Polymorphism of high energy materials

The intimate connection between structure and properties is particularly acute in establishing the effectiveness and safety of high energy materials based on molecular compounds: chemical and physical stability, shelf-life, sensitivity to shock, pressure, and temperature. Compared to other classes of compounds treated in the book for which the polymorphs with less suitable properties are not chosen for use, and thus relegated to lower importance, for high energy materials the risks and dangers of lack of familiarity and control of the polymorphic system can entail considerable long-term risks. The chapter is divided into two major sections distinguishing between aliphatic materials and the aromatic materials, commonly known by their alphabetic moniker. Throughout the chapter the history of the development of many of these materials is provided, including some rather obscure references culled from formerly classified government research reports. A detailed discussion of the classic enigmatic polymorphism of trinitrotoluene (TNT) is presented.

Polymorphism of pharmaceuticals

Chapter 7 deals with polymorphism in pharmaceuticals. Following a discussion of the problem of determining the statistics of the occurrence of polymorphism in pharmaceuticals, I present a discussion and examples of the connection between polymorphism and the rate of dissolution and solubility, bioavailability, and the importance of phase changes and mixtures of forms in pharmaceutical preparations. I survey some of the considerations and techniques involved in screening for crystal forms: solvent selection, specific screening for solvates and hydrates, gel crystallization, crystallization in ionic liquids, the challenge of difficult to obtain stable forms and unstable new forms, and the outlook on new techniques and conditions for crystallization. The chapter also deals with polymorphism in pharmaceutical co-crystals, excipients, and amorphous forms and the importance and utility of chemical microscopy in the study of polymorphism of pharmaceuticals.

Fundamentals

The physical and structural fundamentals of polymorphism are introduced, including a review of the phase rule and the thermodynamic relations in polymorphs. The latter are used to introduce energy–temperature diagrams, leading to the definition of the concepts enantiotropism and monotropism describing the thermodynamic relationships between and among polymorphs with appropriate examples. The alternate representation of phase diagram in terms of pressure and temperature is also presented. These lead to a number of rules regarding the relationships between polymorphs and ways to understand and predict some important physical properties: the heat-of-transition rule, the heat-of-fusion rule, the entropy-of-fusion rule, the heat-capacity rule, the density rule, and the infrared rule. Structural aspects include the distinction between crystal form and crystal habit and methods for characterizing and comparing structures in polymorphic systems. Current developments are discussed that deal with the ramifications of nanoscale situations on structural concepts and thermodynamic relationships.

Introduction and historical background

Chapter 1 provides an introduction to the subject of polymorphism in molecular crystals, including definitions, terminology, nomenclature, and historical development of the subject since the first recognition of the phenomenon in 1823. Topics covered include the difficulty in establishing a database for statistical study of polymorphism, the frequency of occurrence of polymorphism, the literature sources of polymorphic compounds, and literature sources of examples of polymorphism, that is, Cambridge Structural Database, Powder Diffraction File, the patent literature, and the scientific literature. Statistics on crystal polymorphism among the elements in inorganic compounds and macromolecular (i.e., biological) molecules precede the historical perspective. The chapter closes with a brief survey of the commercial importance of polymorphism.

Polymorphism and patents

A brief introduction to patents is followed by a discussion of the two main issues of patents on (pharmaceutical) polymorphs from the scientific perspective: novelty and obviousness, with an emphasis on the latter. The issues, decisions, and ramifications of six landmark patent litigations involving solid forms are described. These involved the following drugs: cefadroxil, terazosin hydrochloride, ranitidine hydrochloride, paroxetine hydrochloride, armodafinil, and tapentadol hydrochloride. The chapter closes with a description of the litigation on the synthetic sweetener aspartame which involved an issue of habit (shape) rather than the form (crystal structure).

Polymorphism and structure–property relations

Chapter 6 deals with the connection between the structure and properties of solids as revealed and studied in polymorphic systems. The subject is divided into properties that depend on the one hand on the bulk—that is, the three-dimensional arrangement of the molecules and the interactions among them—and on the other hand the consideration of the crystal as an “oriented gas” serving to act as a matrix for the molecules to permit the study of molecular properties. Among the properties described in the former category are electrical conductivity, organic magnetic materials, photovoltaicity and photoconductivity, second harmonic generation, chromoisomerism, photochromism, thermochromism and mechanochromism, and the mechanosalient effect. The latter category includes a discussion of spectroscopic studies (infrared, Raman, and ultraviolet/visible), excimer phenomena, time-resolved studies of excited states, photochemical reactions and thermal and gas reactions, along with a variety of emission phenomena. The chapter closes with a brief survey of rapidly emerging and developing high pressure studies

Computational aspects of polymorphism

The application of computational techniques to polymorphic systems is reviewed. Topics covered include the energetics of molecular geometric features (bond lengths, bond angles, torsion angles) and the energetics of intermolecular interactions of various types. Methods and techniques for the presentation of polymorphic structures are described, followed by some historically important early examples of conformational polymorphism. The latter subject is treated in light of recent developments, including some exemplary studies of conformational polymorphism and the prototypical example of “ROY” is discussed in detail. The computational prediction and comparison of polymorphs is discussed in the framework of the computational prediction of crystal structures. Methods discussed on polymorphs include the comparison based on geometric criteria, comparison based on Hirshfeld surfaces, a comparison based on energetic environment, comparison of X-ray diffraction patterns, and the use of partitioned lattice energy to investigate the details of similarities and differences in polymorphic structures.

Exploring the crystal form landscape

Chapter 3 deals with the theoretical background, the strategies, and the experimental techniques for exploring the crystal for landscape. The various and evolving models for aggregation and nucleation are discussed, followed by the description of thermodynamic (i.e., approximately equilibrium) and kinetic crystallization conditions, followed by the use of thermodynamic information obtained in Chapter 2 for designing crystallization strategies. The various aspects of solid form screens—design, composition, time frame, variables to consider, application of high throughput methods—are discussed, followed by a description of the screen on the specific example of axitinib. The chapter closes with discussions of concomitant polymorphs and disappearing polymorphs.

Polymorphism of pigments and dyes

The occurrence of the polymorphism of pigments is surveyed, with a special emphasis on three of the most important classes of pigments: quinacridones, perylenes, and phthalocyanines. Organic pigments are molecular crystals of very low solubility that provide the colors for industrial and consumer products. The properties of those compounds, including color, stability, light fastness, etc., all depend intimately on the structure, hence on the existence of polymorphism and the specific polymorphic form. The chapter summarizes much of the known information of the known and reported polymorphism of pigments in tabular form, including the scientific and patent literature, patent references, and entries in the Cambridge Structural Database. The chapter closes with a discussion of the isomorphism of pigments.

Analytical techniques for studying and characterizing polymorphs and polymorphic transitions

Chapter 4 deals with the analytical methods for the characterization of solid forms, including optical and hot stage microscopy, thermal methods (differential scanning calorimetry, thermal gravimetric analysis, etc.), X-ray diffraction methods (powder and single crystal methods), infrared and Raman spectroscopy, solid state nuclear magnetic resonance spectroscopy, electron microscopy, atomic force microscopy, scanning tunneling microscopy, and pycnometry (density measurements). The principles of each of these techniques are outlined, followed by representative examples of their application in the investigation and characterization of polymorphic systems. The integration of a number of analytical tools—“hyphenated techniques”—into a particular instrument is described for a number of cases, followed by a discussion of the experimental approach for determining if two samples comprise polymorphs of the same compound.