Potential polymorphic systems

All the solid-state properties of the various polymorphic modifications of a compound are different, but the difference is only marginal in nature, sometimes beyond the limit of detection of a particular analytical method. Therefore, to avoid erroneous conclusions it is important to look at potential polymorphic systems using a variety of analytical techniques. " By relying on too few analytical techniques, one may fail to discover a polymorph. It may require substantial effort for complete elucidation of substances with multiple polymorphic forms, especially when previous studies have characterized the forms inadequately. 

It is worth noting that a monotropic polymorphic system offers the potential of annealing the substance to achieve the preferred form of the thermodynamically stable phase. The use of the most stable form is ordinarily preferred to avoid the inexorable tendency of a metastable system to move toward the thermodynamic form. This is especially important especially if someone elects to use a metastable phase of an excipient as part of a tablet coating, since physical changes in the properties of the coating can take place after it has been made. Use of the most stable form avoids any solid-solid transition that could... 

The theoretical basis and practical considerations for the application of SSNMR to the smdy of polymorphism may be found in a number of references, which themselves contain additional primary sources (for instance Yannoni 1982 Fyfe 1983 Komorski 1986 Bugay 1993 Harris 1993 Brittain 1997 Byrn etal. 1999). As with many of the analytical techniques described in this chapter, SSNMR is a rapidly developing field with great potential in the investigation of polymorphic systems. It is not limited to a single nucleus (although most studies to date have concentrated on the nucleus) and it is being adapted for quantitative analysis of polymorphic mixtures and other multicomponent systems. 

The potential application of chemical and physical techniques for the study of polymorphs is virtually limitless. The combination of techniques into a single apparatus in order to extract the maximum information from a single experiment and a single sample is particularly applicable to polymorphic systems. The drawback in... 

In spite of these caveats, there is intense activity in the application of these methods to polymorphic systems and considerable progress has been made. Two general approaches to the use of these methods in the study of polymorphism may be distinguished. In the first, the methods are utilized to compute the energies of the known crystal structures of polymorphs to evaluate lattice energies and determine the relative stabilities of different modifications. By comparison with experimental thermodynamic data, this approach can be used to evaluate the methods and force fields employed. The ofher principal application has been in fhe generation of possible crystal structures for a substance whose crystal structure is not known, or which for experimental reasons has resisted determination. Such a process implies a certain ability to predict the crystal structure of a system. However, the intrinsically approximate energies of different polymorphs, the nature of force fields, and the inherent imprecision and inaccuracy of the computational method still limit the efificacy of such an approach (Lommerse et al. 2000). Nevertheless, in combination with other physical data, in particular the experimental X-ray powder diffraction pattern, these computational methods provide a potentially powerful approach to structure determination. The first approach is the one applicable to the study of conformational polymorphs. The second is discussed in more detail at the end of this chapter. 

Since different crystal forms have different structures, they can, potentially, exhibit different physical properties and different responses to experimental analytical methods. Some of the more commonly used of these methods have been demonstrated above. A central question for any polymorphic system is the relative stability of the various crystal forms. As noted above, these may be investigated qualitatively by HSM methods, and more quantitatively using thermal analytical techniques. The combined results of these measurements are conveniently summarized on a semi-empirical energy-temperature diagram [31], as shown in Fig. 3.3.16. The thermal... 

Although the solid/liquid/vapor triple point is the most commonly encountered, the existence of other solid phases yields additional triple points. The number of triple points possible to a polymorphic system increases very rapidly with the number of potential solid phases. 

Danser, A. H. J., and Schunkert, H. (2000) Renin-angiotensin system gene polymorphisms potential mechanisms for their association with cardiovascular diseases. Eur. J. Pharmacol. 410,303-316. 

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