David J. am Ende, PhD, is President of Nalas Engineering Services, Inc. Previously, he was a Research Fellow at Pfizer Inc. in Chemical Research & Development. He has over 25 years's experience in chemical and pharmaceutical process development. Mary T. am Ende, PhD, is Vice President of Process Development at Lyndra Therapeutics, Inc. Previously, she was a Research Fellow at Pfizer, Inc. in Drug Product Design. She has over 25 years' experience in drug product formulation, process development and computational modeling.

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• List of Contributors xiPreface xvUnit Conversions xviiPart I Introduction 11 Chemical Engineering in the Pharmaceutical Industry: An Introduction 3David J. am Ende and Mary T. am Ende2 Current Challenges and Opportunities in the Pharmaceutical Industry 19Joseph L. Kukura and Michael P. ThienPart II Mass and Energy Balances 273 Process Safety and Reaction Hazard Assessment 29Wim Dermaut4 Calorimetric Approaches to Characterizing Undesired Reactions 61Megan Roth and Tom Vickery5 Case Study of a Borane–THF Explosion 91David J. am Ende and Richard M. Davis6 Analytical Aspects for Determination of Mass Balances 115Matthew Jorgensen7 Quantitative Applications of NMR Spectroscopy 133Brian L. Marquez and R. Thomas WilliamsonPart III Reaction Kinetics and Mixing Processes 1518 Reaction Kinetics and Characterization 153Utpal K. Singh, Brandon J. Reizman, Shujauddin M. Changi, Justin L. Burt, and Chuck Orella9 Understanding Fundamental Processes in Catalytic Hydrogenation Reactions 191Yongkui Sun and Carl LeBlond10 Characterization and First Principles Prediction of API Unit Operations 203Joe Hannon11 Scale-Up of Mass Transfer-Limited Reactions: Fundamentals and a Case Study 227Ayman Allian and Seth Huggins12 Scale-Up of Mixing Processes: A Primer 241Francis X. McConville and Stephen B. Kessler13 Stirred Vessels: Computational Modeling of Multiphase Flows and Mixing 261Avinash R. Khopkar and Vivek V. RanadePart IV Continuous Processing 31914 Process Development and Case Studies of Continuous Reactor Systems for Production of API and Pharmaceutical Intermediates 321Thomas L. LaPorte, Chenchi Wang, and G. Scott Jones15 Development and Application of Continuous Processes for the Intermediates and Active Pharmaceutical Ingredients 341Flavien Susanne16 Design and Selection of Continuous Reactors for Pharmaceutical Manufacturing 367Martin D. Johnson, Scott A. May, Michael E. Kopach, Jennifer McClary Groh, Timothy Braden, Vaidyaraman Shankarraman, and Jeremy Miles MerrittPart V Biologics 38717 Chemical Engineering Principles in Biologics: Unique Challenges and Applications 389Sourav Kundu, Vivek Bhatnagar, Naveen Pathak, and Cenk UndeyPart VI Thermodynamics 41718 Applications of Thermodynamics Toward Pharmaceutical Problem Solving 419Ahmad Y. Sheikh, Alessandra Mattei, Raimundo Ho, Moiz Diwan, Thomas Borchardt, Gerald Danzer, Nadine Ding, and Xinmin (Sam) Xu19 A General Framework for Solid–Liquid Equilibria in Pharmaceutical Systems 439Thomas Lafitte, Vasileios Papaioannou, Simon Dufal, and Constantinos C. Pantelides20 Drug Solubility, Reaction Thermodynamics, and Co-Crystal Screening 467Karin Wichmann, Christoph Loschen, and Andreas Klamt21 Thermodynamic Modeling of Aqueous and Mixed Solvent Electrolyte Systems 493Benjamin Caudle, Toni E. Kirkes, Cheng-Hsiu Yu, and Chau-Chyun Chen22 Thermodynamics and Relative Solubility Prediction of Polymorphic Systems 505Yuriy A. Abramov and Klimentina Pencheva23 Toward a Rational Solvent Selection for Conformational Polymorph Screening 519Yuriy A. Abramov, Mark Zell, and Joseph F. KrzyzaniakPart VII Crystallization and Final Form 53324 Crystallization Design and Scale-Up 535James Wertman, Robert McKeown, Lotfi Derdour, and Philip Dell’Orco25 Introduction to Chiral Crystallization in Pharmaceutical Development and Manufacturing 569Jose E. Tabora, Shawn Brueggemeier, Michael Lovette, and Jason Sweeney26 Measurement of Solubility and Estimation of Crystal Nucleation and Growth Kinetics 591Nandkishor K. Nere, Manish S. Kelkar, Ann M. Czyzewski, Kushal Sinha, and Evelina B. Kim27 Case Studies On Crystallization Scale-Up 617Nandkishor K. Nere, Moiz Diwan, Ann M. Czyzewski, James C. Marek, Kushal Sinha, and Huayu Li28 Population Balance-Enabled Model for Batch and Continuous Crystallization Processes 635Ajinkya Pandit, Rahul Bhambure, and Vivek V. Ranade29 Solid Form Development for Poorly Soluble Compounds 665Alessandra Mattei, Shuang Chen, Jie Chen, and Ahmad Y. Sheikh30 Multiscale Assessment of API Physical Properties in the Context of Materials Science Tetrahedron Concept 689Raimundo Ho, Yujin Shin, Yinshan Chen, Laura Poloni, Shuang Chen, and Ahmad Y. SheikhPart VIII Separations, Filtration, Drying and Milling 71331 The Design and Economics of Large-Scale Chromatographic Separations 715Firoz D. Antia32 Membrane Systems for Pharmaceutical Applications 733Dimitrios Zarkadas and Kamalesh K. Sirkar33 Design of Distillation and Extraction Operations 751Eric M. Cordi34 Case Studies On the Use of Distillation in the Pharmaceutical Industry 787Laurie Mlinar, Kushal Sinha, Elie Chaaya, Subramanya Nayak, and Andrew Cosbie35 Design of Filtration and Drying Operations 799Praveen K. Sharma, Saravanababu Murugesan, and Jose E. Tabora36 Filtration Case Studies 833Seth Huggins, Andrew Cosbie, and John Gaertner37 Drying Case Studies 847John Gaertner, Nandkishor K. Nere, James C. Marek, Shailendra Bordawekar, Laurie Mlinar, Moiz Diwan, and Lei Cao38 Milling Operations in the Pharmaceutical Industry 861Kevin D. Seibert, Paul C. Collins, Carla V. Luciani, and Elizabeth S. FisherPart IX Statistical Models, Pat, and Process Modeling Applications 88139 Experimental Design for Pharmaceutical Development 883Gregory S. Steeno40 Multivariate Analysis in API Development 909James C. Marek41 Probabilistic Models for Forecasting Process Robustness 919Jose E. Tabora, Jacob Albrecht, and Brendan Mack42 Use of Process Analytical Technology (PAT) in Small Molecule Drug Substance Reaction Development 937Dimitri Skliar, Jeffrey Nye, and Antonio Ramirez43 Process Modeling Applications Toward Enabling Development and Scale-Up: Chemical Reactions 957Anuj A. Verma, Steven Richter, Brian Kotecki, and Moiz DiwanPart X Manufacturing 97144 Process Scale-Up and Assessment 973Alan Braem, Jason Sweeney, and Jean Tom45 Scale-Up Do’s and Don’ts 1001Francis X. McConville46 Kilo Lab and Pilot Plant Manufacturing 1011Matthew Casey, Jason Hamm, Melanie Miller, Tom Ramsey, Richard Schild, Andrew Stewart, and Jean Tom47 The Role of Simulation and Scheduling Tools in the Development and Manufacturing of Active Pharmaceutical Ingredients 1037Demetri Petrides, Doug Carmichael, Charles Siletti, Dimitris Vardalis, Alexandros Koulouris, and Pericles LagonikosPart XI Quality by Design and Regulatory 106748 Scientific Opportunities through Quality by Design 1069Timothy J. Watson and Roger Nosal49 Applications of Quality Risk Assessment in Quality by Design (QbD) Drug Substance Process Development 1073Alan Braem and Gillian Turner50 Development of Design Space for Reaction Steps: Approaches and Case Studies for Impurity Control 1091Srinivas Tummala, Antonio Ramirez, Sushil Srivastava, and Daniel M. HallowIndex 1123

David J. am Ende, PhD, is President of Nalas Engineering Services, Inc. Previously, he was a Research Fellow at Pfizer Inc. in Chemical Research & Development. He has over 25 years's experience in chemical and pharmaceutical process development. Mary T. am Ende, PhD, is Vice President of Process Development at Lyndra Therapeutics, Inc. Previously, she was a Research Fellow at Pfizer, Inc. in Drug Product Design. She has over 25 years' experience in drug product formulation, process development and computational modeling.

Select Guide Rating

• List of Contributors xiPreface xvUnit Conversions xviiPart I Introduction 11 Chemical Engineering in the Pharmaceutical Industry: An Introduction 3David J. am Ende and Mary T. am Ende2 Current Challenges and Opportunities in the Pharmaceutical Industry 19Joseph L. Kukura and Michael P. ThienPart II Mass and Energy Balances 273 Process Safety and Reaction Hazard Assessment 29Wim Dermaut4 Calorimetric Approaches to Characterizing Undesired Reactions 61Megan Roth and Tom Vickery5 Case Study of a Borane–THF Explosion 91David J. am Ende and Richard M. Davis6 Analytical Aspects for Determination of Mass Balances 115Matthew Jorgensen7 Quantitative Applications of NMR Spectroscopy 133Brian L. Marquez and R. Thomas WilliamsonPart III Reaction Kinetics and Mixing Processes 1518 Reaction Kinetics and Characterization 153Utpal K. Singh, Brandon J. Reizman, Shujauddin M. Changi, Justin L. Burt, and Chuck Orella9 Understanding Fundamental Processes in Catalytic Hydrogenation Reactions 191Yongkui Sun and Carl LeBlond10 Characterization and First Principles Prediction of API Unit Operations 203Joe Hannon11 Scale-Up of Mass Transfer-Limited Reactions: Fundamentals and a Case Study 227Ayman Allian and Seth Huggins12 Scale-Up of Mixing Processes: A Primer 241Francis X. McConville and Stephen B. Kessler13 Stirred Vessels: Computational Modeling of Multiphase Flows and Mixing 261Avinash R. Khopkar and Vivek V. RanadePart IV Continuous Processing 31914 Process Development and Case Studies of Continuous Reactor Systems for Production of API and Pharmaceutical Intermediates 321Thomas L. LaPorte, Chenchi Wang, and G. Scott Jones15 Development and Application of Continuous Processes for the Intermediates and Active Pharmaceutical Ingredients 341Flavien Susanne16 Design and Selection of Continuous Reactors for Pharmaceutical Manufacturing 367Martin D. Johnson, Scott A. May, Michael E. Kopach, Jennifer McClary Groh, Timothy Braden, Vaidyaraman Shankarraman, and Jeremy Miles MerrittPart V Biologics 38717 Chemical Engineering Principles in Biologics: Unique Challenges and Applications 389Sourav Kundu, Vivek Bhatnagar, Naveen Pathak, and Cenk UndeyPart VI Thermodynamics 41718 Applications of Thermodynamics Toward Pharmaceutical Problem Solving 419Ahmad Y. Sheikh, Alessandra Mattei, Raimundo Ho, Moiz Diwan, Thomas Borchardt, Gerald Danzer, Nadine Ding, and Xinmin (Sam) Xu19 A General Framework for Solid–Liquid Equilibria in Pharmaceutical Systems 439Thomas Lafitte, Vasileios Papaioannou, Simon Dufal, and Constantinos C. Pantelides20 Drug Solubility, Reaction Thermodynamics, and Co-Crystal Screening 467Karin Wichmann, Christoph Loschen, and Andreas Klamt21 Thermodynamic Modeling of Aqueous and Mixed Solvent Electrolyte Systems 493Benjamin Caudle, Toni E. Kirkes, Cheng-Hsiu Yu, and Chau-Chyun Chen22 Thermodynamics and Relative Solubility Prediction of Polymorphic Systems 505Yuriy A. Abramov and Klimentina Pencheva23 Toward a Rational Solvent Selection for Conformational Polymorph Screening 519Yuriy A. Abramov, Mark Zell, and Joseph F. KrzyzaniakPart VII Crystallization and Final Form 53324 Crystallization Design and Scale-Up 535James Wertman, Robert McKeown, Lotfi Derdour, and Philip Dell’Orco25 Introduction to Chiral Crystallization in Pharmaceutical Development and Manufacturing 569Jose E. Tabora, Shawn Brueggemeier, Michael Lovette, and Jason Sweeney26 Measurement of Solubility and Estimation of Crystal Nucleation and Growth Kinetics 591Nandkishor K. Nere, Manish S. Kelkar, Ann M. Czyzewski, Kushal Sinha, and Evelina B. Kim27 Case Studies On Crystallization Scale-Up 617Nandkishor K. Nere, Moiz Diwan, Ann M. Czyzewski, James C. Marek, Kushal Sinha, and Huayu Li28 Population Balance-Enabled Model for Batch and Continuous Crystallization Processes 635Ajinkya Pandit, Rahul Bhambure, and Vivek V. Ranade29 Solid Form Development for Poorly Soluble Compounds 665Alessandra Mattei, Shuang Chen, Jie Chen, and Ahmad Y. Sheikh30 Multiscale Assessment of API Physical Properties in the Context of Materials Science Tetrahedron Concept 689Raimundo Ho, Yujin Shin, Yinshan Chen, Laura Poloni, Shuang Chen, and Ahmad Y. SheikhPart VIII Separations, Filtration, Drying and Milling 71331 The Design and Economics of Large-Scale Chromatographic Separations 715Firoz D. Antia32 Membrane Systems for Pharmaceutical Applications 733Dimitrios Zarkadas and Kamalesh K. Sirkar33 Design of Distillation and Extraction Operations 751Eric M. Cordi34 Case Studies On the Use of Distillation in the Pharmaceutical Industry 787Laurie Mlinar, Kushal Sinha, Elie Chaaya, Subramanya Nayak, and Andrew Cosbie35 Design of Filtration and Drying Operations 799Praveen K. Sharma, Saravanababu Murugesan, and Jose E. Tabora36 Filtration Case Studies 833Seth Huggins, Andrew Cosbie, and John Gaertner37 Drying Case Studies 847John Gaertner, Nandkishor K. Nere, James C. Marek, Shailendra Bordawekar, Laurie Mlinar, Moiz Diwan, and Lei Cao38 Milling Operations in the Pharmaceutical Industry 861Kevin D. Seibert, Paul C. Collins, Carla V. Luciani, and Elizabeth S. FisherPart IX Statistical Models, Pat, and Process Modeling Applications 88139 Experimental Design for Pharmaceutical Development 883Gregory S. Steeno40 Multivariate Analysis in API Development 909James C. Marek41 Probabilistic Models for Forecasting Process Robustness 919Jose E. Tabora, Jacob Albrecht, and Brendan Mack42 Use of Process Analytical Technology (PAT) in Small Molecule Drug Substance Reaction Development 937Dimitri Skliar, Jeffrey Nye, and Antonio Ramirez43 Process Modeling Applications Toward Enabling Development and Scale-Up: Chemical Reactions 957Anuj A. Verma, Steven Richter, Brian Kotecki, and Moiz DiwanPart X Manufacturing 97144 Process Scale-Up and Assessment 973Alan Braem, Jason Sweeney, and Jean Tom45 Scale-Up Do’s and Don’ts 1001Francis X. McConville46 Kilo Lab and Pilot Plant Manufacturing 1011Matthew Casey, Jason Hamm, Melanie Miller, Tom Ramsey, Richard Schild, Andrew Stewart, and Jean Tom47 The Role of Simulation and Scheduling Tools in the Development and Manufacturing of Active Pharmaceutical Ingredients 1037Demetri Petrides, Doug Carmichael, Charles Siletti, Dimitris Vardalis, Alexandros Koulouris, and Pericles LagonikosPart XI Quality by Design and Regulatory 106748 Scientific Opportunities through Quality by Design 1069Timothy J. Watson and Roger Nosal49 Applications of Quality Risk Assessment in Quality by Design (QbD) Drug Substance Process Development 1073Alan Braem and Gillian Turner50 Development of Design Space for Reaction Steps: Approaches and Case Studies for Impurity Control 1091Srinivas Tummala, Antonio Ramirez, Sushil Srivastava, and Daniel M. HallowIndex 1123