Pharmaceutical Crystals

Science and Engineering

Tonglei Li, Alessandra Mattei

• Publisher: Wiley
• Year: 2018
• Print ISBN: 9781119046295
• eBook ISBN: 9781119046349
• Edition: 1
• Topic: Physical Sciences
• Subtopic: Industrial & Technical Chemistry

An important resource that puts the focus on understanding and handling of organic crystals in drug development

Since a majority of pharmaceutical solid-state materials are organic crystals, their handling and processing are critical aspects of drug development. Pharmaceutical Crystals: Science and Engineering offers an introduction to and thorough coverage of organic crystals, and explores the essential role they play in drug development and manufacturing. Written contributions from leading researchers and practitioners in the field, this vital resource provides the fundamental knowledge and explains the connection between pharmaceutically relevant properties and the structure of a crystal.

Comprehensive in scope, the text covers a range of topics including: crystallization, molecular interactions, polymorphism, analytical methods, processing, and chemical stability. The authors clearly show how to find solutions for pharmaceutical form selection and crystallization processes. Designed to be an accessible guide, this book represents a valuable resource for improving the drug development process of small drug molecules. This important text:

• Includes the most important aspects of solid-state organic chemistry and its role in drug development
• Offers solutions for pharmaceutical form selection and crystallization processes
• Contains a balance between the scientific fundamental and pharmaceutical applications
• Presents coverage of crystallography, molecular interactions, polymorphism, analytical methods, processing, and chemical stability

Written for both practicing pharmaceutical scientists, engineers, and senior undergraduate and graduate students studying pharmaceutical solid-state materials, Pharmaceutical Crystals: Science and Engineering is a reference and textbook for understanding, producing, analyzing, and designing organic crystals which is an imperative skill to master for anyone working in the field.

1
Crystallography

Susan M. Reutzel‐Edens¹ and Peter Müller²

¹ Small Molecule Design & Development, Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN, USA

² X‐Ray Diffraction Facility, MIT Department of Chemistry, Cambridge, MA, USA

1.1 Introduction

Functional organic solids, ranging from large‐tonnage commodity materials to high‐value specialty chemicals, are commercialized for their unique physical and chemical properties. However, unlike many substances of scientific, technological, and commercial importance, drug molecules are almost always chosen for development into drug products based solely on their biological properties. The ability of a drug molecule to crystallize in solid forms with optimal material properties is rarely a consideration. Still, with an estimated 90% of small‐molecule drugs delivered to patients in a crystalline state [1], the importance of crystals and crystal structure to pharmaceutical development cannot be overstated. In fact, the first step in transforming a molecule to a medicine (Figure 1.1) is invariably identifying a stable crystalline form, one that:

• Through its ability to exclude impurities during crystallization, can be used to purify the drug substance coming out of the final step of the chemical synthesis.
• May impart stability to an otherwise chemically labile molecule.
• Is suitable for downstream processing and long‐term storage.
• Not only meets the design requirements but also will ensure consistency in the safety and efficacy profile of the drug product throughout its shelf life.

Figure 1.1 Materials science perspective of the steps involved in transforming a molecule to a medicine.

The mechanical, thermodynamic, and biopharmaceutical properties of a drug substance will strongly depend on how a molecule packs in its three‐dimensional (3D) crystal structure, yet it is not given that a drug candidate entering into pharmaceutical development will crystallize, let alone in a form that is amenable to processing, stable enough for long‐term storage, or useful for drug delivery. Because it is rarely possible to manipulate the chemical structure of the drug itself to improve material properties,¹ pharmaceutical scientists will typically explore multicomponent crystal forms, including salts, hydrates, and more recently cocrystals, if needed, in the search for commercially viable forms. A salt is an ionic solid formed between either a basic drug and a sufficiently acidic guest molecule or an acidic drug and basic guest. Cocrystals are crystalline molecular complexes formed between the drug (or its salt) and a neutral guest molecule. Hydrates, a subset of a larger class of crystalline solids, termed solvates, are characterized by the inclusion of water in the crystal structure of the compound. When multiple crystalline options are identified in solid form screening, as is often the case for ever more complex new chemical entities in current drug development pipelines, it is the connection between internal crystal structure, particle properties, processing, and product performance, the components of the materials science tetrahedron, [3] that ultimately determines which form is progressed in developing the drug product. Not surprisingly, crystallography, the science of shapes, structures, and properties of crystals, is a key component of all studies relating the solid‐state chemistry of drugs to their ultimate use in medicinal products.

Crystallization is the process by which molecules (or ion pairs) self‐assemble in ordered, close‐packed arrangements (crystal structures). It usually involves two steps: crystal nucleation, the formation of stable molecular aggregates or clusters (nuclei) capable of growing into macroscopic crystals; and crystal growth, the subsequent development of the nuclei into visible dimensions. Crystals that successfully nucleate and grow will, in many cases, form distinctive, if not spectacular, shapes (habits) characterized by well‐defined faces or facets. Commonly observed habits, which are often described as needles, rods, plates, tablets, or prisms, emerge because crystal growth does not proceed at the same rate in all directions. The slowest‐growing faces are those that are morphologically dominant; however, as the external shape of the crystal depends both on its internal crystal structure and the growth conditions, crystals of the same internal structure (same crystal form) may have different external habits. The low molecular symmetry common to many drug molecules and anisotropic (directional) in...

Table of contents

• Cover
• Table of Contents
• Preface
• 1 Crystallography
• 2 Nucleation
• 3 Solid‐state Characterization Techniques
• 4 Intermolecular Interactions and Computational Modeling
• 5 Polymorphism and Phase Transitions
• 6 Measurement and Mathematical Relationships of Cocrystal Thermodynamic Properties
• 7 Mechanical Properties
• 8 Primary Processing of Organic Crystals
• 9 Secondary Processing of Organic Crystals
• 10 Chemical Stability and Reaction
• 11 Crystalline Nanoparticles
• Index
• End User License Agreement