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The serendipitous formation of Bandrowski's base, an oxidized trimer of p-phenylenediamine, a backbone molecule of the hair dye industry, in the presence of the antifungal/antidandruff agent clotrimazole, and the subsequent formation of a cocrystal has the potential of leading to a new group of commercially important formulations.

The landscape of β-cinnamic acid is explored by an extension of the previously reported fluorosubstitution protocol. Solid solutions of mono- and difluorocinnamic acids allow for the generation of a large number of experimental data points, which in conjunction with computational crystal structure prediction results can be used to profile the structural landscape of β-cinnamic acid. The variation in structure types may be caused by geometrical factors, namely shape-size equivalences, and chemical factors through the intermediacy of weak C–H⋯F hydrogen bonds in the solid solutions.

Weak hydrogen bonds of the type C–H⋯X (X: N, O, S and halogens) have evoked considerable interest over the years, especially in the context of crystal engineering. However, association patterns of weak hydrogen bonds are generally difficult to characterize, and yet the identification of such patterns is of interest, especially in high throughput work or where single crystal X-ray analysis is difficult or impossible. To obtain structural information on such assemblies, we describe here a five step IR spectroscopic method that identifies supramolecular synthons in weak hydrogen bonded dimer assemblies, bifurcated systems, and π-electron mediated synthons. The synthons studied here contain C–H groups as hydrogen bond donors. The method involves: (i) identifying simple compounds/cocrystals/salts that contain the hydrogen bonded dimer synthon of interest or linear hydrogen bonded assemblies between the same functionalities; (ii) scanning infrared (IR) spectra of the compounds; (iii) identifying characteristic spectral differences between dimer and linear; (iv) assigning identified bands as marker bands for identification of the supramolecular synthon, and finally (v) identifying synthons in compounds whose crystal structures are not known. The method has been effectively implemented for assemblies involving dimer/linear weak hydrogen bonds in nitrobenzenes (C–H⋯O–NO), nitro-dimethylamino compounds (NMe2⋯O2N), chalcones (C–H⋯OC), benzonitriles (C–H⋯NC) and fluorobenzoic acids (C–H⋯F–C). Two other special cases of C–H⋯π and N–H⋯π synthons were studied in which the band shape of the C–H stretch in hydrocarbons and the N–H deformation in aminobenzenes was examined.

Cocrystallization experiments of 2-methylresorcinol with several N-bases were performed to identify selective and preferred crystallization routes in relevant structural landscapes. These preferred supramolecular synthon-based crystallization routes were further enhanced by using carefully chosen coformer combinations to synthesize stoichiometric ternary solids. The exercise consists of modular selection and amplification of supramolecular synthons from single through two- to three-component molecular solids, and is equivalent to solid state combinatorial synthesis.

Co-crystal screening of the anti-HIV drug lamivudine was carried out with dicarboxylic acids as co-formers, and three of the resulting crystalline solids, two salts and a co-crystal, were studied with SCXRD, PXRD and FTIR spectroscopy. Salts of cytosine, a molecule that incorporates critical structural features of lamivudine, with the same co-formers, were taken as model systems for IR spectroscopic studies of the synthons in the salts of lamivudine. It is shown that different systems with the same synthon show very similar spectral signatures in the regions corresponding to the synthon absorptions. This reveals again the modular nature of the supramolecular synthon.

We discuss the assembly of a three-dimensional molecular crystal in terms of short-range supramolecular synthons that spontaneously organize themselves according to Aufbau principles into long-range geometries characteristic of the molecules themselves. For this purpose we have examined the systematic changes in the known crystal structures of a family of fluorobenzenes, C6H6-nFn, where 0 2D -> 3D assembly seem to be more influenced by the packing of LSAMs than by any other factor. In these final stages, there may not be so much influence exerted by the stronger short-range synthons. We discuss the evolution of these fluorobenzene crystal structures in terms of putative LSAMs and the purely geometric relationships between the n and (6 - n) compounds that can thus be expected. Such particle-hole pairs show structural similarities. Our discussion is quantified by the interpretation of intermolecular distances in terms of atomic sizes and with qualitative predictions of magnetic model systems.

Dinitro and tetracyano derivatives of tetraphenylmethane (TPM) are identified as new host materials that include THF, water and MeCN. The crystal structures of the host–guest complexes are reminiscent to those of the related host compound tetranitrotetraphenylmethane (TNTPM) studied by us previously. Guest loss has been measured quantitatively. The crystal structures are characterized by O–H⋯O, C–H⋯O, C–H⋯N and C–H⋯π interactions. It is interesting to note that while the unsubstituted TPM and some of its other derivatives form guest-free crystals, the nitro and cyano derivatives form more open structures.

The crystal structures of the molecular complexes of sym-trinitrobenzene (TNB) with acridine, 1,10-phenanthroline and phenazine are discussed. In all three cases, the structures are held together by C–H⋯O and π⋯π interactions, and TNB forms hydrogen bonded dimers and tapes that are not found in its native crystal structure. Acridine and 1,10-phenanthroline yield 1 ∶ 1 complexes that have very similar structures. The related molecule phenazine, however, gives a different 2 ∶ 3 complex in which guest exchange, as seen in other recently reported examples, is not observed. A case is made for the reporting of such ‘low yield’ supramolecular reactions because they still provide valuable information about the packing characteristics of organic molecules.

The title system yields polymorph and bi-component crystals readily under cryocrystallisation conditions; the present study clarifies inconsistencies in the literature and defines a new structural landscape.

The presence of multiple molecules in the asymmetric unit (Z9) has been noted from the earliest days of crystallography, when such an occurrence might even have prevented structure solution and refinement, till today when the phenomenon is being commented upon regularly and, as some claim, can even be engineered. In the end, however, the fact that some crystals take more than one symmetry independent molecule is still something of an enigma. Is it a matter of no consequence whatsoever, which occurs randomly, or is there a deeper underlying reason why Z9 . 1? Perhaps high Z9 structures appear mysterious simply because there is still not a critical mass of relevant literature on their phenomenological analysis. However, a few authors have attempted to study this difficult problem. Brock has surveyed alcohols and phenols extensively and has given an elegant explanation as to why these compounds have a higher proportion of Z9 . 1 crystal structures when compared with the global sampling of organic molecular crystals. According to her, the tendency of these hydroxy compounds (ROH) to form cooperative hydrogen bonded chains of the O–H...O–H type is countered by the steric demands of the R-groups, and high Z9 is one of the outcomes (the other is crystallisation in a high symmetry system). In general, there seems to be a consensus that when packing problems make it difficult to achieve a structure with Z9 = 1, a higher Z9 is a good alternative option. The idea of interaction frustration has also echoes in the work of Nangia, Steed and Clegg among others. These authors have also elaborated other interesting themes: that structures with high Z9 have a loose packing but good interactions; that crystals which are grown from the melt or by sublimation have a significantly higher proportion of Z9 . 1 structures; that high Z9 structures can be described as modulations; that high Z9 is obtained when the molecule has a large number of equi-energetic conformations, these conformations co-existing in the crystal. Pseudosymmetry is certainly implicated in some cases and the pseudo-elements of symmetry may be either global or local. In the latter category, we noted a very unusual subset more than 15 years ago of P1 crystals which have Z9 = 2, the two symmetry independent molecules being related by a local pseudo-centre of inversion. Why does the crystal take this pseudo-centre, an ‘‘extra’’, almost ‘‘wasted’’ symmetry element? All these observations are undoubtedly interesting, and possibly important, but what struck me as the most unusual fact about high Z9 structures, an observation that seemed almost counter-intuitive, is that the proportion of Z9 . 1 structures relative to all crystal structures has remained practically invariant over the decades. I must admit that I had always felt (and I daresay that this might be true of others, too) that with the advent of CCD diffractometers and high throughput crystallography, the proportion of high Z9 structures should be steadily increasing. Reality is different. During the period 1970–2006, during which time the CSD has become nearly 43 times larger, the proportion of Z9 = 1, Z9 , 1 and Z9 . 1 organic structures has remained virtually constant (i1%) at 73, 16 and 11%. Does this constancy of numbers say anything about the origin of this phenomenon? Is there a basic, universal reason why high Z9 structures are obtained? I would like to suggest that the secrets of high Z9 structures will be most easily revealed through a study of polymorphic systems, wherein a high Z9 structure may be most easily compared with a lower Z9 structure (ideally one with Z9 = 1) of the same chemical substance. We noted that at least in two cases, pentafluorophenol and trans-1,4-bis(phenylethynyl)cyclohexane-1,4-diol, there are two structures with different Z9 values. The structure with the lower Z9 is the more stable structure; the one with the higher Z9 value is obtained under what essentially amount to kinetic conditions: cryo-crystallography for the phenol and melt cooling for the diol. These observations are suggestive. Steed put forth the idea a few years ago that a high Z9 structure is a ‘‘fossil relic’’ of a more stable form. In this way, it is not difficult to associate the higher Z9 polymorphs of these two compounds with kinetic modifications. Indeed, we showed that the discrete O–H...O–H...O–H trimer synthon in the high Z9 polymorph of pentafluorophenol is an ‘‘incomplete’’ version of the infinite O–H...O–H chain in the low Z9 polymorph. Similarly, the high Z9 polymorph of the diol contains a large number of molecular conformations that are essentially ‘‘frozen’’ into the crystal, and these anneal out in the lower Z9 high temperature modification. It is worthwhile to reflect that all the reasons which have been put forward in the past for the adoption of high Z9 structures (packing difficulties and inconsistencies, modulation, pseudosymmetry, equi-energetic conformations, better interactions) are simply different ways of saying the same thing. A high Z9 structure is a crystal ‘‘on the way’’. Many of Brock’s observations on alcohols and phenols follow from the idea that molecules which form stable clusters in solution because of strong hydrogen bonding have a higher tendency to form Z9 . 1 crystals because these clusters are carried forward more or less unaltered into the crystal. Possibly, O–H...O hydrogen bonding in alcohols and phenols is so strong and directional that it becomes difficult to observe a better packed, School of Chemistry, University of Hyderabad, Hyderabad, 500 046, India LETTER www.rsc.org/crystengcomm | CrystEngComm

IR spectroscopy has been widely employed to distinguish between different crystal forms such as polymorphs, clathrates, hydrates and co-crystals. IR has been used to monitor co-crystal formation and single synthon detection. In this work, we have developed a strategy to identify multiple supramolecular synthons in polymorphs and co-crystals with this technique. The identification of multiple synthons in co-crystals with IR is difficult for several reasons. In this paper, a four step method involving well assigned IR spectral markers that correspond to bonds in a synthon is used. IR spectra of three forms of the co-crystal system, 4-hydroxybenzoic acid:4,4′-bipyridine (2 : 1), show clear differences that may be attributed to differences in the synthon combinations existing in the forms (synthon polymorphism). These differences were picked out from the three IR spectra and the bands analysed and assigned to synthons. Our method first identifies IR marker bands corresponding to (covalent) bonds in known/model crystals and then the markers are mapped in known co-crystals having single synthons. Thereafter, the IR markers are queried in known co-crystals with multiple synthons. Finally they are queried in unknown co-crystals with multiple synthons. In the last part of the study, the N–H stretching absorptions of primary amides that crystallize with the amide dimers linked in a ladder like chain show two specific absorptions which are used as marker absorptions and all variations of this band structure have been used to provide details on the environment around the dimer. The extended dimer can accordingly be easily distinguished from the isolated dimer.

The crystal structures of two polymorphs and two polymorphic hemihydrates of Etoricoxib are reported. Etoricoxib is a non-steroidal anti-inflammatory drug (NSAID) that is a selective inhibitor of COX-2. It is used in the treatment of various types of inflammation, pain and fever. Clas et al. have reported four polymorphs (labeled I through IV) and two solvates (hemi- and sesquihydrate) of the API in US patent 6,441,002 (Clas et al, US patent 6,441,002, 2002). However, no crystal structures have been reported for any of these forms. A comparison was made between the PXRD patterns reported in patent ’002 and the powder spectra simulated from single crystal data. The two polymorphs characterized here correspond to form I and form IV of the patent. Form II of the patent could not be obtained by us with a variety of experimental conditions. Form III of the patent corresponds to hemihydrate II of this study. Form III is therefore not a polymorph of form I and form IV. What we have termed hemihydrate I in this study is obtained under a wide variety of conditions and it is also the only hemihydrate reported as such in the patent. Because the Etoricoxib molecule contains no conventional hydrogen bond donors, there cannot be any strong hydrogen bonds in the crystal structures of forms I and IV. The packing is accordingly characterized by weak hydrogen bonds of the C–H⋯OS and C–H⋯N type. Thermal data were collected for form I, form IV and hemihydrate I to shed some light on relative stabilities. PXRD diffractograms show the transformation of form IV to form I at elevated temperature, indicating that form I is more stable than form IV. However, this transformation occurs only in samples of form IV that contain some form I; it does not occur in pure form IV. The formation of the two hemihydrates could follow from the known tendency of an acceptor-rich molecule to crystallize as a hydrate.

Two drug-drug co-crystals of the anti-tuberculosis drugs isoniazid (INH), pyrazinamide (PYR) and 4-aminosalicylic acid (PAS) are reported. The first is the 1 : 1 molecular complex of INH and PAS. The second is the monohydrate of the 1 : 1 complex of PYR and PAS. The crystal structures of both co-crystals are characterized by a number of hydrogen bonded synthons. Hydrogen bonding of the COOH center dot center dot center dot N-pyridine type is found in both cases. In the INH : PAS co-crystal, there are two symmetry independent COOH center dot center dot center dot center dot N-pyridine hydrogen bonds. In one of these, the H-atom is located on the carboxylic group and is indicative of a co-crystal. In the second case, partial proton transfer occurs across the hydrogen bond, and the extent of proton transfer depends on the temperature. This is more indicative of a salt. Drug-drug co-crystals may have some bearing in the treatment of tuberculosis.

Co-crystal formation with a heavy atom containing compound enables the determination of the absolute configuration of a chiral organic compound.

Two earlier crystal structure predictions (CSP) of aminophenol compounds are checked against experimental structure determinations. One of the predictions classified originally as “good” is verified and is now seen to be somewhat correct. The other prediction, which was classified earlier as “unclear”, is incorrect. The two experimental crystal structures are characterized by small and large synthons both of which contain O–H⋯N and N–H⋯O hydrogen bonds. The evolving nature of the CSP exercise is noted.

The less stable polymorph of the title compound has the better synthon while the more stable polymorph the better packing. The possibility of polymorphism in a closely related isomer is examined computationally.

The formation of dimers and catemers in a number of phenylpyruvic acids is strongly influenced by the nature of the substituent group. In all cases, the acid exists as the enol tautomer in the solid state.

The presence of two molecules in the crystallographic asymmetric unit in a pair of closely related keto-bisphenols that differ by a methyl substituent only, leads to open frameworks that fill space through self-inclusion in one case, and through interpenetration in the other.