Melinda J. Duer

Dehydration and crystallization of amorphous calcium carbonate in solution and in air

The mechanisms by which amorphous intermediates transform into crystalline materials are poorly understood. Currently, attracting enormous interest is the crystallization of amorphous calcium carbonate, a key intermediary in synthetic, biological and environmental systems. Here we attempt to unify many contrasting and apparently contradictory studies by investigating this process in detail. We show that amorphous calcium carbonate can dehydrate before crystallizing, both in solution and in air, while thermal analyses and solid-state nuclear magnetic resonance measurements reveal that its water is present in distinct environments. Loss of the final water fraction—comprising less than 15% of the total—then triggers crystallization. The high activation energy of this step suggests that it occurs by partial dissolution/recrystallization, mediated by surface water, and the majority of the particle then crystallizes by a solid-state transformation. Such mechanisms are likely to be widespread in solid-state reactions and their characterization will facilitate greater control over these processes.

Citrate bridges between mineral platelets in bone.

Significance Bone contains ∼2% wt citrate; however, its role in bone remains a much-debated question. We propose a new structure for bone mineral in which citrate in hydrated layers forms bridges between mineral platelets, which can explain a number of observations at odds with previous models. The incorporation of citrate between mineral platelets can explain the flat, plate-like morphology of bone mineral platelets and may be important in controlling the crystallinity of bone mineral, which in turn, is highly relevant to the mechanical properties of bone. We provide evidence that citrate anions bridge between mineral platelets in bone and hypothesize that their presence acts to maintain separate platelets with disordered regions between them rather than gradual transformations into larger, more ordered blocks of mineral. To assess this hypothesis, we take as a model for a citrate bridging between layers of calcium phosphate mineral a double salt octacalcium phosphate citrate (OCP-citrate). We use a combination of multinuclear solid-state NMR spectroscopy, powder X-ray diffraction, and first principles electronic structure calculations to propose a quantitative structure for this material, in which citrate anions reside in a hydrated layer, bridging between apatitic layers. To assess the relevance of such a structure in native bone mineral, we present for the first time, to our knowledge, 17O NMR data on bone and compare them with 17O NMR data for OCP-citrate and other calcium phosphate minerals relevant to bone. The proposed structural model that we deduce from this work for bone mineral is a layered structure with thin apatitic platelets sandwiched between OCP-citrate–like hydrated layers. Such a structure can explain a number of known structural features of bone mineral: the thin, plate-like morphology of mature bone mineral crystals, the presence of significant quantities of strongly bound water molecules, and the relatively high concentration of hydrogen phosphate as well as the maintenance of a disordered region between mineral platelets.

Mineral Surface in Calcified Plaque Is Like That of Bone: Further Evidence for Regulated Mineralization

Objectives—Cell biological studies demonstrate remarkable similarities between mineralization processes in bone and vasculature, but knowledge of the components acting to initiate mineralization in atherosclerosis is limited. The molecular level microenvironment at the organic–inorganic interface holds a record of the mechanisms controlling mineral nucleation. This study was undertaken to compare the poorly understood interface in mineralized plaque with that of bone, which is considerably better characterized. Methods and Results—Solid state nuclear magnetic resonance (SSNMR) spectroscopy provides powerful tools for studying the organic–inorganic interface in calcium phosphate biominerals. The rotational echo double resonance (REDOR) technique, applied to calcified human plaque, shows that this interface predominantly comprises sugars, most likely glycosaminoglycans (GAGs). In this respect, and in the pattern of secondary effects seen to protein (mainly collagen), calcified plaque strongly resembles bone. Conclusion—The similarity between biomineral formed under highly controlled (bone) and pathological (plaque) conditions suggests that the control mechanisms are more similar than previously thought, and may be adaptive. It is strong further evidence for regulation of plaque mineralization by osteo/chondrocytic vascular smooth muscle cells.

Mechanosynthesis of the Metallodrug Bismuth Subsalicylate from Bi2O3 and Structure of Bismuth Salicylate without Auxiliary Organic Ligands

Mechanochemical reactions are versatile for the synthesis of new pharmaceutical forms, particularly cocrystals, salts and, since very recently, coordination complexes. Mechanochemistry can be very efficient for the synthesis of metal–organic frameworks (MOFs) and magnesium-based pharmaceuticals directly from inexpensive and otherwise inert materials, such as metal oxides or carbonates. In addition to short reaction times and the lack of bulk solvents, oxide-based mechanosynthesis also has the advantage of generating water as the sole byproduct. We now demonstrate how ionand liquid-assisted grinding (ILAG), previously utilized for the mechanosynthesis of large-pore MOFs and zeolitic imidazolate frameworks 6] based on zinc, can be extended to the pharmaceutical chemistry of bismuth oxide. We demonstrate the rapid and efficient conversion of Bi2O3 into a variety of bismuth salicylate complexes, including the commercial active pharmaceutical ingredient (API) bismuth subsalicylate (1), marketed under the trade name Pepto-Bismol. The pharmaceutical value of bismuth complexes with salicylic acid (H2sal) has been established over a century ago and still remains an area of active research. At least three different forms of bismuth salicylate, which differ in the stoichiometric ratio of bismuth and H2sal, have been reported. These are the API bismuth subsalicylate BiO(Hsal), the disalicylate (2) with assigned formula Bi2O(Hsal)4, [8] and the trisalicylate (3) involving bismuth and salicylic acid in the 1:3 stoichiometric ratio. Until now, the structure for any of these materials has remained unknown. Models for 1 and its biological activity were initially devised by Thurston et al. who used auxiliary chelating ligands to trap discrete oligonuclear clusters of Bi and salicylate anions (Hsal ), and by Burford et al. who explored complexation of Bi with thiosalicylic acid. The potential of mechanochemistry to generate bismuth carboxylates was revealed by Andrews and co-workers, 12] who investigated combined mechanoand thermochemical routes involving carboxylic acids and triphenylbismuth. With H2sal this approach provides different organobismuth salicylates unless the ratio of Bi to acid is 1:3, in which case it leads to the tricarboxylate 3 (Figure 1a). Recrystallization of 3 from acetone yielded metal–organic clusters containing coordinated solvent that are currently the best models for the structure of 1 (Figure 1b). Unfortunately, this synthetic pathway is of limited use due to regulatory aspects of organobismuth precursor and the formation of aromatic hydrocarbon byproducts.

Towards an environmentally-friendly laboratory: dimensionality and reactivity in the mechanosynthesis of metal–organic compounds

We present a proof-of-principle study of an environmentally-friendly approach to laboratory research, in which the synthesis and structural characterisation of metal-organic complexes and frameworks are achieved without using bulk solvents; our study addresses the use of heteroditopic ligands for manipulating the dimensionality of metal-organic materials and describes how kinetic obstacles in such mechanosynthesis can be overcome.

The curious case of (caffeine)·(benzoic acid): How heteronuclear seeding allowed the formation of an elusive cocrystal

Cocrystals are modular multicomponent solids with exceptional utility in synthetic chemistry and materials science. A variety of methods exist for the preparation of cocrystals, yet, some promising cocrystal phases have proven to be intractable synthetic targets. We describe a strategy for the synthesis of the pharmaceutically relevant (caffeine)·(benzoic acid) cocrystal (1), which persistently failed to form using a broad range of established techniques. State-of-the-art crystal structure prediction methods were employed to assess the possible existence of a thermodynamically stable form of 1, hence to identify appropriate heteronuclear seeds for cocrystallization. Once introduced, the designed heteronuclear seeds facilitated the formation of 1 and, significantly they (or seeds of the product cocrystal) continued to act as long-lasting laboratory “contaminants”, which encouraged cocrystal formation even when present at such low levels as to evade detection. The seeding technique described thus enables the synthesis of cocrystals regarded as unobtainable under desired conditions, and potentially signifies a new direction in the field of materials research.

The effect of particle agglomeration on the formation of a surface-connected compartment induced by hydroxyapatite nanoparticles in human monocyte-derived macrophages

Agglomeration dramatically affects many aspects of nanoparticle–cell interactions. Here we show that hydroxyapatite nanoparticles formed large agglomerates in biological medium resulting in extensive particle uptake and dose-dependent cytotoxicity in human macrophages. Particle citration and/or the addition of the dispersant Darvan 7 dramatically reduced mean agglomerate sizes, the amount of particle uptake and concomitantly cytotoxicity. More surprisingly, agglomeration governed the mode of particle uptake. Agglomerates were sequestered within an extensive, interconnected membrane labyrinth open to the extracellular space. In spite of not being truly intracellular, imaging studies suggest particle degradation occurred within this surface-connected compartment (SCC). Agglomerate dispersion prevented the SCC from forming, but did not completely inhibit nanoparticle uptake by other mechanisms. The results of this study could be relevant to understanding particle–cell interactions during developmental mineral deposition, in ectopic calcification in disease, and during application of hydroxyapatite nanoparticle vectors in biomedicine.

The Mineral Phase of Calcified Cartilage: Its Molecular Structure and Interface with the Organic Matrix

We have studied the atomic level structure of mineralized articular cartilage with heteronuclear solid-state NMR, our aims being to identify the inorganic species present at the surfaces of the mineral crystals which may interact with the surrounding organic matrix and to determine which components of the organic matrix are most closely involved with the mineral crystals. One-dimensional (1)H and (31)P and two-dimensional (1)H-(31)P heteronuclear correlation NMR experiments show that the mineral component is very similar to that in bone with regard to its surface structure. (13)C{(31)P} rotational echo double resonance experiments identify the organic molecules at the mineral surface as glycosaminoglycans, which concurs with our recent finding in bone. There is also evidence of gamma-carboxyglutamic acid residues interacting with the mineral. However, other matrix components appear more distant from the mineral compared with bone. This may be due to a larger hydration layer on the mineral crystal surfaces in calcified cartilage.

A model for a solvent-free synthetic organic research laboratory: click-mechanosynthesis and structural characterization of thioureas without bulk solvents

The mechanochemical click coupling of isothiocyanates and amines has been used as a model reaction to demonstrate that the concept of a solvent-free research laboratory, which eliminates the use of bulk solvents for either chemical synthesis or structural characterization, is applicable to the synthesis of small organic molecules. Whereas the click coupling is achieved in high yields by simple manual grinding of reactants, the use of an electrical, digitally controllable laboratory mill provides a rapid, quantitative and general route to symmetrical and non-symmetrical aromatic or aromatic–aliphatic thioureas. The enhanced efficiency of electrical ball milling techniques, neat grinding or liquid-assisted grinding, over manual mortar-and-pestle synthesis is demonstrated in the synthesis of 49 different thiourea derivatives. Comparison of powder X-ray diffraction data of mechanochemical products with structural information found in the Cambridge Structural Database (CSD), or obtained herein through single crystal X-ray diffraction, indicates that the mechanochemically obtained thiourea derivatives are pure in a chemical sense, but can also demonstrate purity in a supramolecular sense, i.e. in all structurally explored cases the product consisted of a single polymorph. As an extension of our previous work on solvent-free synthesis of coordination polymers, it is now demonstrated that such polymorphic and chemical purity of selected thiourea derivatives, the latter being evidenced through quantitative reaction yields, can enable the direct solvent-free structural characterization of mechanochemical products through powder X-ray diffraction aided by solid-state NMR spectroscopy.

Tuning hardness in calcite by incorporation of amino acids

Structural biominerals are inorganic/organic composites that exhibit remarkable mechanical properties. However, the structure-property relationships of even the simplest building unit-mineral single crystals containing embedded macromolecules-remain poorly understood. Here, by means of a model biomineral made from calcite single crystals containing glycine (0-7 mol%) or aspartic acid (0-4 mol%), we elucidate the origin of the superior hardness of biogenic calcite. We analysed lattice distortions in these model crystals by using X-ray diffraction and molecular dynamics simulations, and by means of solid-state nuclear magnetic resonance show that the amino acids are incorporated as individual molecules. We also demonstrate that nanoindentation hardness increased with amino acid content, reaching values equivalent to their biogenic counterparts. A dislocation pinning model reveals that the enhanced hardness is determined by the force required to cut covalent bonds in the molecules.