PART IX: STATISTICAL MODELS, PAT, AND PROCESS MODELING APPLICATIONS
by Mary T. am Ende, David J. am Ende
Chemical Engineering in the Pharmaceutical Industry, Active Pharmaceutical Ingredients, 2nd Edition
- Cover
- LIST OF CONTRIBUTORS
- PREFACE
- UNIT CONVERSIONS
- PART I: INTRODUCTION
- PART II: MASS AND ENERGY BALANCES
- 3 PROCESS SAFETY AND REACTION HAZARD ASSESSMENT
- 4 CALORIMETRIC APPROACHES TO CHARACTERIZING UNDESIRED REACTIONS
- 4.1 INTRODUCTION
- 4.2 BACKGROUND
- 4.3 THERMAL STABILITY SCREENING: DIFFERENTIAL SCANNING CALORIMETRY (DSC)
- 4.4 PRESSURE SCREENING OF DECOMPOSITIONS: TECHNIQUES
- 4.5 HAZARD SCENARIOS
- 4.6 CASE STUDY 1: REACTION IN DIMETHYL SULFOXIDE (DMSO)
- 4.7 CASE STUDY 2: CONTINUOUS GAS GENERATION IN A WASTE STREAM CONTAINING CARBONATE
- 4.8 CASE STUDY 3: EVALUATING A FUNCTIONAL GROUP
- 4.9 CASE STUDY 4: USE OF THERMAL AND PRESSURE SCREENING TOOLS TO ASSESS AN mCPBA SOLUTION
- 4.10 NOTATIONS
- ACKNOWLEDGMENTS
- REFERENCES
- 5 CASE STUDY OF A BORANE–THF EXPLOSION
- 5.1 INTRODUCTION
- 5.2 BACKGROUND
- 5.3 INVESTIGATION
- 5.4 ARC DATA OF BTHF FROM AN ADJACENT CYLINDER
- 5.5 TEMPERATURE HISTORY OF THE BORANE–THF CYLINDERS
- 5.6 HEAT LOSS MEASUREMENTS
- 5.7 THERMAL STABILITY OF FRESH 2M BORANE–THF
- 5.8 KINETICS OF DECOMPOSITION
- 5.9 CONCLUSIONS
- ACKNOWLEDGMENTS
- 5.A BORON NMR KINETIC DATA FROM FIGURE 5.13
- 5.B CALIBRATION FOR PHI FOR ARC ANALYSIS
- REFERENCES
- 6 ANALYTICAL ASPECTS FOR DETERMINATION OF MASS BALANCES
- 7 QUANTITATIVE APPLICATIONS OF NMR SPECTROSCOPY
- PART III: REACTION KINETICS AND MIXING PROCESSES
- 8 REACTION KINETICS AND CHARACTERIZATION
- 9 UNDERSTANDING FUNDAMENTAL PROCESSES IN CATALYTIC HYDROGENATION REACTIONS
- 9.1 INTRODUCTION
- 9.2 SOLUTION HYDROGEN CONCENTRATION DURING HYDROGENATION REACTIONS, [H2]
- 9.3 IMPACT OF kLa ON REACTION KINETICS AND SELECTIVITY
- 9.4 CHARACTERIZATION OF GAS–LIQUID MASS TRANSFER PROCESS
- 9.5 CHARACTERIZATION OF CATALYST REDUCTION PROCESS
- 9.6 BASIC SCALE‐UP STRATEGY FOR HYDROGENATION PROCESSES
- 9.7 SUMMARY
- ACKNOWLEDGMENTS
- REFERENCES
- 10 CHARACTERIZATION AND FIRST PRINCIPLES PREDICTION OF API UNIT OPERATIONS
- 10.1 INTRODUCTION
- 10.2 BATCH PROCESSES WITH HOMOGENEOUS REACTIONS
- 10.3 MULTIPHASE BATCH PROCESSES WITH REACTIONS
- 10.4 FED‐BATCH PROCESSES WITH REACTIONS
- 10.5 APPLICATION TO CONTINUOUS FLOW SYSTEMS
- 10.6 EQUIPMENT CHARACTERIZATION AND ASSESSMENT
- 10.7 MODEL VERIFICATION STATISTICS
- 10.8 NOTATIONS
- REFERENCES
- 11 SCALE‐UP OF MASS TRANSFER‐LIMITED REACTIONS: FUNDAMENTALS AND A CASE STUDY
- 12 SCALE‐UP OF MIXING PROCESSES: A PRIMER
- 13 STIRRED VESSELS: COMPUTATIONAL MODELING OF MULTIPHASE FLOWS AND MIXING*
- 13.1 ENGINEERING OF MULTIPHASE STIRRED REACTORS
- PART I: COMPUTATIONAL MODELING OF MULTIPHASE FLOWS IN STIRRED VESSELS
- 13.2 COMPUTATIONAL MODELING OF MULTIPHASE STIRRED REACTOR
- PART II: APPLICATION TO MIXING IN STIRRED VESSELS
- 13.3 APPLICATION TO ENGINEERING OF STIRRED VESSELS
- 13.4 SUMMARY AND PATH FORWARD
- 13.5 NOTATIONS
- REFERENCES
- PART IV: CONTINUOUS PROCESSING
- 14 PROCESS DEVELOPMENT AND CASE STUDIES OF CONTINUOUS REACTOR SYSTEMS FOR PRODUCTION OF API AND PHARMACEUTICAL INTERMEDIATES
- 14.1 INTRODUCTION
- 14.2 BENEFITS OF CONTINUOUS PROCESSING
- 14.3 CONTINUOUS REACTOR AND ANCILLARY SYSTEMS CONSIDERATIONS
- 14.4 PROCESS DEVELOPMENT OF THE CONTINUOUS REACTION
- 14.5 SCALE‐UP: VOLUMETRIC VERSUS NUMBERING UP
- 14.6 PLANT OPERATIONS
- 14.7 CASE STUDY: CONTINUOUS DEPROTECTION REACTION – LAB TO KILO LAB SCALE‐UP
- 14.8 CASE STUDY: CONTINUOUS PRODUCTION OF A CYCLOPROPONATING REAGENT
- 14.9 INTEGRATED CONTINUOUS PROCESSING IN PHARMA
- 14.10 BARRIERS TO IMPLEMENTATION OF CONTINUOUS PROCESSING IN PHARMA
- 14.11 SUMMARY
- REFERENCES
- 15 DEVELOPMENT AND APPLICATION OF CONTINUOUS PROCESSES FOR THE INTERMEDIATES AND ACTIVE PHARMACEUTICAL INGREDIENTS
- 16 DESIGN AND SELECTION OF CONTINUOUS REACTORS FOR PHARMACEUTICAL MANUFACTURING
- 16.1 DRIVERS FOR CONTINUOUS REACTIONS IN DRUG SUBSTANCE MANUFACTURING
- 16.2 TWO MAIN CATEGORIES OF CONTINUOUS REACTORS: PFRs AND CSTRs
- 16.3 EXAMPLE OF COILED TUBE PFR FOR TWO‐PHASE GAS–LIQUID REACTIONS
- 16.4 EXAMPLE OF CSTR FOR GRIGNARD FORMATION REACTION WITH SEQUESTERED Mg SOLIDS
- 16.5 NUMERICAL MODELING TO SELECT THE BEST REACTOR TYPE FOR MINIMIZING IMPURITIES
- 16.6 WHAT CAN BE DONE BATCH BEFORE RUNNING CONTINUOUS REACTION EXPERIMENTS?
- 16.7 WHAT IS DIFFICULT TO PREDICT FROM BATCH EXPERIMENTS?
- ACKNOWLEDGMENTS
- REFERENCES
- 14 PROCESS DEVELOPMENT AND CASE STUDIES OF CONTINUOUS REACTOR SYSTEMS FOR PRODUCTION OF API AND PHARMACEUTICAL INTERMEDIATES
- PART V: BIOLOGICS
- 17 CHEMICAL ENGINEERING PRINCIPLES IN BIOLOGICS: UNIQUE CHALLENGES AND APPLICATIONS
- 17.1 WHY ARE BIOLOGICS UNIQUE FROM A MASS, HEAT, AND MOMENTUM TRANSFER STANDPOINT?
- 17.2 SCALE‐UP APPROACHES AND ASSOCIATED CHALLENGES IN BIOLOGICS MANUFACTURING
- 17.3 CHALLENGES IN LARGE‐SCALE PROTEIN MANUFACTURING
- 17.4 SPECIALIZED APPLICATIONS OF CHEMICAL ENGINEERING CONCEPTS IN BIOLOGICS MANUFACTURING
- 17.5 CONCLUSIONS
- REFERENCES
- 17 CHEMICAL ENGINEERING PRINCIPLES IN BIOLOGICS: UNIQUE CHALLENGES AND APPLICATIONS
- PART VI: THERMODYNAMICS
- 18 APPLICATIONS OF THERMODYNAMICS TOWARD PHARMACEUTICAL PROBLEM SOLVING
- 18.1 INTRODUCTION
- 18.2 DESOLVATION OF PARECOXIB SODIUM
- 18.3 SOLID FORM CONTROL OF PARITAPREVIR
- 18.4 SCALABLE SOLUTION CYRYSTALLIZATION OF CO‐CRYSTALS
- 18.5 THERMODYNAMICS OF COATING PROCESS DURING THE MANUFACTURE OF DRUG‐ELUTING BIORESORBABLE VASCULAR SCAFFOLD
- 18.6 POLYMER–PLASTICIZER MIXING PERFORMANCE IN THE PRESENCE OF WATER
- REFERENCES
- 19 A GENERAL FRAMEWORK FOR SOLID–LIQUID EQUILIBRIA IN PHARMACEUTICAL SYSTEMS
- 19.1 INTRODUCTION
- 19.2 THERMODYNAMIC FUNDAMENTALS FOR SOLUBILITY CALCULATIONS
- 19.3 THE SAFT‐γ MIE GROUP CONTRIBUTION EoS
- 19.4 SYSTEM CHARACTERIZATION FOR SOLUBILITY CALCULATIONS
- 19.5 ILLUSTRATIVE EXAMPLES
- 19.6 DISCUSSION
- 19.7 CONCLUSIONS
- 19.A USING FORMATION PROPERTIES IN THE INFINITE DILUTION STATE
- 19.B SAFT‐γ MIE FUNCTIONAL GROUP DECOMPOSITION
- REFERENCES
- 20 DRUG SOLUBILITY, REACTION THERMODYNAMICS, AND CO‐CRYSTAL SCREENING
- 20.1 INTRODUCTION
- 20.2 SOLUBILITY PREDICTION WITH COSMO‐RS
- 20.3 CHEMICAL REACTIONS IN SOLUTION
- 20.4 SCREENING OF CO‐CRYSTALS
- 20.5 CONCLUSION AND OUTLOOK
- 20.A DETAILS OF COSMO AND GAS‐ PHASE CALCULATIONS
- 20.B STEPS FOR CALCULATING THE FREE ENERGY OR ENTHALPY OF A COMPOUND
- ABBREVIATIONS
- SYMBOLS
- REFERENCES
- 21 THERMODYNAMIC MODELING OF AQUEOUS AND MIXED SOLVENT ELECTROLYTE SYSTEMS
- 22 THERMODYNAMICS AND RELATIVE SOLUBILITY PREDICTION OF POLYMORPHIC SYSTEMS
- 22.1 INTRODUCTION
- 22.2 METHODS
- 22.3 RESULTS AND DISCUSSION
- 22.4 APPLICATION TO AN ESTIMATION OF LIKELY IMPACT ON DRUG SOLUBILITY BY UNKNOWN MORE STABLE FORM
- 22.5 CONCLUSION
- 22.A PROPAGATION OF ERRORS OF THE SOLUBILITY RATIO MEASUREMENTS
- 22.B SUMMARY OF EXPLICIT EQUATIONS USED FOR THE SOLUBILITY RATIO PREDICTIONS
- ACKNOWLEDGMENTS
- REFERENCES
- 23 TOWARD A RATIONAL SOLVENT SELECTION FOR CONFORMATIONAL POLYMORPH SCREENING
- 18 APPLICATIONS OF THERMODYNAMICS TOWARD PHARMACEUTICAL PROBLEM SOLVING
- PART VII: CRYSTALLIZATION AND FINAL FORM
- 24 CRYSTALLIZATION DESIGN AND SCALE‐UP
- 25 INTRODUCTION TO CHIRAL CRYSTALLIZATION IN PHARMACEUTICAL DEVELOPMENT AND MANUFACTURING
- 25.1 TERNARY PHASE DIAGRAMS
- 25.2 TERNARY PHASE DIAGRAMS OF CHIRAL SYSTEMS CONTAINING SOLIDS
- 25.3 EXPERIMENTAL CHARACTERIZATION OF CHIRAL SYSTEMS
- 25.4 CHIRAL ANALYTICAL METHODS IN PHARMACEUTICAL DEVELOPMENT
- 25.5 PROCESS DESIGN OF CHIRAL CRYSTALLIZATIONS
- 25.6 SUMMARY AND CONCLUSIONS
- ACKNOWLEDGMENT
- REFERENCES
- 26 MEASUREMENT OF SOLUBILITY AND ESTIMATION OF CRYSTAL NUCLEATION AND GROWTH KINETICS
- 27 CASE STUDIES ON CRYSTALLIZATION SCALE‐UP
- 27.1 INTRODUCTION
- 27.2 CASE STUDY I: DESIGNING SHEAR EXPOSURE TO ACHIEVE SIMILAR BREAKAGE/ATTRITION ACROSS SCALES
- 27.3 CASE STUDY II: TAILORING MIXING TO ACHIEVE DESIRED CRYSTAL FORM AND PARTICLE SIZE DISTRIBUTION
- 27.4 CASE STUDY III: SCALE‐UP CONSIDERATIONS FOR ANTISOLVENT ADDITION INTO A RECIRCULATION LOOP
- 27.5 CASE STUDY IV: MORPHOLOGY CONTROL IN A REACTIVE CRYSTALLIZATION
- ACKNOWLEDGMENT
- REFERENCES
- 28 POPULATION BALANCE‐ENABLED MODEL FOR BATCH AND CONTINUOUS CRYSTALLIZATION PROCESSES
- 28.1 INTRODUCTION
- 28.2 POPULATION BALANCE FRAMEWORK FOR CRYSTALLIZATION
- 28.3 A GENERALIZED MODEL FOR BATCH AND CONTINUOUS CRYSTALLIZATION PROCESSES
- 28.4 CASE I: PARACETAMOL–ETHANOL SYSTEM
- 28.5 CASE II: SODIUM NITRITE–WATER CRYSTALLIZATION
- 28.6 SUMMARY AND RECOMMENDATIONS
- 28.A APPENDIX
- ACKNOWLEDGMENT
- NOTATIONS
- REFERENCES
- 29 SOLID FORM DEVELOPMENT FOR POORLY SOLUBLE COMPOUNDS
- 30 MULTISCALE ASSESSMENT OF API PHYSICAL PROPERTIES IN THE CONTEXT OF MATERIALS SCIENCE TETRAHEDRON CONCEPT
- PART VIII: SEPARATIONS, FILTRATION, DRYING AND MILLING
- 31 THE DESIGN AND ECONOMICS OF LARGE‐SCALE CHROMATOGRAPHIC SEPARATIONS
- 32 MEMBRANE SYSTEMS FOR PHARMACEUTICAL APPLICATIONS
- 33 DESIGN OF DISTILLATION AND EXTRACTION OPERATIONS
- 34 CASE STUDIES ON THE USE OF DISTILLATION IN THE PHARMACEUTICAL INDUSTRY
- 35 DESIGN OF FILTRATION AND DRYING OPERATIONS
- 36 FILTRATION CASE STUDIES
- 37 DRYING CASE STUDIES
- 38 MILLING OPERATIONS IN THE PHARMACEUTICAL INDUSTRY
- PART IX: STATISTICAL MODELS, PAT, AND PROCESS MODELING APPLICATIONS
- 39 EXPERIMENTAL DESIGN FOR PHARMACEUTICAL DEVELOPMENT
- 40 MULTIVARIATE ANALYSIS IN API DEVELOPMENT
- 41 PROBABILISTIC MODELS FOR FORECASTING PROCESS ROBUSTNESS
- 41.1 INTRODUCTION
- 41.2 MEASURING PROCESS ROBUSTNESS
- 41.3 REGULATORY REQUIREMENTS FOR PROCESS ROBUSTNESS
- 41.4 MODELING PROCESS ROBUSTNESS
- 41.5 PROCESS UNCERTAINTY
- 41.6 BRIEF OVERVIEW OF PROBABILISTIC GRAPHICAL MODELS
- 41.7 SIMULATION TOOLS FOR BAYESIAN STATISTICS
- 41.8 EXAMPLE OF MODELING PROCESS ROBUSTNESS
- SUMMARY
- SUPPORTING INFORMATION
- REFERENCES
- 42 USE OF PROCESS ANALYTICAL TECHNOLOGY (PAT) IN SMALL MOLECULE DRUG SUBSTANCE REACTION DEVELOPMENT
- 43 PROCESS MODELING APPLICATIONS TOWARD ENABLING DEVELOPMENT AND SCALE‐UP: CHEMICAL REACTIONS
- PART X: MANUFACTURING
- PART XI: QUALITY BY DESIGN AND REGULATORY
- INDEX
- End User License Agreement
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