Chemical Engineering in the Pharmaceutical Industry Active Pharmaceutical Ingredients

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 2^nd 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 Industryf ocuses on the development and chemical engineering as well as operations specific to the design, formulation, and manufacture of drug substance and products.

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.

List of Contributors xi

Preface xv

Unit Conversions xvii

Part I Introduction 1

1 Chemical Engineering in the Pharmaceutical Industry: An Introduction 3
David J. am Ende and Mary T. am Ende

2 Current Challenges and Opportunities in the Pharmaceutical Industry 19
Joseph L. Kukura and Michael P. Thien

Part II Mass and Energy Balances 27

3 Process Safety and Reaction Hazard Assessment 29
Wim Dermaut

4 Calorimetric Approaches to Characterizing Undesired Reactions 61
Megan Roth and Tom Vickery

5 Case Study of a Borane–THF Explosion 91
David J. am Ende and Richard M. Davis

6 Analytical Aspects for Determination of Mass Balances 115
Matthew Jorgensen

7 Quantitative Applications of NMR Spectroscopy 133
Brian L. Marquez and R. Thomas Williamson

Part III Reaction Kinetics and Mixing Processes 151

8 Reaction Kinetics and Characterization 153
Utpal K. Singh, Brandon J. Reizman, Shujauddin M. Changi, Justin L. Burt, and Chuck Orella

9 Understanding Fundamental Processes in Catalytic Hydrogenation Reactions 191
Yongkui Sun and Carl LeBlond

10 Characterization and First Principles Prediction of API Unit Operations 203
Joe Hannon

11 Scale-Up of Mass Transfer-Limited Reactions: Fundamentals and a Case Study 227
Ayman Allian and Seth Huggins

12 Scale-Up of Mixing Processes: A Primer 241
Francis X. McConville and Stephen B. Kessler

13 Stirred Vessels: Computational Modeling of Multiphase Flows and Mixing 261
Avinash R. Khopkar and Vivek V. Ranade

Part IV Continuous Processing 319

14 Process Development and Case Studies of Continuous Reactor Systems for Production of API and Pharmaceutical Intermediates 321
Thomas L. LaPorte, Chenchi Wang, and G. Scott Jones

15 Development and Application of Continuous Processes for the Intermediates and Active Pharmaceutical Ingredients 341
Flavien Susanne

16 Design and Selection of Continuous Reactors for Pharmaceutical Manufacturing 367
Martin D. Johnson, Scott A. May, Michael E. Kopach, Jennifer McClary Groh, Timothy Braden, Vaidyaraman Shankarraman, and Jeremy Miles Merritt

Part V Biologics 387

17 Chemical Engineering Principles in Biologics: Unique Challenges and Applications 389
Sourav Kundu, Vivek Bhatnagar, Naveen Pathak, and Cenk Undey

Part VI Thermodynamics 417

18 Applications of Thermodynamics Toward Pharmaceutical Problem Solving 419
Ahmad Y. Sheikh, Alessandra Mattei, Raimundo Ho, Moiz Diwan, Thomas Borchardt, Gerald Danzer, Nadine Ding, and Xinmin (Sam) Xu

19 A General Framework for Solid–Liquid Equilibria in Pharmaceutical Systems 439
Thomas Lafitte, Vasileios Papaioannou, Simon Dufal, and Constantinos C. Pantelides

20 Drug Solubility, Reaction Thermodynamics, and Co-Crystal Screening 467
Karin Wichmann, Christoph Loschen, and Andreas Klamt

21 Thermodynamic Modeling of Aqueous and Mixed Solvent Electrolyte Systems 493
Benjamin Caudle, Toni E. Kirkes, Cheng-Hsiu Yu, and Chau-Chyun Chen

22 Thermodynamics and Relative Solubility Prediction of Polymorphic Systems 505
Yuriy A. Abramov and Klimentina Pencheva

23 Toward a Rational Solvent Selection for Conformational Polymorph Screening 519
Yuriy A. Abramov, Mark Zell, and Joseph F. Krzyzaniak

Part VII Crystallization and Final Form 533

24 Crystallization Design and Scale-Up 535
James Wertman, Robert McKeown, Lotfi Derdour, and Philip Dell’Orco

25 Introduction to Chiral Crystallization in Pharmaceutical Development and Manufacturing 569
Jose E. Tabora, Shawn Brueggemeier, Michael Lovette, and Jason Sweeney

26 Measurement of Solubility and Estimation of Crystal Nucleation and Growth Kinetics 591
Nandkishor K. Nere, Manish S. Kelkar, Ann M. Czyzewski, Kushal Sinha, and Evelina B. Kim

27 Case Studies On Crystallization Scale-Up 617
Nandkishor K. Nere, Moiz Diwan, Ann M. Czyzewski, James C. Marek, Kushal Sinha, and Huayu Li

28 Population Balance-Enabled Model for Batch and Continuous Crystallization Processes 635
Ajinkya Pandit, Rahul Bhambure, and Vivek V. Ranade

29 Solid Form Development for Poorly Soluble Compounds 665
Alessandra Mattei, Shuang Chen, Jie Chen, and Ahmad Y. Sheikh

30 Multiscale Assessment of API Physical Properties in the Context of Materials Science Tetrahedron Concept 689
Raimundo Ho, Yujin Shin, Yinshan Chen, Laura Poloni, Shuang Chen, and Ahmad Y. Sheikh

Part VIII Separations, Filtration, Drying and Milling 713

31 The Design and Economics of Large-Scale Chromatographic Separations 715
Firoz D. Antia

32 Membrane Systems for Pharmaceutical Applications 733
Dimitrios Zarkadas and Kamalesh K. Sirkar

33 Design of Distillation and Extraction Operations 751
Eric M. Cordi

34 Case Studies On the Use of Distillation in the Pharmaceutical Industry 787
Laurie Mlinar, Kushal Sinha, Elie Chaaya, Subramanya Nayak, and Andrew Cosbie

35 Design of Filtration and Drying Operations 799
Praveen K. Sharma, Saravanababu Murugesan, and Jose E. Tabora

36 Filtration Case Studies 833
Seth Huggins, Andrew Cosbie, and John Gaertner

37 Drying Case Studies 847
John Gaertner, Nandkishor K. Nere, James C. Marek, Shailendra Bordawekar, Laurie Mlinar, Moiz Diwan, and Lei Cao

38 Milling Operations in the Pharmaceutical Industry 861
Kevin D. Seibert, Paul C. Collins, Carla V. Luciani, and Elizabeth S. Fisher

Part IX Statistical Models, Pat, and Process Modeling Applications 881

39 Experimental Design for Pharmaceutical Development 883
Gregory S. Steeno

40 Multivariate Analysis in API Development 909
James C. Marek

41 Probabilistic Models for Forecasting Process Robustness 919
Jose E. Tabora, Jacob Albrecht, and Brendan Mack

42 Use of Process Analytical Technology (PAT) in Small Molecule Drug Substance Reaction Development 937
Dimitri Skliar, Jeffrey Nye, and Antonio Ramirez

43 Process Modeling Applications Toward Enabling Development and Scale-Up: Chemical Reactions 957
Anuj A. Verma, Steven Richter, Brian Kotecki, and Moiz Diwan

Part X Manufacturing 971

44 Process Scale-Up and Assessment 973
Alan Braem, Jason Sweeney, and Jean Tom

45 Scale-Up Do’s and Don’ts 1001
Francis X. McConville

46 Kilo Lab and Pilot Plant Manufacturing 1011
Matthew Casey, Jason Hamm, Melanie Miller, Tom Ramsey, Richard Schild, Andrew Stewart, and Jean Tom

47 The Role of Simulation and Scheduling Tools in the Development and Manufacturing of Active Pharmaceutical Ingredients 1037
Demetri Petrides, Doug Carmichael, Charles Siletti, Dimitris Vardalis, Alexandros Koulouris, and Pericles Lagonikos

Part XI Quality by Design and Regulatory 1067

48 Scientific Opportunities through Quality by Design 1069
Timothy J. Watson and Roger Nosal

49 Applications of Quality Risk Assessment in Quality by Design (QbD) Drug Substance Process Development 1073
Alan Braem and Gillian Turner

50 Development of Design Space for Reaction Steps: Approaches and Case Studies for Impurity Control 1091
Srinivas Tummala, Antonio Ramirez, Sushil Srivastava, and Daniel M. Hallow

Index 1123

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