Organic crystals, polymorphism

This report describes some recent developments in the understanding of the thermodynamic, kinetic and structural aspects of organic crystal polymorphism with an emphasis on the application of newer methodology used for its study, since this is one of the areas in which significant progress has been made in recent years. Numerous examples of polymorphic systems are described to illustrate the applications of both older and newer techniques for their investigation. These include studies of pseudopolymorphism manifested by hydrates and solvates of the parent organic molecule. Finally, the crucial question of... 

Some new insights into the nature of organic crystal polymorphism have been gleaned from a recent systematic analysis [79] of data for polymorphic structures retrieved from the Cambridge Structural Database. A total of 345 crystal structures were reduced to 163 clusters (a cluster referring to a group of two or more polymorphs of the same compound). These clusters comprised 147... 

Having outlined the methods of preparation of polymorphs and pseudopolymorphs, this report now focuses on the methodology used to study these forms. The discussion commences with a survey of some well established and still widely used techniques, each of which is illustrated by one or more applications. This is followed by a survey of newer methodology which is being used to probe organic crystal polymorphism. 

Four selected case studies are cited here to illustrate some of the difficulties encountered in research on organic crystal polymorphism, even when relatively simple molecules are involved. Since space does not permit discussion, precis of these model studies are presented in the hope that the interested reader will consult the original, absorbing accounts for details. 

The famous organic crystal polymorph school at the University of Innsbruck started with L. and A. Kofler, continued with M.Kuhnert-Brandstaetter and A. Burger, and is now led by Ulrich Griesser. 

In some cases there is evidence of multiple solid-solid transitions, either crystal-crystal polymorphism (seen for Cl salts [20]) or, more often, formation of plastic crystal phases - indicated by solid-solid transitions that consume a large fraction of the enthalpy of melting [21], which also results in low-energy melting transitions. The overall enthalpy of the salt can be dispersed into a large number of fluxional modes (vibration and rotation) of the organic cation, rather than into enthalpy of fusion. Thus, energetically, crystallization is often not overly favored. 

In spite of the great interest in the phenomenon of polymorphism and of the increased research activity beyond the boundaries of organic solid-state chemistry, it is a fact that only a few molecular compounds possess several crystalline forms, whereas for many other tens of thousands of molecular compounds only one crystalline form is known. In other words, why are there so few molecular crystals polymorphs The often quoted association between number of known forms and the time and energy spent in searching for them put forward by McCrone probably contains the answer to this question. It is probable that if thorough (combinatorial ) crystallization experiments were carried out on any given molecular species or molecular salt, alternative crystalline forms would be found. It is probable but not certain. 

A total of 163 clusters were obtained, where a cluster is a group of polymorphic crystal structures of the same compound. Of the 163 clusters, 147 contained two structures, 13 had three, and three had four structures. The authors note that these numbers are first evidence of the high frequency of polymorphism in organic crystals , although the number of clusters is a relatively small percentage of the entries in the database. The number of these clusters is probably more a measure of certain authors interest in the particular polymorphic system in question. A more realistic measure (although certainly not precise because of the caveats mentioned above) of the frequency of polymorphism in these compounds wouid be the fraction of compounds in the database known to be polymorphic, whether multiple structures have been done or not. 

Bernstein, J. (1993). Crystal growth, polymorphism and structure-property relationships in organic crystals. J. Phys. D, 26, B66-76. [189]... 

Louis Pasteur was the first scientist to study the effect of molecular chirality on the crystal structure of organic compoimds [23], finding that the resolved enantiomers of sodium ammonium tartrate could be obtained in a crystalline form that featured nonsuperimposable hemihedral facets (see Fig. 9.1). Pasteur was quite surprised to learn that when he conducted the crystallization of racemic sodium ammonium tartrate at temperatures below 28 °C, he also obtained crystals of that contained nonsuperimposable hemihedral facets. He was able to manually separate the left-handed crystals from the right-handed ones, and foimd that these separated forms were optically active upon dissolution. More surprising was the discovery that when the crystallization was conducted at temperatures exceeding 28 °C, he obtained crystals having different morphologies that did not contain the hemihedral crystal facets (also illustrated in Fig. 9.1). Later workers established that this was a case of crystal polymorphism. 

Gavezzotti, A. Filippini, G. Polymorphic forms of organic crystals at room conditions - thermodynamic and structural implications. J. Am. Chem. Soc. 1995,117 (49), 12,299-12,305. 

X-ray powder diffraction More highly organized crystals afford more intense diffraction peaks. Polymorphs can be distinguished, depending on crystal lattice differences. Detection limit 5—15% for minor polymorph."... 

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