Polymorphism conformationally different molecules

B. Polymorphism Resulting from the Packing of Conformationally Different Molecules... 

When polymorphism occurs, the molecules arrange themselves in tv/o or more different v/ays in the crystal either they may be packed differently in the crystal lattice, or there may be differences in the orientation or the conformation of the molecules at the lattice site. These variations cause differences in X-ray diffraction patterns of the polymorphs and this technique is one of the main methods in detecting them. The polymorphs have different physical and chemical properties. 

At first glance this definition seems straightforward. What are some of the complications For flexible molecules McCrone would include conformational polymorphs, wherein the molecule can adopt different conformations in the different crystal structures (Corradini 1973 Panagiotopoulis et al. 1974 Bernstein and Hagler 1978 Bernstein 1987). But this is a matter of degree dynamic isomerism or tautomerism... 

One of the common features of the growing number of studies on conformational polymorphs is the utilization of a number of analytical and computational techniques to characterize the systems (e.g. Bauer et al. 2001). The emphasis differs from study to study, as demonstrated below, but these multidisciplinary approaches are to be encouraged and hopefully expanded. Another common feature of these investigations is the nature of the molecules investigated—relatively small molecules, with a limited number of conformational parameters. This allows a more direct comparison of conformational differences and the energies associated with those differences. As our understanding of the phenomenon increases and the computational capabilities to deal with larger systems improve, we can expect that more and more complex systems will be studied. 

Many drugs exist in several polymorphic forms. The various polymorphs of a dmg differ in the packing of the molecules in the crystal lattice or in the conformation of the molecules at the lattice sites. The different polymorphs have different physical and chemical properties and usually exist in different habits. The transformation between... 

Solid-state SS-NMR and XRPD take advantage of different phenomena to evaluate polymorphism. XRPD is sensitive to differences in unit cell dimensions, whereas SS-NMR is sensitive to conformational changes and differences in magnetic environments.94 One can think of two hypothetical situations. If two polymorphic forms differ exclusively in their unit cell dimensions but the conformation of the molecule is preserved, then the XRPD patterns are likely to be substantially different, whereas SS-NMR may not register any changes. On the other hand, if the unit cell dimensions are preserved while the molecular conformation changes substantially, SS-NMR is likely to pick up the differences and the XRPD patterns might be the same. In this sense, both techniques provide information that is complementary to the other.94... 

Besides the previous considerations, the mere existence of a crystal or aggregate requires that the participant molecules can form more than one bond with different molecules. The topology of these bonds has been found to be an important tool to analyze and distinguish between different polymorphic forms. When one molecule can form more than one bond then the cooperativity between these bonds becomes an important issue. Thus, the interaction energy of a carboxylic acid in its ring conformation is more than twice that found in the linear conformation (both conformers are plotted in Fig. 8). 

We recently discovered a novel polymorph, designated form 6, with unit cell parameters significantly different from both forms [29], Single crystal X-ray structures of form 3 (melt phase), form 4 (hydrate/solvate) and form 5 (sublimed phase) [30] are not known and they are therefore not relevant to the present discussion on molecular conformations and multiple Z. The conformation of molecule 10 in form 1 and 2 is different only in the opposite orientation of OCH3 group, while the rest of the tricyclic skeleton overlays very nicely. Interestingly, form 6 has both these... 

The existence of more than one type of network super-stracture for the same molecular building block represents supramolecular isomerism. Therefore, it is related to stractural isomerism at the molecular level. Supramolecular isomerism is the existence of different architectures (i.e., architectural isomerism) or superstructures. Polymorphism is a type of supramolecular isomerism but not vice versa. Supramolecular isomerism can be classified as structural (the same components result in different network superstructures), conformational (different conformations of a flexible molecule generate different, but often related, network architectures), catenane (the different maimer and degrees in which networks interpenetrate or interweave), and optical (chirai networks that... 

FTIR and Raman spectroscopy are frequently used to characterize polymorphs. Both the molecular conformation and the crystal packing may lead to differences in the FTIR spectra of polymorphs the differences are more pronounced for compounds capable of hydrogen bonding. Characteristic shifts in C=0, N-H, and O-H stretching frequencies often lead to unequivocal polymorphic identification. Differences in fine structure and in the positions and intensities of IR bands enabled seven crystalline forms of the steroid prasterone 3 to be distinguished."" The presence of characteristic absorption bands due to included solvent molecules allows ready distinction between polymorphs and pseudopolymorphs. 

Polymorphism can result from conformational differences in a chain molecule or different packings of molecules with the same conformation. Such differences can be induced by slight alterations in the crystallization conditions, for example, by varying the crystallization temperature. 

Thus, solid 1 exists as at least four forms differing in both crystalline and molecular structure two yellow crystalline 1 1 solvates with toluene and THF (lb and Ic), and two solvent-free forms orange crystals (la) and a yellow powder (Id). Bernstein [10] uses a term conformational polymorphism for this phenomenon, that is, existence of several forms of a conformationally flexible molecule (with energy difference between the conformers less then 2 kcal/mol) depending on crystallization conditions. Our experience with a step-by-step serendipitous finding of new conformational polymorphs of 1 ([1, 4-6] and this paper) closely resembles the classical story about analogous forms of dimethylbenzylideneaniline, described vividly in [10]. 

Different crystalline structures of one substance (single- or multicomponent) are named polymorphs [9, 10]. Polymorphism, which exists as a result of different crystal packing of rigid molecules, is called a packing polymorphism. Conformational polymorphism is a more common phenomenon for typically flexible drug-like molecules and results from crystallization of different conformers of the same molecule. At a given enviromnental conditions (temperature, humidity, pressure, etc.) only one solid form is thermodynamically stable (lowest free energy), while all other forms are considered metastable. 

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