Understanding exceptional polymorphs.

In an engaging and thoughtful article in this issue Carol Brock (Brock, 2016) of the University of Kentucky puts forward a typically insightful, modestly understated and detailed analysis of some of the organizing principles behind crystal structures with high Z0. Did I lose your interest already? It sounds obscure doesn’t it? Some crystallographic parameter . . . a few odd, niche structures. Who cares, right? Wrong! Let me tell you why. Of course you already know what Z0 is; loosely the number of symmetry-independent molecules in the asymmetric unit. As an Acta B reader you also know just how extraordinarily important the organic/molecular solid state is. The understanding and control of solid forms in general is the Holy Grail of structural scientists. Industry, particularly pharma and agrichem, cares enormously about the solid form of molecules. The solid form impinges directly on solubility, bioavailability, processing characteristics, bulk density, dissolution rate, permeability, surface electrostatic charge and so on (Brittain, 1999). It is all true. All that background justification you have been reading in grant applications for so long. Moreover, understanding and even predicting crystal structure is one of the grand fundamental challenges in science. So any step forward in that direction is extremely important. What do I mean by solid form exactly? It is a catch-all phrase that encompasses the science of polymorphism, co-crystals, solvates and perhaps salt form. There is no doubt that polymorphism and co-crystal formation are extremely hot topics at present. There has been all sorts of excitement about the FDA classification of co-crystals as being akin to new polymorphs of active pharmaceutical ingredients (US Department of Health and Human Services, 2016) and of course the burgeoning number of litigations concerning polymorphism ever since the original Zantac case (Bernstein, 2002) speaks to their commercial importance. But, where does Z0 fit in? In effect the understanding of structures with Z0 > 1 is equivalent to the understanding of polymorphism itself. The phenomenon is also related to the understanding of co-crystals since a structure with Z0 = 2 has two symmetry-independent molecules and so does a binary co-crystal (with Z0 = 1). In terms of crystallographic symmetry, and for that matter computational complexity, the two situations are conceptually related. A holistic understanding of polymorphism, cocrystal formation and structures with multiple symmetry-independent molecules go hand-in-hand with one another (Steed & Steed, 2015). Indeed it is a fact that compounds that crystallize with Z0 > 1 also have a tendency to form co-crystals (Anderson et al., 2009). It has gradually become clear that the simple Z0 parameter is a ‘catch all’ description of a variety of phenomena with diverse causes. As many crystallographers have noted, however, the presence of many symmetry-independent molecules in a structure is a sure sign that something interesting is going on. Perhaps if we can understand these ‘exceptions’ (less than 10% of structures in the CSD are Z0 > 1; Steed & Steed, 2015) we may move a little closer to addressing the bigger problem of understanding the molecular solid state in general. After all, who could fail to be impressed and intrigued by the new high Z0 world record holder, the eightfold polycatenated structure of 1,3,5-tris(4carboxyphenyl)benzene with Z0 = 56 (Fig. 1; Zentner et al., 2015). Carol Brock has been interested in the underlying principles of crystal packing for a very long time. Her 1994 review co-authored with Jack Dunitz entitled ‘Towards a grammar of crystal packing’ laid out some rigorous principles that have stood the test of time (Brock & Dunitz, 1994). In that same year she also pointed out the first well argued chemical-structure-based explanation for the occurrence of high Z0, pointing out that monoalcohols, depending on the steric constraints of the substituent and the need to ISSN 2052-5206