Desolvation Processes in Channel Solvates of Niclosamide.

The antiparasitic drug niclosamide (NCL) is notable for its ability to crystallize in multiple 1:1 channel solvate forms, none of which are isostructural. Here, using a combination of time-resolved synchrotron powder X-ray diffraction and thermogravimetry, the process-induced desolvation mechanisms of methanol and acetonitrile solvates are investigated. Structural changes in both solvates follow a complicated molecular-level trajectory characterized by a sudden shift in lattice parameters several degrees below the temperature where the desolvated phase first appears. Model fitting of kinetic data obtained under isothermal heating conditions suggests that the desolvation is rate-limited by the nucleation of the solvent-free product. The desolvation pathways identified in these systems stand in contrast to previous investigations of the NCL channel hydrate, where water loss by diffusion initially yields an anhydrous isomorph that converts to the thermodynamic polymorph at significantly higher temperatures. Taking the view that each solvate lattice is a unique "pre-organized" precursor, a comparison of the pathways from different starting topologies to the same final product provides the opportunity to reevaluate assumptions of how various factors (e.g., solvent binding strength, density) influence solid-state desolvation processes.

An Improved Model for Biogenic Ammonium Urate.

The pathological crystallization of ammonium urate inside the urinary tract is a well-documented medical condition; however, structural studies of the biogenic material have proven challenging owing to its propensity to precipitate as a powder and to exhibit diffraction patterns with widely varying intensities. Using block Rietveld refinement methods of powder diffraction data, here we identify ammonium urate hydrate (AUH) as a likely component in natural uroliths. AUH has a planar 2-D hydrogen-bonded organic framework of urate ions separated by ammonium ions with water molecules residing in bisecting channels. AUH is stable up to 150 °C for short time periods but begins to decompose with prolonged heating times and/or at higher temperatures. Changes in the solid-state structure and composition of synthetic material over a temperature range from 25 to 300 °C are elucidated through thermogravimetric and spectroscopic data, combustion analysis, and time-resolved synchrotron powder X-ray diffraction studies. We contend that biogenic ammonium urate is more accurately modeled as a mixture of AUH and anhydrous ammonium urate, in ratios that can vary depending on the growth environment. The similar but not identical diffraction patterns of these two forms likely account for much of the variability seen in natural ammonium urate samples.

Enhancement of Hydrate Stability through Substitutional Defects.

Cytosine monohydrate (CM) and anhydrate crystal forms reversibly interconvert under high temperatures or high humidity conditions. Here, we demonstrate through defect engineering the ability to expand the thermal stability range of CM through the targeted creation of quantifiable defects in low-level concentrations. Twelve different molecular dyes with a variety of core structures and charges were screened as potential dopants in CM. CM-dye phases prepared with Congo red (CR), Evans blue (EB), and Azocarmine G (AG) exhibited the highest inclusion levels (up to 1.1 wt %). In these doped isomorphous materials, each dye is presumed to substitute for 4-7 cytosine molecules within the low-rugosity (102) planes of the CM matrixes, thereby creating a quantifiable substitutional defect and an impediment to the cooperative molecular motions which enable the transformation to the anhydrate. Dehydration of materials with these engineered defects requires significantly higher temperatures and proceeds with slower kinetics compared to pure CM. The CM-dye phases also exhibit a reduction in the thermal expansion along key crystallographic axes and yield dehydration products with altered particle morphologies.

Dehydration of Niclosamide Monohydrate Polymorphs: Different Mechanistic Pathways to the Same Product.

Many active pharmaceutical ingredients (APIs) can crystallize as hydrates or anhydrates, the relative stability of which depends on their internal structures as well as the external environment. Hydrates may dehydrate unexpectedly or intentionally, though the molecular-level mechanisms by which such transformations occur are difficult to predict a priori. Niclosamide is an anthelmintic drug on the World Health Organization's "List of Essential Medicines" that crystallizes in two monohydrate forms: HA and HB. Through complementary time-resolved synchrotron powder X-ray diffraction and thermogravimetric kinetic studies, we demonstrate that the two monohydrates dehydrate via distinctly different solid state pathways yet yield the same final anhydrate phase. Water loss from HA via diffusion yields an isomorphous desolvate intermediate which can rearrange to at least two different polymorphs, only one of which exhibits long-term stability. In contrast, dehydration of HB proceeds via a surface nucleation process where simultaneous water loss and product formation occur with no detectable crystalline intermediates. Comparative analysis of the two systems serves to highlight the complex relationship between lattice structure and solid state dehydration processes.

Crystal structure of a di-aryl carbonate: 1,3-phenyl-ene bis-(phenyl carbonate).

The whole mol-ecule of the title compound, C20H14O6, is generated by mirror symmetry, the mirror bis-ecting the central benzene ring. The carbonate groups adopt an s-cis-s-cis conformation, with torsion angles of 58.7 (2) and 116.32 (15)°. The crystal structure of 1,3-phenyl-ene bis-(phenyl carbonate) contains no strong hydrogen bonds, though weak C-H⋯O and offset π-π inter-actions are observed, forming layers parallel to the ac plane.

A new polymorph of 2,6-diaminopyridine.

2,6-Diaminopyridine (26-DAP, C5H7N3) is a common intermediate in the synthesis of aromatic azo chromophores, which are widespread in the dyes and pigments industry. Sublimation of commercial 26-DAP powder yielded a new polymorph, denoted Form II, which grew as colorless orthorhombic needles. Recrystallization from acetone or toluene also yielded Form II as the major phase. Thermal analysis shows that Form II is a less stable polymorph and it converts upon heating at 335 K to the previously reported Form I.

Concomitant polymorphs of 1,3-bis(3-fluorophenyl)urea.

Hydrogen bonding between urea functionalities is a common structural motif employed in crystal-engineering studies. Crystallization of 1,3-bis(3-fluorophenyl)urea, C13H10F2N2O, from many solvents yielded concomitant mixtures of at least two polymorphs. In the monoclinic form, one-dimensional chains of hydrogen-bonded urea molecules align in an antiparallel orientation, as is typical of many diphenylureas. In the orthorhombic form, one-dimensional chains of hydrogen-bonded urea molecules have a parallel orientation rarely observed in symmetrically substituted diphenylureas.

Two tautomeric forms of 2-amino-5,6-dimethylpyrimidin-4-one.

Derivatives of 4-hydroxypyrimidine are an important class of biomolecules. These compounds can undergo keto-enol tautomerization in solution, though a search of the Cambridge Structural Database shows a strong bias toward the 3H-keto tautomer in the solid state. Recrystallization of 2-amino-5,6-dimethyl-4-hydroxypyrimidine, C6H9N3O, from aqueous solution yielded triclinic crystals of the 1H-keto tautomer, denoted form (I). Though not apparent in the X-ray data, the IR spectrum suggests that small amounts of the 4-hydroxy tautomer are also present in the crystal. Monoclinic crystals of form (II), comprised of a 1:1 ratio of both the 1H-keto and the 3H-keto tautomers, were obtained from aqueous solutions containing uric acid. Forms (I) and (II) exhibit one-dimensional and three-dimensional hydrogen-bonding motifs, respectively.

Adhesion properties of uric acid crystal surfaces.

Two key steps in kidney stone formation--crystal aggregation and attachment to renal tissues--depend on the surface adhesion properties of the crystalline components. Anhydrous uric acid (UA) is the most common organic crystalline phase found in human kidney stones. Using chemical force microscopy, the adhesion force between various functional groups and the largest (100) surface of UA single crystals was measured in both aqueous solution and model urine. Adhesion trends in the two solutions were identical, but were consistently lower in the latter. Changes in the solution ionic strength and pH were also found to affect the magnitude of the adhesion. UA surfaces showed the strongest adhesion to cationic functionalities, which is consistent with ionization of some surface uric acid molecules to urate. Although hydrogen-bonding and van der Waals interactions are usually considered to be dominant forces in the association between neutral organic compounds, this work demonstrates that electrostatic interactions can be important, particularly when dealing with weak acids under certain solution conditions.

Controlling molecular crystal polymorphism with self-assembled monolayer templates.

The control of crystal polymorphism is a long-standing issue in solid-state chemistry, which has many practical implications for a variety of commercial applications. At least four different crystalline forms of 1,3-bis(m-nitrophenyl) urea (MNPU), a classic molecular crystal system, are known to crystallize from solution in various concomitant combinations. Herein we demonstrate that the introduction of gold-thiol self-assembled monolayers (SAMs) of substituted 4'-X-mercaptobiphenyls (X = H, I, and Br) into the crystallization solution can serve as an effective means to selectively template the nucleation and growth of alpha-, beta-, and gamma-MNPU phases, respectively. Polymorph control in the presence of SAM surfaces persists under a variety of solution conditions and consistently results in crystalline materials with high phase purity. The observed selectivity is rationalized on the basis of long-range two-dimensional geometric lattice matching and local complementary chemical interactions at the SAM/crystal interfaces.

An in situ atomic force microscopy study of uric acid crystal growth.

Kidney stones are heterogeneous polycrystalline aggregates that can consist of several different building blocks. A significant number of human stones contain uric acid crystals as a crystalline component, though the molecular-level growth of this important biomaterial has not been previously well-characterized. In the present study, in situ atomic force microscopy (AFM) is used to investigate the real-time growth on the (100) surface of uric acid (UA) single crystals as a function of fundamental solution parameters. Layer-by-layer growth on UA (100) was found to be initiated at screw dislocation sites and to proceed via highly anisotropic rates which depend on the crystallographic direction. The smallest b-steps exhibited minimum heights corresponding to two molecular layers, while fast-moving c-steps more commonly showed monolayer heights. Growth kinetics measured under a range of flow rates, supersaturation levels, and pH values reveal linear trends in the growth kinetics, with faster growth attained in solutions with higher supersaturation and/or pH. The calculated kinetic parameters for UA growth derived from these experiments are in good agreement with the values reported for other crystal systems.

Selective growth of a less stable polymorph of 2-iodo-4-nitroaniline on a self-assembled monolayer template.

Orthorhombic and triclinic crystals of 2-iodo-4-nitroaniline (INA) grow concomitantly from supersaturated ethanol solutions, but the less stable orthorhombic phase can be selectively grown on 3'-X-4-mercaptobiphenyl (X = NO(2), I) self-assembled monolayer templates.

Epitaxial relationships between uric acid crystals and mineral surfaces: a factor in urinary stone formation.

Uric acid (C5H4N4O3) is one of the final products of purine metabolism. Its concentration balance is maintained in the kidneys, but compromised kidney function can result in its crystallization either in the renal tract or in the interstitial fluid of joints. In physiological deposits, crystalline uric acid is most frequently found either in a protonated state (anhydrous or dihydrate phases) or as a deprotonated urate ion (sodium or ammonium salts). Often these precipitates are found in association with a number of mineral phases (e.g., calcium oxalates, calcium phosphates, and magnesium phosphates). Their frequent and common coexistence suggests that synergistic relationships between these crystalline phases may exist. A comprehensive list of different heterogeneous uric acid/uric acid and uric acid/mineral interfaces that are epitaxially matched was generated with the lattice-matching program EpiCalc. Two hundred twenty-five coincident epitaxial matches and four commensurate epitaxial matches were identified using this screening procedure.

The epitaxial growth of cholesterol crystals from bile solutions on calcite substrates.

Epitaxial relationships between the surfaces of inorganic and bioorganic crystals can be an important factor in crystal nucleation and growth processes in a variety of biological environments. Crystalline cholesterol monohydrate (ChM), a constituent of both gallstone and atherosclerotic plaques, is often found in association with assorted mineral phases. Using in situ atomic force microscopy (AFM) and well-characterized model bile solutions, the nucleation and epitaxial growth of ChM on calcite (104) surfaces in real-time is demonstrated. The growth rates of individual cholesterol islands formed on calcite substrates were determined at physiological temperatures. Evidence of Ostwald's ripening was also observed under these experimental conditions. The energetics of various (104) calcite/(001) ChM interfaces were calculated to determine the most stable interfacial structure. These simulations suggest that the interface is fully hydrated and that cholesterol hydroxyl groups are preferentially positioned above carbonate ions in the calcite surface. This combination of experimental and theoretical work provides a clearer picture of how preexisting mineral seeds might provide a viable growth template that can reduce the energetic barrier to cholesterol nucleation under some physiological conditions.

Selective growth and distribution of crystalline enantiomers in hydrogels.

The crystallization of sodium chlorate (NaClO3) is a classic example of spontaneous chirality, since it is achiral in solution but adopts a chiral form in the solid state. While crystal growth of NaClO3 from pure aqueous solutions yields a 50:50 statistical distribution of d- and l-crystals, large enantiomeric excesses of either d- and l-crystals can be achieved by crystal growth in agarose gel, a naturally occurring chiral polysaccharide. The influence of gel density (0.1-0.75 wt %), temperature, and the diffusion of cosolvents on crystal distribution was discerned from statistical data obtained from 752 gel-mediated crystallization experiments yielding 12,384 individual crystals. These studies demonstrate that the magnitude and direction of the bias can be selectively engineered toward either d- or l-forms by changing the gelation conditions. Aqueous agarose gels infused with 48 wt % NaClO3 at 6 degrees C, favored the growth of d-NaClO3 crystals, with ee's reaching 22% at the highest gel concentrations. Crystal growth under methanol diffusion favored deposition of the opposite enantiomorph, l-NaClO3. The bias in the crystal distribution is enhanced at higher temperatures. Aqueous gels at 24 degrees C infused with methanol cosolvent favored l-NaClO3, with ee's reaching 53%. The changing magnitude and direction of the enantiomorph bias can be ascribed to differences in the agarose conformation and intermolecular interactions between the gel and crystal surfaces that inhibit the formation of the two enantiomers to different extents.

Dyeing uric acid crystals with methylene blue.

The growth of anhydrous uric acid (UA) and uric acid dihydrate (UAD) crystals from supersaturated aqueous solutions containing methylene blue, a cationic organic dye, has been investigated. Low concentrations of dye molecules were found to be included in both types of crystal matrixes during the growth process. Incorporation of dye into UA crystals occurs with high specificity, affecting primarily [001] and [201] growth sectors, while UAD crystals grown from solutions of similar dye concentration show inclusion but little specificity. The orientation of the UA-trapped species was determined from polarization data obtained from visible light microspectrometry. To achieve charge neutrality, a second anionic species must also be included with the methylene blue into UA and UAD crystal matrices. Under high pH conditions, crystallization of 1:1 stoichiometric mixtures of methylene blue and urate yields methylene blue hexahydrate (MBU.6(H2O). The crystal structure of MBU.6(H2O) reveals continuous pi-pi stacks of planes of dye cations and urate anions mediated by water molecules. This structure provides an optimal geometry for methylene blue-urate pairs and additional support for the incorporation of these dimers in uric acid single-crystal matrices. The strikingly different inclusion patterns in UA and UAD demonstrate that subtle changes in the crystal surfaces and/or growth dynamics can greatly affect recognition events.