Pharmaceuticals, crystal polymorphism studies

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. 

The identification, structural and thermal characterization of new polymorphs is an important topic in solid-state chemistry and requires a battery of techniques that includes X-ray diffraction and spectroscopic methods, in addition to thermal analysis methods and dissolution techniques to determine solubility trends. Such studies are described by Caira in Chapter 16, as well as more recent theoretical techniques aimed at the prediction of the crystal structures of new polymorphs. Crystal polymorphism is particularly important in pharmaceutical products, so there is an emphasis on this area. Systems displaying solvatomorphism (the ability of a substance to exist in two or more crystalline phases arising from differences in their solvation states) molecular inclusion and isostructurality (the inverse of polymorphism) are also given due attention in this chapter. 

In Structural analysis of active pharmaceutical ingredients, crystal polymorphism is an important subject of study. Crystal structures are determined by X-ray diffraction studies. Once the correlation between crystal polymorphs and their infrared spectra has been established, it can then become a relatively easy task to distinguish polymorphs by measuring their microphotographs and corresponding microscopic infrared spectra, as infrared microspectrometric measurements can be conveniently performed within a much shorter time than X-diffraction analysis. 

The pharmaceutical industry has taken great interest of late in the study of polymorphism and solvatomorphism in its materials, since a strong interest in the phenomena has developed now that regulatory authorities understand that the nature of the structure adopted by a given compound upon crystallization can exert a profound effect on its solid-state properties. For a given material, the heat capacity, conductivity, volume, density, viscosity, surface tension, diffusivity, crystal... 

Preferred orientation of the particles must be minimized. One of the most effective ways to achieve this is to reduce the particle size by grinding the sample [1], As already discussed in Section III.A, however, grinding can disorder the crystal lattice. Grinding can also induce other undesirable transitions, such as polymorphic transformations [59]. In order to obtain reproducible intensities, there is an optimum crystallite size. The crystallites have to be sufficiently small so that the diffracted intensities are reproducible. Careful studies have been carried out to determine the desired crystallite size of quartz, but no such studies have been reported for pharmaceutical solids [60]. Care should be taken to ensure that the crystallites are not very small, since decreased particle size can cause a broadening of x-ray lines. This effect, discussed earlier (Eq. 9), usually becomes apparent when the particle size is below 0.1 jum. 

The topic of polymorphism is of tremendous and increasing academic and industrial importance in modern crystal chemistry and crystal engineering. The industrial interest stems from the pharmaceutical industry and has stimulated wide-ranging academic study. Legally, a molecule (termed an active pharmaceutical Ingredient, API) with particular biological activity in vivo can be patented as a new invention. Moreover, particular crystal forms of that molecule (polymorphs) can be separately patented as distinct inventions. If particular polymorphs are patented after the original API patent then upon the... 

In an example from the pharmaceutical industry Sudo et a/. (1991) studied the relative nucleation properties of forms A and B of cimetidine, which is reported to have four polymorphic non-solvated forms and three polymorphic monohydrates. Modification A is preferred for pharmaceutical formulations. The waiting time method was used to study the primary nucleation process (Harano and Oota 1978), mainly for competitive crystallization of the A and B modifications. A is a thermodynamically metastable form and is more soluble than B in any solvent. At high supersaturation... 

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. 

While establishing molecular networks for cocrystal design and determining crystal structures is very important, the value of cocrystals of pharmaceutical components lies in the ability to tailor the functionality of materials. In contrast to polymorphs that have the same chemical composition, cocrystals do not. As such, one would expect that with cocrystals one could introduce greater changes in material properties than with polymorphs. Properties that relate to pharmaceutical performance and that can be controlled by cocrystal formation include melting point, solubility, dissolution, chemical stability, hygroscopicity, mechanical properties, and bioavailability. The cocrystals for which pharmaceutical properties have been studied are few and some of these are presented below. Clearly further research in this area is needed. 

Of all the methods available for the physical characterization of solid materials, it is generally agreed that crystallography, microscopy, thermal analysis, solubility studies, vibrational spectroscopy, and nuclear magnetic resonance are the most useful for characterization of polymorphs and solvates. However, it cannot be overemphasized that the defining criterion for the existence of polymorphic types must always be a non-equivalence of crystal structures. For compounds of pharmaceutical interest, this ordinarily implies that a non-equivalent X-ray powder diffraction pattern is observed for each suspected polymorphic variation. All other methodologies must be considered as sources of supporting and ancillary information, but cannot be taken as definitive proof for the existence of polymorphism by themselves. 

In the pharmaceutical industry, SSNMR is commonly used to study polymorphism, hydrogen bonding, crystal packing, and solid-solid interactions. Shelf life or activity decay is often determined by the bioavailability of different polymorphs. Fig. 12 shows very different CP/MAS spectra from two polymorphs of an analgesic, flufenamic acid. It is also used for the study of inclusion complexes, drug-excipient interactions, or the effect of moisture on drug substances or formulations. 

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