Cover: Solid State Development and Processing of Pharmaceutical Molecules, 1 by Michael Gruss

Methods and Principles in Medicinal Chemistry

Edited by

R. Mannhold, H. Buschmann, J. Holenz

Editorial Board

G. Folkers, H. Kubinyi, H. Timmerman, H. van de Waterbeemd, J. Bondo Hansen

Bachhav, Y. (Ed.)

Innovative Dosage Forms

Designs and Development at Early Stage


ISBN: 978‐3‐527‐34396‐6

Vol. 79

Gervasio, F. L., Spiwok, V. (Eds.)

Biomolecular Simulations in Structure‐based Drug Discovery


ISBN: 978‐3‐527‐34265‐5

Vol. 75

Sippl, W., Jung, M. (Eds.)

Epigenetic Drug Discovery


ISBN: 978‐3‐527‐34314‐0

Vol. 74

Giordanetto, F. (Ed.)

Early Drug Development


ISBN: 978‐3‐527‐34149‐8

Vol. 73

Handler, N., Buschmann, H. (Eds.)

Drug Selectivity


ISBN: 978‐3‐527‐33538‐1

Vol. 72

Vaughan, T., Osbourn, J., Jalla, B. (Eds.)

Protein Therapeutics


ISBN: 978‐3‐527‐34086‐6

Vol. 71

Ecker, G. F., Clausen, R. P., and Sitte, H. H. (Eds.)

Transporters as Drug Targets


ISBN: 978‐3‐527‐33384‐4

Vol. 70

Martic‐Kehl, M. I., Schubiger, P.A. (Eds.)

Animal Models for Human Cancer

Discovery and Development of Novel Therapeutics


ISBN: 978‐3‐527‐33997‐6

Vol. 69

Solid State Development and Processing of Pharmaceutical Molecules

Salts, Cocrystals, and Polymorphism


Volume 79


Edited by
Michael Gruss






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Series Editors Preface

Michael Gruß works as an independent scientific consultant for the pharmaceutical, chemical, and nutrition industry, and he is known and well recognized as an expert in this field. During his industrial career, he conducted solid‐state investigations on pharmaceutical drug substances and intermediates. He is author or co‐author of more than 15 patent applications in the field of salts, cocrystals, and polymorphs, and some of the drugs are globally marketed.

Polymorphism presents opportunities as well as challenges. Investigation of the properties of different forms of a commercial drug can lead to new products with improved onset time, greater bioavailability, sustained release properties, or other therapeutic enhancements. New forms can bring improvements in manufacturing costs or API purity.

The potential for solid form variation does not end at API production. Solid form issues remain through formulation, manufacture, storage, and use of drug product. It is common to observe form transformation during standard manufacturing operations like wet granulation and milling. Excipient interactions and compaction can induce form changes. Changes can occur in the final dosage form over time.

Whenever there is a specification failure in drug product or drug substance, solid form changes should be considered in the search for causes. Particularly, symptomatic is failure to meet melting point or dissolution specifications. Changes in humidity, crystallization conditions, or crystallization solvent can produce unwanted forms.

Due to the importance of solid‐phase characteristics in pharmaceutical industry, several brilliant review articles and books have been published.

The current volume entitled Solid‐State Development and Processing of Pharmaceutical Molecules in our book series Methods and Principles in Medicinal Chemistry is focused on specific aspects of salts, cocrystals, and polymorphism in drug development. The book compiles general concepts and their latest applications along with well‐selected case studies considering experiences and publications from the last 10 to 12 years. It considers new developments in science and knowledge that has been contributed by academic and industrial researchers during the last decade.

This book clearly goes beyond the classical description of solid‐state properties. It encourages out‐of‐the‐box thinking and allows a look beyond the science. In defining the scope of the book, one intention was to allow the identification of beneficial synergies for successful integration of solid‐state form development workflows into general management strategies for R&D and production.

The editors would like to thank Michael and all contributing authors for such a successful compilation, which will stimulate the awareness of the impact of solid‐state‐related topics and enhance the importance of salts, cocrystals, and polymorphic forms throughout the pharmaceutical value chain.

Aachen, Düsseldorf and Boston Helmut Buschmann
July 2021 Raimund Mannhold
Jörg Holenz


“[…] Cuius rei demonstrationem mirabilem sane detexi. Hanc marginis exiguitas non caperet.” Pierre de Fermat wrote a note that states that no three positive integers a, b, and c satisfy the equation an + bn = cn for any integer value of n greater than 2 in a copy of his book of the Arithmetica of Diophantos of Alexandria. The quote translates to “I have discovered a truly remarkable proof of this theorem which this margin is too small to contain.”

The present edition of “Solid‐State Development and Processing of Pharmaceutical molecules” may be considered as a margin that is likewise too small to cover all aspects of relevance and interest in this vast field addressed in the title. However, it is an attempt to collect and consider at least some aspects which are important from an industrial perspective on developing and processing crystalline forms in the pharmaceutical value chain.

Being a topic of some interest already since many years, solid‐state investigation of crystalline pharmaceuticals gained more and more attention and commercial relevance in the last 20–25 years. Nevertheless, approaches to cover the challenges and obstacles coming along with the peculiarities of crystalline pharmaceutical molecules and their development and processing are manifold. Although sophisticated analytical devices are available on the market to investigate solid forms, not every project can be supported by all technical and personal intelligence. There are limitations framed by limited resources of financial funding and manpower. Eventually, no excuses count when safety and efficacy of medicines are of concern. However, if not all, but many routes lead to Rome.

Some of the routes are presented in this edition. Readers are called to wisely select the right means and measures for their particular projects. Besides the essential and unavoidable basics to reach the goal, there are add‐ons and nice‐to‐haves that may shorten the route to process understanding and market entrance.

Starting with important general considerations in Chapter 1, the subsequent chapters lighten the road along solid‐state development and processing. Chapter 2 describes entry points into a solid‐state‐related project. Investigation of the polymorphic landscape is exemplified in Chapter 3 and complemented by Chapter 4 which is divided into 10 subchapters describing various solid‐state characterization techniques. Treatment of solid pharmaceutical drug substances upon scale‐up is covered in Chapter 5, while Chapter 6 considers the challenges for Drug Product development and manufacturing. From my perspective often neglected but essential support processes addressing simplification of daily routines, best practices and documentation are described in Chapters 7 and 8. Chapter 9 covers ensuring the return of investment by the protection of intellectual property, while Chapter 10 addresses the regulatory aspects of relevance. Last but not least, the perspective of extension of the value chain of pharmaceutical molecules is given in Chapter 11.

Clearly, without all the authors who accepted to contribute, this edition would never have been possible. Thank you a lot. You made this book to a valuable collection of practical knowledge and expertise. It was my pleasure and honor to cooperate with you. Sincere thanks to Wiley‐VCH, namely Dr. Frank Weinreich, Stefanie Volk, and N. Kiruthigadevi for answering my questions and acting behind the scenes to drive this publication, as well as Felix Bloeck who worked with the graphic designers on the book cover. Finally, I would especially like to thank Dr. Helmut Buschmann for his everlasting supportive initiative to motivate and develop people.

Aachen Michael Gruss
July 2021