Understanding exceptional polymorphs

Abstract

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 Z 0 . 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 Z 0 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 Z 0 fit in? In effect the understanding of structures with Z 0 > 1 is equivalent to the understanding of polymorphism itself. The phenomenon is also related to the understanding of co-crystals since a structure with Z 0 = 2 has two symmetry-independent molecules and so does a binary co-crystal (with Z 0 = 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 Z 0 > 1 also have a tendency to form co-crystals (Anderson et al.,It has gradually become clear that the simple Z 0 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 '...

Conformational Polymorphism in Safinamide Acid Hydrochloride (Z′ = 3 and Z′ = 1) and Observation of a Temperature-Dependent Reversible Single-Crystal to Single-Crystal Phase Transformation of High-Z′ form (Z′ = 3 ↔ Z′ = 2 via an Intermediate Z′ = 4)

“…Organic molecules which crystallize with multiple molecules in the asymmetric unit, referred to as Z ′ > 1 or high- Z ′ structures, − continue to fascinate researchers, although several groups in the past have attempted to understand the Z ′ > 1 phenomenon. − The Cambridge Structural Database (CSD) reached a major milestone by depositing the millionth crystal structure in 2019 . The recent statistics of Z ′ > 1 in the CSD continue to be approximately 10–11% in organic structures and 8% in total CSD structures. − ,, A proper understanding of Z ′ and the expectation of a possible Z ′ > 1 crystal structure based on the molecular structure, functional groups, shape, and symmetry is regarded as an important strategy for an accurate crystal structure prediction (CSP) of drug molecules, − a structure determination by the powder X-ray diffraction (PXRD) method, − and the development of chiral materials. , The Z ′ > 1 structures are often termed as “frustrated” structures which are thought to arise from packing difficulties to crystallize as a single molecular entity .…”

“…Organic molecules which crystallize with multiple molecules in the asymmetric unit, referred to as Z ′ > 1 or high- Z ′ structures, − continue to fascinate researchers, although several groups in the past have attempted to understand the Z ′ > 1 phenomenon. − The Cambridge Structural Database (CSD) reached a major milestone by depositing the millionth crystal structure in 2019 . The recent statistics of Z ′ > 1 in the CSD continue to be approximately 10–11% in organic structures and 8% in total CSD structures. − ,, A proper understanding of Z ′ and the expectation of a possible Z ′ > 1 crystal structure based on the molecular structure, functional groups, shape, and symmetry is regarded as an important strategy for an accurate crystal structure prediction (CSP) of drug molecules, − a structure determination by the powder X-ray diffraction (PXRD) method, − and the development of chiral materials. , The Z ′ > 1 structures are often termed as “frustrated” structures which are thought to arise from packing difficulties to crystallize as a single molecular entity . Steed wrote two detailed reviews on high- Z ′ structures, and the reasons for Z ′ > 1 occurrence are attributed to awkward molecular shape, the choice of slightly different molecular conformations, conflict from strong intermolecular interactions and crystal packing, pseudosymmetry, disorder, and temperature effects. , Experimental conditions under which the crystals are grown are shown to have a strong correlation with Z ′ > 1 behavior. , The connection between high- Z ′ structures and strong hydrogen bonds was noted by Gavezzotti, Nangia, Desiraju, Brock, , and others. …”

“…Steed commented that understanding Z ′ > 1 is equivalent to understanding the polymorphism itself and the phenomenon of cocrystallization, considering that these topics have some connections at the structural level . Polymorphism, by definition, is the occurrence of multiple crystalline forms of the same compound .…”

At the Interface of Isomorphous Behavior in a 3 × 3 Isomer Grid of Monochlorobenzamides: Analyses of the Interaction Landscapes via Contact Enrichment Studies

“…The Clpo, Clmo, Cloo series: polymorphism in Clpo (Clpo_O and Clpo_N) [76][77][78][79][80] Clpo crystallises as two polymorphs, both P-syn, (Figures 7, 8 (16) rings. [25][26][27][28][29][30] Clpo_O with amide…amide interactions is distinctly different to the related orthopyridine (Yxo) structures (Y = Me, 45 F, 43 Cl (see below), Br), e.g.…”

“…The notable structural results for the Clxx series are: (i) the Clpo_O, Clpo_N polymorphic pair [76][77][78][79][80] (both as Z'=1 in space group C2/c) and with voids present in the Clpo_N polymorph, (ii) the Clmp and Clpm structures having a relatively high Z'=4 in the asymmetric unit, [73][74][75] which is rather uncommon in benzamide structures reported to date, 43 and (iii) the distinct lack of intermolecular Cl…O and Cl…N halogen bonding, apart from clear-cut cases such as Clop (as aromatic C-Cl…O=C interactions) and Clom (with aromatic C-Cl…Cl-C contacts). There is, however, a C-Cl… intermolecular contact where the Cl -hole faces the pyridine ring in Clpp at an angle (C-Cl,  ring centroid) = 163.34(7).…”