, revised second edition

The revised and updated second edition of Chemical Engineering in the Pharmaceutical Industry is a practical book that highlights chemistry and chemical engineering. The book’s regulatory quality strategies target the development and manufacturing of pharmaceutically active ingredients of pharmaceutical products. The expanded second edition contains revised content with many new case studies and additional example calculations that are of interest to chemical engineers. The 2nd Edition is divided into two separate books: 1) Active Pharmaceutical Ingredients (API’s) and 2) Drug Product Design, Development and Modeling.

The active pharmaceutical ingredients book puts the focus on the chemistry, chemical engineering, and unit operations specific to development and manufacturing of the active ingredients of the pharmaceutical product. The drug substance operations section includes information on chemical reactions, mixing, distillations, extractions, crystallizations, filtration, drying, and wet and dry milling. In addition, the book includes many applications of process modeling and modern software tools that are geared toward batch-scale and continuous drug substance pharmaceutical operations. This updated second edition:

•    Contains 30new chapters or revised chapters specific to API, covering topics including: manufacturing quality by design, computational approaches, continuous manufacturing, crystallization and final form, process safety

•    Expanded topics of scale-up, continuous processing, applications of thermodynamics and thermodynamic modeling, filtration and drying

•    Presents updated and expanded example calculations

•    Includes contributions from noted experts in the field

Written for pharmaceutical engineers, chemical engineers, undergraduate and graduate students, and professionals in the field of pharmaceutical sciences and manufacturing, the second edition of Chemical Engineering in the Pharmaceutical Industry focuses on the development and chemical engineering as well as operations specific to the design, formulation, and manufacture of drug substance and products.

Table of Contents

  1. Cover
  2. LIST OF CONTRIBUTORS
  3. PREFACE
  4. UNIT CONVERSIONS
    1. REFERENCES
  5. PART I: INTRODUCTION
    1. 1 CHEMICAL ENGINEERING IN THE PHARMACEUTICAL INDUSTRY: AN INTRODUCTION
      1. 1.1 GLOBAL IMPACT OF THE INDUSTRY
      2. 1.2 INVESTMENTS IN PHARMACEUTICAL R&D
      3. 1.3 BEST SELLERS
      4. 1.4 PHARMACEUTICAL RESEARCH AND DEVELOPMENT EXPENDITURES
      5. 1.5 RECENT TRENDS FOR PHARMACEUTICAL DRUG AND MANUFACTURING
      6. 1.6 CHEMICAL ENGINEERS SKILLED TO IMPACT FUTURE OF PHARMACEUTICAL INDUSTRY
      7. REFERENCES
    2. 2 CURRENT CHALLENGES AND OPPORTUNITIES IN THE PHARMACEUTICAL INDUSTRY
      1. 2.1 INTRODUCTION
      2. 2.2 INDUSTRY‐WIDE CHALLENGES
      3. 2.3 OPPORTUNITIES FOR CHEMICAL ENGINEERS
      4. 2.4 PROSPECTS FOR CHEMICAL ENGINEERS
      5. REFERENCES
  6. PART II: MASS AND ENERGY BALANCES
    1. 3 PROCESS SAFETY AND REACTION HAZARD ASSESSMENT
      1. 3.1 INTRODUCTION
      2. 3.2 GENERAL CONCEPTS
      3. 3.3 STUDYING THE DESIRED SYNTHESIS REACTION AT LAB SCALE
      4. 3.4 SCALE‐UP OF THE DESIRED REACTION
      5. 3.5 STUDYING THE DECOMPOSITION REACTION AT LAB SCALE
      6. 3.6 REACTIVE WASTE
      7. 3.7 CONTINUOUS PROCESSING
      8. 3.8 OTHER POINTS TO CONSIDER
      9. REFERENCES
    2. 4 CALORIMETRIC APPROACHES TO CHARACTERIZING UNDESIRED REACTIONS
      1. 4.1 INTRODUCTION
      2. 4.2 BACKGROUND
      3. 4.3 THERMAL STABILITY SCREENING: DIFFERENTIAL SCANNING CALORIMETRY (DSC)
      4. 4.4 PRESSURE SCREENING OF DECOMPOSITIONS: TECHNIQUES
      5. 4.5 HAZARD SCENARIOS
      6. 4.6 CASE STUDY 1: REACTION IN DIMETHYL SULFOXIDE (DMSO)
      7. 4.7 CASE STUDY 2: CONTINUOUS GAS GENERATION IN A WASTE STREAM CONTAINING CARBONATE
      8. 4.8 CASE STUDY 3: EVALUATING A FUNCTIONAL GROUP
      9. 4.9 CASE STUDY 4: USE OF THERMAL AND PRESSURE SCREENING TOOLS TO ASSESS AN mCPBA SOLUTION
      10. 4.10 NOTATIONS
      11. ACKNOWLEDGMENTS
      12. REFERENCES
    3. 5 CASE STUDY OF A BORANE–THF EXPLOSION
      1. 5.1 INTRODUCTION
      2. 5.2 BACKGROUND
      3. 5.3 INVESTIGATION
      4. 5.4 ARC DATA OF BTHF FROM AN ADJACENT CYLINDER
      5. 5.5 TEMPERATURE HISTORY OF THE BORANE–THF CYLINDERS
      6. 5.6 HEAT LOSS MEASUREMENTS
      7. 5.7 THERMAL STABILITY OF FRESH 2M BORANE–THF
      8. 5.8 KINETICS OF DECOMPOSITION
      9. 5.9 CONCLUSIONS
      10. ACKNOWLEDGMENTS
      11. 5.A BORON NMR KINETIC DATA FROM FIGURE 5.13
      12. 5.B CALIBRATION FOR PHI FOR ARC ANALYSIS
      13. REFERENCES
    4. 6 ANALYTICAL ASPECTS FOR DETERMINATION OF MASS BALANCES
      1. 6.1 INTRODUCTION
      2. 6.2 THE USE OF ANALYTICAL METHODS APPLIED TO ENGINEERING
      3. 6.3 METHODS USED AND BACKGROUND
      4. 6.4 THINGS TO WATCH OUT FOR IN LC AND GC
      5. 6.5 USE OF MULTIPLE ANALYTICAL TECHNIQUES
      6. 6.6 CONCLUSION
      7. REFERENCES
    5. 7 QUANTITATIVE APPLICATIONS OF NMR SPECTROSCOPY
      1. 7.1 INTRODUCTION
      2. 7.2 ONE‐DIMENSIONAL NMR METHODS
      3. 7.3 TWO‐DIMENSIONAL NMR METHODS
      4. 7.4 QUANTITATIVE NMR SPECTROSCOPY (qNMR)
      5. REFERENCES
  7. PART III: REACTION KINETICS AND MIXING PROCESSES
    1. 8 REACTION KINETICS AND CHARACTERIZATION
      1. 8.1 INTRODUCTION
      2. 8.2 FUNDAMENTALS OF CHEMICAL REACTION KINETICS
      3. 8.3 METHODS FOR THE CHARACTERIZATION OF CHEMICAL KINETICS
      4. 8.4 TRANSFORMING EXPERIMENTAL DATA INTO A KINETIC MODEL
      5. 8.5 EMERGING AREAS FOR INNOVATION AND IMPLEMENTATION
      6. 8.6 CONCLUSIONS
      7. 8.7 QUESTIONS
      8. REFERENCES
    2. 9 UNDERSTANDING FUNDAMENTAL PROCESSES IN CATALYTIC HYDROGENATION REACTIONS
      1. 9.1 INTRODUCTION
      2. 9.2 SOLUTION HYDROGEN CONCENTRATION DURING HYDROGENATION REACTIONS, [H2]
      3. 9.3 IMPACT OF kLa ON REACTION KINETICS AND SELECTIVITY
      4. 9.4 CHARACTERIZATION OF GAS–LIQUID MASS TRANSFER PROCESS
      5. 9.5 CHARACTERIZATION OF CATALYST REDUCTION PROCESS
      6. 9.6 BASIC SCALE‐UP STRATEGY FOR HYDROGENATION PROCESSES
      7. 9.7 SUMMARY
      8. ACKNOWLEDGMENTS
      9. REFERENCES
    3. 10 CHARACTERIZATION AND FIRST PRINCIPLES PREDICTION OF API UNIT OPERATIONS
      1. 10.1 INTRODUCTION
      2. 10.2 BATCH PROCESSES WITH HOMOGENEOUS REACTIONS
      3. 10.3 MULTIPHASE BATCH PROCESSES WITH REACTIONS
      4. 10.4 FED‐BATCH PROCESSES WITH REACTIONS
      5. 10.5 APPLICATION TO CONTINUOUS FLOW SYSTEMS
      6. 10.6 EQUIPMENT CHARACTERIZATION AND ASSESSMENT
      7. 10.7 MODEL VERIFICATION STATISTICS
      8. 10.8 NOTATIONS
      9. REFERENCES
    4. 11 SCALE‐UP OF MASS TRANSFER‐LIMITED REACTIONS: FUNDAMENTALS AND A CASE STUDY
      1. 11.1 INTRODUCTION
      2. 11.2 MASS TRANSFER IN A SOLID–LIQUID SYSTEM WITHOUT REACTION
      3. 11.3 MASS TRANSFER WITH CHEMICAL REACTION
      4. 11.4 CASE STUDY: SCALING OF A MASS TRANSFER‐LIMITED REACTION
      5. 11.5 NOTATIONS
      6. ACKNOWLEDGMENTS
      7. REFERENCES
    5. 12 SCALE‐UP OF MIXING PROCESSES: A PRIMER
      1. 12.1 INTRODUCTION
      2. 12.2 BASIC APPROACHES TO MIXING SCALE‐UP
      3. 12.3 OTHER CONSIDERATIONS IN MIXING SCALE‐UP
      4. 12.4 COMMON MIXING EQUIPMENT
      5. 12.5 SCALE‐UP OF CHEMICAL REACTIONS
      6. 12.6 CFD AND OTHER MODELING TECHNIQUES
      7. 12.7 NOTATIONS
      8. REFERENCES
    6. 13 STIRRED VESSELS: COMPUTATIONAL MODELING OF MULTIPHASE FLOWS AND MIXING*
      1. 13.1 ENGINEERING OF MULTIPHASE STIRRED REACTORS
      2. PART I: COMPUTATIONAL MODELING OF MULTIPHASE FLOWS IN STIRRED VESSELS
      3. 13.2 COMPUTATIONAL MODELING OF MULTIPHASE STIRRED REACTOR
      4. PART II: APPLICATION TO MIXING IN STIRRED VESSELS
      5. 13.3 APPLICATION TO ENGINEERING OF STIRRED VESSELS
      6. 13.4 SUMMARY AND PATH FORWARD
      7. 13.5 NOTATIONS
      8. REFERENCES
  8. PART IV: CONTINUOUS PROCESSING
    1. 14 PROCESS DEVELOPMENT AND CASE STUDIES OF CONTINUOUS REACTOR SYSTEMS FOR PRODUCTION OF API AND PHARMACEUTICAL INTERMEDIATES
      1. 14.1 INTRODUCTION
      2. 14.2 BENEFITS OF CONTINUOUS PROCESSING
      3. 14.3 CONTINUOUS REACTOR AND ANCILLARY SYSTEMS CONSIDERATIONS
      4. 14.4 PROCESS DEVELOPMENT OF THE CONTINUOUS REACTION
      5. 14.5 SCALE‐UP: VOLUMETRIC VERSUS NUMBERING UP
      6. 14.6 PLANT OPERATIONS
      7. 14.7 CASE STUDY: CONTINUOUS DEPROTECTION REACTION – LAB TO KILO LAB SCALE‐UP
      8. 14.8 CASE STUDY: CONTINUOUS PRODUCTION OF A CYCLOPROPONATING REAGENT
      9. 14.9 INTEGRATED CONTINUOUS PROCESSING IN PHARMA
      10. 14.10 BARRIERS TO IMPLEMENTATION OF CONTINUOUS PROCESSING IN PHARMA
      11. 14.11 SUMMARY
      12. REFERENCES
    2. 15 DEVELOPMENT AND APPLICATION OF CONTINUOUS PROCESSES FOR THE INTERMEDIATES AND ACTIVE PHARMACEUTICAL INGREDIENTS
      1. 15.1 INTRODUCTION
      2. 15.2 VALUE OF CONTINUOUS PROCESSES FOR THE PHARMACEUTICAL INDUSTRY
      3. 15.3 CONTINUOUS PROCESS DEVELOPMENT WORKFLOW
      4. 15.4 CONTINUOUS TECHNOLOGY
      5. 15.5 PROCESS DESIGN METHODOLOGY FOR ORGANOMETALLIC CHEMISTRY IN CONTINUOUS: FROM R&D TO MANUFACTURE
      6. REFERENCES
    3. 16 DESIGN AND SELECTION OF CONTINUOUS REACTORS FOR PHARMACEUTICAL MANUFACTURING
      1. 16.1 DRIVERS FOR CONTINUOUS REACTIONS IN DRUG SUBSTANCE MANUFACTURING
      2. 16.2 TWO MAIN CATEGORIES OF CONTINUOUS REACTORS: PFRs AND CSTRs
      3. 16.3 EXAMPLE OF COILED TUBE PFR FOR TWO‐PHASE GAS–LIQUID REACTIONS
      4. 16.4 EXAMPLE OF CSTR FOR GRIGNARD FORMATION REACTION WITH SEQUESTERED Mg SOLIDS
      5. 16.5 NUMERICAL MODELING TO SELECT THE BEST REACTOR TYPE FOR MINIMIZING IMPURITIES
      6. 16.6 WHAT CAN BE DONE BATCH BEFORE RUNNING CONTINUOUS REACTION EXPERIMENTS?
      7. 16.7 WHAT IS DIFFICULT TO PREDICT FROM BATCH EXPERIMENTS?
      8. ACKNOWLEDGMENTS
      9. REFERENCES
  9. PART V: BIOLOGICS
    1. 17 CHEMICAL ENGINEERING PRINCIPLES IN BIOLOGICS: UNIQUE CHALLENGES AND APPLICATIONS
      1. 17.1 WHY ARE BIOLOGICS UNIQUE FROM A MASS, HEAT, AND MOMENTUM TRANSFER STANDPOINT?
      2. 17.2 SCALE‐UP APPROACHES AND ASSOCIATED CHALLENGES IN BIOLOGICS MANUFACTURING
      3. 17.3 CHALLENGES IN LARGE‐SCALE PROTEIN MANUFACTURING
      4. 17.4 SPECIALIZED APPLICATIONS OF CHEMICAL ENGINEERING CONCEPTS IN BIOLOGICS MANUFACTURING
      5. 17.5 CONCLUSIONS
      6. REFERENCES
  10. PART VI: THERMODYNAMICS
    1. 18 APPLICATIONS OF THERMODYNAMICS TOWARD PHARMACEUTICAL PROBLEM SOLVING
      1. 18.1 INTRODUCTION
      2. 18.2 DESOLVATION OF PARECOXIB SODIUM
      3. 18.3 SOLID FORM CONTROL OF PARITAPREVIR
      4. 18.4 SCALABLE SOLUTION CYRYSTALLIZATION OF CO‐CRYSTALS
      5. 18.5 THERMODYNAMICS OF COATING PROCESS DURING THE MANUFACTURE OF DRUG‐ELUTING BIORESORBABLE VASCULAR SCAFFOLD
      6. 18.6 POLYMER–PLASTICIZER MIXING PERFORMANCE IN THE PRESENCE OF WATER
      7. REFERENCES
    2. 19 A GENERAL FRAMEWORK FOR SOLID–LIQUID EQUILIBRIA IN PHARMACEUTICAL SYSTEMS
      1. 19.1 INTRODUCTION
      2. 19.2 THERMODYNAMIC FUNDAMENTALS FOR SOLUBILITY CALCULATIONS
      3. 19.3 THE SAFT‐γ MIE GROUP CONTRIBUTION EoS
      4. 19.4 SYSTEM CHARACTERIZATION FOR SOLUBILITY CALCULATIONS
      5. 19.5 ILLUSTRATIVE EXAMPLES
      6. 19.6 DISCUSSION
      7. 19.7 CONCLUSIONS
      8. 19.A USING FORMATION PROPERTIES IN THE INFINITE DILUTION STATE
      9. 19.B SAFT‐γ MIE FUNCTIONAL GROUP DECOMPOSITION
      10. REFERENCES
    3. 20 DRUG SOLUBILITY, REACTION THERMODYNAMICS, AND CO‐CRYSTAL SCREENING
      1. 20.1 INTRODUCTION
      2. 20.2 SOLUBILITY PREDICTION WITH COSMO‐RS
      3. 20.3 CHEMICAL REACTIONS IN SOLUTION
      4. 20.4 SCREENING OF CO‐CRYSTALS
      5. 20.5 CONCLUSION AND OUTLOOK
      6. 20.A DETAILS OF COSMO AND GAS‐ PHASE CALCULATIONS
      7. 20.B STEPS FOR CALCULATING THE FREE ENERGY OR ENTHALPY OF A COMPOUND
      8. ABBREVIATIONS
      9. SYMBOLS
      10. REFERENCES
    4. 21 THERMODYNAMIC MODELING OF AQUEOUS AND MIXED SOLVENT ELECTROLYTE SYSTEMS
      1. 21.1 INTRODUCTION
      2. 21.2 MODELING THERMODYNAMIC PROPERTIES OF ELECTROLYTE SOLUTIONS
      3. 21.3 ELECTROLYTE THERMODYNAMIC MODELS
      4. 21.4 EXAMPLES: MODELING WITH eNRTL
      5. 21.5 ONGOING DEVELOPMENTS
      6. 21.6 CONCLUDING REMARKS
      7. REFERENCES
    5. 22 THERMODYNAMICS AND RELATIVE SOLUBILITY PREDICTION OF POLYMORPHIC SYSTEMS
      1. 22.1 INTRODUCTION
      2. 22.2 METHODS
      3. 22.3 RESULTS AND DISCUSSION
      4. 22.4 APPLICATION TO AN ESTIMATION OF LIKELY IMPACT ON DRUG SOLUBILITY BY UNKNOWN MORE STABLE FORM
      5. 22.5 CONCLUSION
      6. 22.A PROPAGATION OF ERRORS OF THE SOLUBILITY RATIO MEASUREMENTS
      7. 22.B SUMMARY OF EXPLICIT EQUATIONS USED FOR THE SOLUBILITY RATIO PREDICTIONS
      8. ACKNOWLEDGMENTS
      9. REFERENCES
    6. 23 TOWARD A RATIONAL SOLVENT SELECTION FOR CONFORMATIONAL POLYMORPH SCREENING
      1. 23.1 INTRODUCTION
      2. 23.2 METHODS
      3. 23.3 RESULTS AND DISCUSSION
      4. 23.4 CONCLUSIONS
      5. ACKNOWLEDGMENTS
      6. REFERENCES
  11. PART VII: CRYSTALLIZATION AND FINAL FORM
    1. 24 CRYSTALLIZATION DESIGN AND SCALE‐UP
      1. 24.1 INTRODUCTION
      2. 24.2 CRYSTALLIZATION DESIGN OBJECTIVES AND CONSTRAINTS
      3. 24.3 SOLUBILITY ASSESSMENT AND PRELIMINARY SOLVENT SELECTION
      4. 24.4 CRYSTALLIZATION KINETICS AND PROCESS SELECTION
      5. 24.5 APPLICATION OF SOLUBILITY AND KINETICS DATA TO CRYSTALLIZATION MODES
      6. 24.6 ADVANCED TOPICS
      7. REFERENCES
    2. 25 INTRODUCTION TO CHIRAL CRYSTALLIZATION IN PHARMACEUTICAL DEVELOPMENT AND MANUFACTURING
      1. 25.1 TERNARY PHASE DIAGRAMS
      2. 25.2 TERNARY PHASE DIAGRAMS OF CHIRAL SYSTEMS CONTAINING SOLIDS
      3. 25.3 EXPERIMENTAL CHARACTERIZATION OF CHIRAL SYSTEMS
      4. 25.4 CHIRAL ANALYTICAL METHODS IN PHARMACEUTICAL DEVELOPMENT
      5. 25.5 PROCESS DESIGN OF CHIRAL CRYSTALLIZATIONS
      6. 25.6 SUMMARY AND CONCLUSIONS
      7. ACKNOWLEDGMENT
      8. REFERENCES
    3. 26 MEASUREMENT OF SOLUBILITY AND ESTIMATION OF CRYSTAL NUCLEATION AND GROWTH KINETICS
      1. 26.1 INTRODUCTION
      2. 26.2 SOLUBILITY
      3. 26.3 ESTIMATION OF NUCLEATION AND GROWTH KINETICS
      4. 26.4 SUMMARY
      5. ACKNOWLEDGMENT
      6. REFERENCES
    4. 27 CASE STUDIES ON CRYSTALLIZATION SCALE‐UP
      1. 27.1 INTRODUCTION
      2. 27.2 CASE STUDY I: DESIGNING SHEAR EXPOSURE TO ACHIEVE SIMILAR BREAKAGE/ATTRITION ACROSS SCALES
      3. 27.3 CASE STUDY II: TAILORING MIXING TO ACHIEVE DESIRED CRYSTAL FORM AND PARTICLE SIZE DISTRIBUTION
      4. 27.4 CASE STUDY III: SCALE‐UP CONSIDERATIONS FOR ANTISOLVENT ADDITION INTO A RECIRCULATION LOOP
      5. 27.5 CASE STUDY IV: MORPHOLOGY CONTROL IN A REACTIVE CRYSTALLIZATION
      6. ACKNOWLEDGMENT
      7. REFERENCES
    5. 28 POPULATION BALANCE‐ENABLED MODEL FOR BATCH AND CONTINUOUS CRYSTALLIZATION PROCESSES
      1. 28.1 INTRODUCTION
      2. 28.2 POPULATION BALANCE FRAMEWORK FOR CRYSTALLIZATION
      3. 28.3 A GENERALIZED MODEL FOR BATCH AND CONTINUOUS CRYSTALLIZATION PROCESSES
      4. 28.4 CASE I: PARACETAMOL–ETHANOL SYSTEM
      5. 28.5 CASE II: SODIUM NITRITE–WATER CRYSTALLIZATION
      6. 28.6 SUMMARY AND RECOMMENDATIONS
      7. 28.A APPENDIX
      8. ACKNOWLEDGMENT
      9. NOTATIONS
      10. REFERENCES
    6. 29 SOLID FORM DEVELOPMENT FOR POORLY SOLUBLE COMPOUNDS
      1. 29.1 INTRODUCTION
      2. 29.2 PERSPECTIVE ON SOLID FORM SCREENING IN DRUG DEVELOPMENT
      3. 29.3 SOLID FORM CONTROL OF LINIFANIB
      4. 29.4 SOLID FORM CONTROL OF DASABUVIR
      5. ACKNOWLEDGMENTS
      6. REFERENCES
    7. 30 MULTISCALE ASSESSMENT OF API PHYSICAL PROPERTIES IN THE CONTEXT OF MATERIALS SCIENCE TETRAHEDRON CONCEPT
      1. 30.1 INTRODUCTION
      2. 30.2 STRUCTURAL, SURFACE, BULK, AND MECHANICAL CHARACTERIZATION TOOLS
      3. 30.3 MODELING POWDER FLOWABILITY FROM FUNDAMENTAL PHYSICAL PROPERTIES
      4. 30.4 IMPACT OF API INTRINSIC MECHANICAL PROPERTIES ON PROCESS‐INDUCED DISORDER
      5. ACKNOWLEDGMENTS
      6. REFERENCES
  12. PART VIII: SEPARATIONS, FILTRATION, DRYING AND MILLING
    1. 31 THE DESIGN AND ECONOMICS OF LARGE‐SCALE CHROMATOGRAPHIC SEPARATIONS
      1. 31.1 INTRODUCTION
      2. 31.2 KEY DESIGN ELEMENTS
      3. 31.3 FUNDAMENTAL CHROMATOGRAPHIC RELATIONSHIPS
      4. 31.4 CHROMATOGRAPHIC ADSORBENT CHEMISTRIES AND BASIS OF RETENTION
      5. 31.5 OPERATIONAL ASPECTS
      6. 31.6 EQUIPMENT
      7. 31.7 SCALE‐UP
      8. 31.8 DESIGN SPACE
      9. 31.9 ECONOMICS
      10. 31.10 CONCLUSIONS
      11. ACKNOWLEDGMENTS
      12. REFERENCES
    2. 32 MEMBRANE SYSTEMS FOR PHARMACEUTICAL APPLICATIONS
      1. 32.1 INTRODUCTION
      2. 32.2 PERVAPORATION IN THE PHARMACEUTICAL INDUSTRY
      3. 32.3 OSN IN PHARMACEUTICAL INDUSTRY
      4. 32.4 NONDISPERSIVE MEMBRANE SOLVENT EXTRACTION
      5. 32.5 CONCLUDING REMARKS
      6. REFERENCES
    3. 33 DESIGN OF DISTILLATION AND EXTRACTION OPERATIONS
      1. 33.1 INTRODUCTION TO SEPARATION DESIGN BY DISTILLATION AND EXTRACTION
      2. 33.2 DESIGN OF DISTILLATION OPERATIONS
      3. 33.3 DESIGN OF EXTRACTION OPERATIONS
      4. 33.A GUIDE TO GENERATION OF BINARY INTERACTION PARAMETERS FOR SOLVENT PAIRS
      5. REFERENCES
    4. 34 CASE STUDIES ON THE USE OF DISTILLATION IN THE PHARMACEUTICAL INDUSTRY
      1. 34.1 INTRODUCTION
      2. 34.2 INTRODUCTION TO DISTILLATION
      3. 34.3 DISTILLATION MODELING
      4. 34.4 CASE STUDIES ON THE USE OF DISTILLATION MODELS
      5. ACKNOWLEDGMENTS
      6. REFERENCES
    5. 35 DESIGN OF FILTRATION AND DRYING OPERATIONS
      1. 35.1 INTRODUCTION
      2. 35.2 FILTRATION
      3. 35.3 DRYING
      4. REFERENCES
    6. 36 FILTRATION CASE STUDIES
      1. 36.1 INTRODUCTION
      2. 36.2 FILTRATION DECISION TREE
      3. 36.3 LOW TO MODERATE CAKE RESISTANCE
      4. 36.4 MODERATE TO HIGH CAKE RESISTANCE
      5. 36.5 REDESIGN OF SOLID‐STATE PROPERTIES FOR IMPROVED FILTRATION
      6. 36.6 CUMULATIVE PLUGGING OF AGITATED FILTER DRYER PLATE
      7. REFERENCES
    7. 37 DRYING CASE STUDIES
      1. 37.1 INTRODUCTION
      2. 37.2 PROCESS TRANSFER TO ALTERNATE EQUIPMENT TRAIN
      3. 37.3 OPTIMIZATION OF SOLVATE DRYING THROUGH HEAT TRANSFER MODELING
      4. 37.4 DRYING WITH HUMIDIFIED NITROGEN
      5. 37.5 DISTILLATIVE DRYING IN AN AGITATED FILTER DRYER
      6. 37.6 CONCLUDING REMARKS
      7. ACKNOWLEDGMENTS
      8. REFERENCES
    8. 38 MILLING OPERATIONS IN THE PHARMACEUTICAL INDUSTRY
      1. 38.1 INTRODUCTION
      2. 38.2 SAFETY AND QUALITY CONCERNS
      3. 38.3 TYPES OF MILLING AND MILL EQUIPMENT
      4. 38.4 MECHANISTIC MODELS
      5. 38.5 CASE STUDIES
      6. 38.6 CONCLUSIONS
      7. 38.7 NOMENCLATURE
      8. REFERENCES
  13. PART IX: STATISTICAL MODELS, PAT, AND PROCESS MODELING APPLICATIONS
    1. 39 EXPERIMENTAL DESIGN FOR PHARMACEUTICAL DEVELOPMENT
      1. 39.1 INTRODUCTION
      2. 39.2 THE TWO‐LEVEL FACTORIAL DESIGN
      3. 39.3 BLOCKING
      4. 39.4 FRACTIONAL FACTORIALS
      5. 39.5 DESIGN PROJECTION
      6. 39.6 STEEPEST ASCENT
      7. 39.7 CENTER RUNS
      8. 39.8 RESPONSE SURFACE DESIGNS
      9. 39.9 COMPUTER‐GENERATED DESIGNS
      10. 39.10 MULTIPLE RESPONSES
      11. 39.11 ADVANCED TOPICS
      12. REFERENCES
    2. 40 MULTIVARIATE ANALYSIS IN API DEVELOPMENT
      1. 40.1 INTRODUCTION
      2. 40.2 APPROACHES TO MODEL DEVELOPMENT
      3. 40.3 BUILDING THE CALIBRATION MODEL
      4. 40.4 CASE STUDY
      5. ACKNOWLEDGMENTS
      6. REFERENCES
    3. 41 PROBABILISTIC MODELS FOR FORECASTING PROCESS ROBUSTNESS
      1. 41.1 INTRODUCTION
      2. 41.2 MEASURING PROCESS ROBUSTNESS
      3. 41.3 REGULATORY REQUIREMENTS FOR PROCESS ROBUSTNESS
      4. 41.4 MODELING PROCESS ROBUSTNESS
      5. 41.5 PROCESS UNCERTAINTY
      6. 41.6 BRIEF OVERVIEW OF PROBABILISTIC GRAPHICAL MODELS
      7. 41.7 SIMULATION TOOLS FOR BAYESIAN STATISTICS
      8. 41.8 EXAMPLE OF MODELING PROCESS ROBUSTNESS
      9. SUMMARY
      10. SUPPORTING INFORMATION
      11. REFERENCES
    4. 42 USE OF PROCESS ANALYTICAL TECHNOLOGY (PAT) IN SMALL MOLECULE DRUG SUBSTANCE REACTION DEVELOPMENT
      1. 42.1 INTRODUCTION
      2. 42.2 PAT METHODS
      3. 42.3 PAT APPLICATION IN PHARMACEUTICAL REACTION ENGINEERING
      4. 42.4 CASE STUDIES
      5. 42.5 SUMMARY
      6. ACKNOWLEDGMENTS
      7. REFERENCES
    5. 43 PROCESS MODELING APPLICATIONS TOWARD ENABLING DEVELOPMENT AND SCALE‐UP: CHEMICAL REACTIONS
      1. 43.1 INTRODUCTION
      2. 43.2 PREDICTIVE SCALE‐UP OF A HIGHLY EXOTHERMIC REACTION
      3. 43.3 EFFICIENT SCALE‐UP OF A MULTIPHASE EXOTHERMIC NITRATION REACTION
      4. 43.4 KINETIC JUSTIFICATION‐BASED CONTROL FOR POTENTIAL MUTAGENIC IMPURITIES
      5. ACKNOWLEDGMENTS
      6. LIST OF SYMBOLS
      7. REFERENCES
  14. PART X: MANUFACTURING
    1. 44 PROCESS SCALE‐UP AND ASSESSMENT
      1. 44.1 INTRODUCTION
      2. 44.2 DRIVERS FOR DEVELOPMENT/RISK ASSESSMENT
      3. 44.3 UNIT OPERATIONS
      4. SUMMARY
      5. REFERENCES
    2. 45 SCALE‐UP DO'S AND DON'TS
      1. 45.1 INTRODUCTION
      2. 45.2 LEARNING THE HARD WAY
      3. 45.3 TYPICAL SCALE‐UP ISSUES
      4. 45.4 PURPOSE OF THIS CHAPTER
      5. 45.5 THINGS TO DO DURING SCALE‐UP
      6. 45.6 THINGS TO AVOID DURING SCALE‐UP
      7. 45.7 CONCLUSIONS AND FINAL THOUGHTS
      8. REFERENCES
    3. 46 KILO LAB AND PILOT PLANT MANUFACTURING
      1. 46.1 INTRODUCTION
      2. 46.2 KILO LAB AND PILOT PLANT FACILITY DESIGN AND UNIT OPERATIONS
      3. 46.3 OPERATING PRINCIPLES AND REGULATORY DRIVERS
      4. 46.4 SUMMARY
      5. 46.5 EXERCISE
      6. REFERENCES
    4. 47 THE ROLE OF SIMULATION AND SCHEDULING TOOLS IN THE DEVELOPMENT AND MANUFACTURING OF ACTIVE PHARMACEUTICAL INGREDIENTS
      1. 47.1 INTRODUCTION
      2. 47.2 COMMERCIALLY AVAILABLE SIMULATION AND SCHEDULING TOOLS
      3. 47.3 MODELING AND ANALYSIS OF AN API MANUFACTURING PROCESS
      4. 47.4 UNCERTAINTY AND VARIABILITY ANALYSIS
      5. 47.5 PRODUCTION SCHEDULING
      6. 47.6 CAPACITY ANALYSIS AND PRODUCTION PLANNING
      7. 47.7 SUMMARY
      8. REFERENCES
  15. PART XI: QUALITY BY DESIGN AND REGULATORY
    1. 48 SCIENTIFIC OPPORTUNITIES THROUGH QUALITY BY DESIGN
      1. ACKNOWLEDGMENT
      2. REFERENCE
    2. 49 APPLICATIONS OF QUALITY RISK ASSESSMENT IN QUALITY BY DESIGN (QbD) DRUG SUBSTANCE PROCESS DEVELOPMENT
      1. 49.1 WHY RISK ASSESSMENT IS USED IN THE PHARMACEUTICAL INDUSTRY
      2. 49.2 OVERVIEW OF RISK ASSESSMENT PROCESS
      3. 49.3 RISK ASSESSMENT TYPES
      4. 49.4 RISK ASSESSMENT TOOLS
      5. 49.5 RISK ASSESSMENT BEST PRACTICES
      6. 49.6 RISK ASSESSMENTS THROUGH THE PRODUCT LIFE CYCLE
      7. 49.7 CONCLUDING REMARKS
      8. REFERENCES
    3. 50 DEVELOPMENT OF DESIGN SPACE FOR REACTION STEPS: APPROACHES AND CASE STUDIES FOR IMPURITY CONTROL
      1. 50.1 INTRODUCTION
      2. 50.2 ELEMENTS OF PHARMACEUTICAL DEVELOPMENT
      3. 50.3 REACTION DESIGN SPACE DEVELOPMENT
      4. 50.4 DEFINING THE DESIGN SPACE
      5. 50.5 VERIFICATION OF THE DESIGN SPACE
      6. 50.6 CASE STUDIES
      7. 50.7 CONCLUSIONS
      8. 50.8 GLOSSARY OF TERMS
      9. REFERENCES
  16. INDEX
  17. End User License Agreement
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