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) interactions within the crystal structure often lead to acicular (needle shaped) or platy crystals with notoriously poor filtration and flow properties [4]. Since crystal size and shape can have a strong impact on release characteristics (dissolution rate), material handling (filtration, flow), and mechanical properties (plasticity, elasticity, density) relevant to tablet formulation, crystallization processes targeting a specific crystal form are also designed with exquisite control of crystal shape and size in mind.

Some compounds (their salts, hydrates, and cocrystals included) crystallize in a single solid form, while others crystallize in possibly many different forms. Polymorphism [Greek: poly?=?many, morph?=?form] is the ability of a molecule to crystallize in multiple crystal forms (of identical composition) that differ in molecular packing and, in some cases, conformation [5]. A compelling example of a highly polymorphic molecule is 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile, also known as ROY, an intermediate in the synthesis of the schizophrenia drug olanzapine. Polymorphs of ROY, mostly named for their red-orange-yellow spectrum of colors and unique and distinguishable crystal shapes, are shown in Figure 1.2 [6]. Multiple crystal forms of ROY were first suggested by the varying brilliant colors and morphologies of individual crystals in a single batch of the compound. Confirmation of polymorphism later came with the determination of many of their crystal structures by X-ray diffraction (Table 1.1) [7]. In this example, the color differences were traced to different molecular conformations, characterized by ?, the torsion angle relating the rigid o-nitroaniline and thiophene rings in the crystal structures of the different ROY polymorphs [8].

Figure 1.2 (a) Crystal polymorphs of ROY highlighting the diverse colors and shapes of crystals grown from different solutions and (b) photomicrographs showing the concurrent cross nucleation of the R polymorph on Y04 produced by melt crystallization and (c) single crystals of YT04 grown by seeding a supersaturated solution.

Source: Adapted with permission from Yu et al. [6], copyright 2000, and from Chen et al. [7], copyright 2005, American Chemical Society.

Table 1.1 Crystallographic data from X-ray structure determinations of seven ROY polymorphs.