Joel Bernstein

Graph-set analysis of hydrogen-bond patterns in organic crystals

A method is presented based on graph theory for categorizing hydrogen-bond motifs in such a way that complex hydrogen-bond patterns can be disentangled, or decoded, systematically and consistently. This method is based on viewing hydrogen-bond patterns topologically as if they were intertwined nets with molecules as the nodes and hydrogen bonds as the lines. Surprisingly, very few parameters are needed to define the hydrogen-bond motifs comprising these networks. The methods for making these assignments, and examples of their chemical utility are given.

Topical capsaicin treatment of chronic postherpetic neuralgia

Uncontrolled studies have indicated that topically applied capsaicin may be a safe and effective treatment for postherpetic neuralgia. In a double-blind study 32 elderly patients with chronic postherpetic neuralgia were treated with either capsaicin cream or its vehicle for a 6-week period. Response to treatment was evaluated by visual analogue scales of pain and of pain relief, together with changes in a categoric pain scale and in a physicians global evaluation. Significantly greater relief in the capsaicin-treated group compared with vehicle was observed for all efficacy variables. After 6 weeks almost 80% of capsaicin-treated patients experienced some relief from their pain. Because capsaicin avoids problems with drug interactions and systemic toxicity, we suggest that topical capsaicin be considered for initial management of postherpetic neuralgia.

Treatment of chronic postherpetic neuralgia with topical capsaicin. A preliminary study.

Continuing pain following herpes zoster is common in patients 60 years of age or older. Current treatments are generally unsatisfactory. The endogenous neuropeptide substance P is an important chemomediator of nociceptive impulses from the periphery to the central nervous system and has been demonstrated in high levels in sensory nerves supplying sites of chronic inflammation. In an attempt to alleviate the pain of 14 patients with postherpetic neuralgia, capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), known to deplete substance P, was applied topically to painful areas of skin for 4 weeks. Of the 12 patients completing this preliminary study, 9 (75%) experienced substantial relief of their pain. The only adverse reaction was an intermittent, localized burning sensation experienced by one patient with application of capsaicin. Although these results are preliminary, they suggest that topical application of capsaicin may provide a useful approach for alleviating postherpetic neuralgia and other syndromes characterized by severe localized pain.

Graph-set analysis of hydrogen-bond patterns: some mathematical concepts

To provide a foundation for further theoretical and software development of the application of graph sets to patterns of hydrogen bonding and other intermolecular interactions a number of mathematical concepts and tools are defined, developed and demonstrated. Following a review of the basic definitions and uses of graph sets, the directional properties of hydrogen bonds are now included in the treatment. The concepts of a constructor graph and covalent distance matrix have been developed to aid in the generation of a qualitative descriptor for the straightforward, consistent and ultimately automatic (with appropriate software) definition of patterns. An additional mathematical tool, the arrowed T-labeling, has been developed to deal with situations in which pattern-forming moieties are located on crystallographic special positions. To demonstrate the utility and various features of these concepts they are applied in detail to two particular structures, polymorphic iminodiacetic acid [N-(carboxymethyl)glycine] and trans-tetraamminedinitrocobalt(III) acetate. To facilitate the application and use of graph sets many of these developments have already been incorporated into the software of the Cambridge Structural Database, as described in the accompanying paper.

Facts and fictions about polymorphism

We present new facts about polymorphism based on (i) crystallographic data from the Cambridge Structural Database (CSD, a database built over 50 years of community effort), (ii) 229 solid form screens conducted at Hoffmann-La Roche and Eli Lilly and Company over the course of 8+ and 15+ years respectively and (iii) a dataset of 446 polymorphic crystals with energies and properties computed with modern DFT-d methods. We found that molecular flexibility or size has no correlation with the ability of a compound to be polymorphic. Chiral molecules, however, were found to be less prone to polymorphism than their achiral counterparts and compounds able to hydrogen bond exhibit only a slightly higher propensity to polymorphism than those which do not. Whilst the energy difference between polymorphs is usually less than 1 kcal mol(-1), conformational polymorphs are capable of differing by larger values (up to 2.5 kcal mol(-1) in our dataset). As overall statistics, we found that one in three compounds in the CSD are polymorphic whilst at least one in two compounds from the Roche and Lilly set display polymorphism with a higher estimate of up to three in four when compounds are screened intensively. Whilst the statistics provide some guidance of expectations, each compound constitutes a new challenge and prediction and realization of targeted polymorphism still remains a holy grail of materials sciences.

Disappearing Polymorphs Revisited

Nearly twenty years ago, Dunitz and Bernstein described a selection of intriguing cases of polymorphs that disappear. The inability to obtain a crystal form that has previously been prepared is indeed a frustrating and potentially serious problem for solid-state scientists. This Review discusses recent occurrences and examples of disappearing polymorphs (as well as the emergence of elusive crystal forms) to demonstrate the enduring relevance of this troublesome, but always captivating, phenomenon in solid-state research. A number of these instances have been central issues in patent litigations. This Review, therefore, also highlights the complex relationship between crystal chemistry and the law.

Crystal growth, polymorphism and structure-property relationships in organic crystals

Understanding the role of structure in determining the properties of materials is a crucial aspect of the design of new materials. The existence of polymorphic crystal structures provides a unique opportunity to study structure-property relationships, since the only variable among polymorphic forms is that of structure, and variation in properties must be due to differences in structure. Systematic characterization of the polymorphic forms and acquisition of the ability to grow crystals of a desired form are additional elements in the design strategy of new materials. The conditions and techniques required to obtain a particular polymorph, combined with knowledge of the crystal structures, can also provide information on the relative stability of the different structures. Studies of representative systems which illustrate the intimate connections between polymorphism, structure-property relations and crystal growth are presented.

One-pot covalent and supramolecular synthesis of pharmaceutical co-crystals using the API isoniazid: a potential supramolecular reagent

The synthon approach has been applied to synthesizing pharmaceutical co-crystals using the anti-tuberculosis drug isonicotinic acid hydrazide (ISONIAZID). Isoniazid has the potential to be a supramolecular reagent and so far has been put to very limited use in making co-crystals. In this report, we co-crystallize isoniazid with the dicarboxylic acids malonic (1), succinic (2), glutaric (3), adipic (4) and pimelic acid (5), and the monocarboxylic acids 4-hydroxybenzoic acid (6) and 2,4-dihydroxybenzoic acid (7). By surveying the literature through the Cambridge Structural Database, we identified the possible homosynthons and heterosynthons that are likely to form in the co-crystallization of isonizaid with carboxylic acids. The dominant interaction is the COOH⋯N hydrogen bond, which is used in all seven co-crystals. In addition, we present an example in which both a covalent and supramolecular synthesis occurs without affecting the vital supramolecular co-crystal forming synthon, the carboxylic acid⋯pyridine pair functionality, by reacting isoniazid with 2-butanone and acetone while co-crystallizing it with 3-hydroxybenzoic acid (8 and 9) in a one-pot synthesis.

A New Electron Donor: synthesis of 2,3,6,7-tetra(ethyltellurio)tetrathiafulvalene

Abstract A new tetratellurio substituted derivative of tetrathiafulvalene has been prepared via a direct one pot three step synthesis.

Generation of unknown crystal phases for aromatic hydrocarbons by packing energy calculations

Abstract Using geometrical inferences from known crystal structures of aromatic hydrocarbons, some novel orthorhombic crystal structures are proposed for naphthalene, anthracene and biphenyl. Their packing energies and relative stabilities are discussed.