Importance of polymorphism in pharmaceuticals

The solid nature of the excipient may influence the final physical form of the tablet (Byrn et al. 2001), such as a tendency to stick (Schmid et al. 2000), or may induce a polymorphic conversion of the active ingredient (Kitamura et al. 1994). Hence, there have been attempts to develop protocols for the selection of compatible active ingredient-excipient compositions (Serajuddin et al. 1999). For instance, nuclear magnetic resonance spectroscopy has been employed to study the structural changes in epichlorohydrin cross-linked high amylose starch excipient (Shiftan et al. 2000), and has also been used to discriminate between two polymorphs of prednisolone present in tablets with excipients, even at low concentrations (5 per cent w/w) of the active ingredient (Saindon et al. 1993). The characterization of excipients by thermal methods has also been reviewed by Giron (1997). 

Polymorphism can influence every aspect of the solid state properties of a drug. Many of the examples given in preceding chapters on the preparation of different crystal modifications, on analytical methods to determine the existence of polymorphs and to characterize them and to study structure/property relations, were taken from the pharmaceutical industry, in part because there is a vast and growing body of literature to provide examples. One of the important aspects of polymorphism in pharmaceuticals is the possibility of interconversion among polymorphic forms, whether by design or happenstance. This topic has also been recently reviewed (Byrn et al. 1999, especially Chapter 13) and will not be covered here. Rather, in this section, we will present some additional examples of the variation of properties relevant to the use, efficacy, stability, etc. of pharmaceutically important compounds that have been shown to vary among different crystal modifications. 

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The importance of polymorphism in pharmaceuticals cannot be overemphasized. Some crystal structures contain molecules of water or solvents, known as hydrates or solvates, respectively, and they are also called as pseudopolymorphs. Identifying all relevant polymorphs and solvates at an early stage of development for new chemical entities has become a well-accepted concept in pharmaceutical industry. For poorly soluble compounds, understanding their polymorphic behavior is even more important since solubility, crystal shape, dissolution rate, and bioavailability may vary with the polymorphic form. Conversion of a drug substance to a more thermodynamically stable form in the formulation can signiLcantly increase the development cost or even result in product failure. 

A polymorph is a solid crystalline phase of a compound resulting from the possibility of at least two different crystal lattice arrangements of that compound in the solid state [42], Polymorphs of a compound are, however, identical in the liquid and vapor states. They usually melt at different temperatures but give melts of identical composition. Two polymorphs of a compound may be as different in structure and properties as crystals of two different compounds [43,44], Apparent solubility, melting point, density, hardness, crystal shape, optical and electrical properties, vapor pressure, etc. may all vary with the polymorphic form. The polymorphs that are produced depend upon factors such as storage temperature, recrystallization solvent, and rate of cooling. Table 2 suggests the importance of polymorphism in the field of pharmaceutics [45],... 

Nevertheless, this observation cannot be reproduced because of the polymorphic changes that occur when the drug is stored. Until the challenge of controlling or stabilizing the polymorphism conversion is met, the application of polymorphism in pharmaceuticals will be questionable. The knowledge and data on polymorphism are important to the pharmaceutical industry. Many pharmaceutical problems can be explained or avoided if the concept of polymorphism is understood and methods of detection, control, purification, and isolation are available. 

Without a doubt, one of the most important uses of XRPD in pharmaceuticals is derived from application as the primary determinant of polymorphic or solvatomorphic identity [34], Since these effects are due to purely crystallographic phenomena, it is self-evident that x-ray diffraction techniques would represent the primary method of determination. Owing to its ease of data acquisition, XRPD is particularly... 

As polymorphism has become an increasingly important factor in the commercial aspects of many solid materials, the number of patents relating to the discovery and use of particular polymorphic forms has increased. This is particularly important for pharmaceuticals, pigments and dyes, and explosive materials, which are discussed in Chapters 7-9. Some examples of the role of polymorphism in patent litigation are described in detail in Chapter 10. The patent literature is readily searchable using terms such as crystal form , polymorph etc., and since polymorphic behaviour often forms the basis of a patent (as opposed to many journal publications, where it may be peripheral to the main point of the paper) instances of polymorphism are relatively straightforward to locate. 

The phenomenon of X-ray diffraction has found widespread use as a means to determine the structures of single crystals and represents the most powerful and direct method to obtain bond lengths and bond angles for molecules in the solid state. This information is of extreme importance to workers in pharmaceutics when they encounter the existence of polymorphism or solvatomorphism. 

The importance of polymorphism within crystal engineering is substantial and in the area of pharmaceutical crystals has proven to be of great importance financially (Chapter 3.3). Studies using pressure as a variable have been applied recently to the studies of pharmaceutical or related compounds to explore more widely potential polymorphism in such compounds. The examples of glycine and paracetamol are discussed below. 

Thermal analysis is an extremely important analytical tool for the pharmaceutical industry. All transitions in materials involve the flow of heat (either into the sample during an endothermic event or out of the sample during an exothermic event) and DSC is the universal detector for measuring a wide variety of transitions in pharmaceutical materials. These include measurement of amorphous structure, crystallinity (and polymorphs), drug-excipient interaction and many other applications. 

Supramolecular Materials Chemistry). Supramolecular isomerism is related to polymorphism in that, in both cases, the chemical constituents of two or more crystalline substances are identical. Indeed, polymorphs may generally be regarded as being supramolecular isomers of one another, although the reverse is not always true." Polymorphism of molecular crystals, in particular, remains an important phenomenon, especially in pharmaceuticals. However, although reports of polymorphs have increased significantly... 

The topics of polymorphism and pseudopolymorphism dominate the majority of publications that deal with utilizing infrared spectroscopy for the physical characterization of pharmaceutical solids. Typically, in each of the publications, IR spectroscopy is only one technique used to characterize the various physical forms. It is important to realize that a multidisciplinary approach must be taken for the complete physical characterization of a pharmaceutical solid. Besides polymorphism, mid- and near-IR have been utilized for identity testing at the bulk and formulated product level, contaminant analysis, and drug-excipient interactions. A number of these applications will be highlighted within the next few sections. 

In a manner similar to that just described for differential thermal analysis, DSC can be used to obtain useful and characteristic thermal and melting point data for crystal polymorphs or solvate species. This information is of great importance to the pharmaceutical industry since many compounds can crystallize in more than one structural modification, and the FDA is vitally concerned with this possibility. Although the primary means of polymorph or solvate characterization s centered around x-ray diffraction methodology, in suitable situations thermal analysis can be used to advantage. 

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